{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "Vascular Hypothesis of Dementia", "entry_form": "phenomenon", "gradeable_restatement": "Cerebrovascular dysfunction, including blood–brain barrier breakdown, pericyte loss and chronic hypoperfusion, initiates the Alzheimer amyloid and tau cascades and thereby dementia.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Baseline vascular disease, genotype, proteinopathy status, region, age, vascular lesion, intervention and timing", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "Vascular Hypothesis of Dementia", "central_claim": "Cerebrovascular dysfunction, including blood–brain barrier breakdown, pericyte loss and chronic hypoperfusion, initiates the Alzheimer amyloid and tau cascades and thereby dementia.", "proposed_mechanism": "Cerebrovascular dysfunction, including blood–brain barrier breakdown, pericyte loss and chronic hypoperfusion, initiates the Alzheimer amyloid and tau cascades and thereby dementia.", "claimed_scope": "Vascular initiation of AD-specific amyloid/tau, separated from vascular cognitive impairment and inherited vasculopathies", "claimed_level": [ "initiation", "progression" ], "is_conjunctive": true, "conjunctive_note": "Use the index Two-Hit proposition. Vascular injury causing cognitive impairment is distinct from vascular initiation of AD-specific pathology. SC3 gates the distinguishing claim; universal dementia extrapolation is separately reported." }, "rubric_routing": { "primary_rubric": "01-neurodegeneration.md", "secondary_rubrics": [], "index_notes_applied": [ "Use the index Two-Hit proposition. Vascular injury causing cognitive impairment is distinct from vascular initiation of AD-specific pathology. SC3 gates the distinguishing claim; universal dementia extrapolation is separately reported." ], "rubric_fit_note": "Exact archived v5.3 framework. Any stale index empirical framing is rechecked against primary results." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "Vascular risk and cerebrovascular lesions predict dementia.", "subclaim_type": "existence", "scope": "baseline midlife exposures and late-life incident dementia", "claimed_scope": "baseline midlife exposures and late-life incident dementia", "governing_rubric": "01-neurodegeneration.md", "key_evidence_anchor": "Prospective risk and MRI cohorts", "hsef_level": "Β", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Midlife risks, imaging and mixed autopsy lesions predict dementia, with substantial age, region and assay dependence. The descriptive association claim is Β; intervention evidence is assigned to SC2 rather than silently changing SC1." }, { "id": "SC2", "statement": "Cerebrovascular injury causes cognitive impairment.", "subclaim_type": "sufficiency", "scope": "defined infarction, small-vessel disease and vascular interventions", "claimed_scope": "defined infarction, small-vessel disease and vascular interventions", "governing_rubric": "01-neurodegeneration.md", "key_evidence_anchor": "Natural experiments and randomized prevention", "hsef_level": "Ζ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Adult pericyte ablation with PTN rescue, endogenous ischemia/cis-tau subtraction, rare genetic vasculopathies and randomized blood-pressure treatment converge on vascular cognitive injury across different failure structures. China incident dementia and PROGRESS stroke-linked cognitive benefit add human functional evidence. SPRINT primary dementia, preDIVA and INFINITY cognitive nulls limit universal therapeutic efficacy but do not negate the assembled causal set. Ζ applies to defined vascular injury, not an AD-specific initiating cascade or universal Η trajectory." }, { "id": "SC3", "statement": "Vascular breakdown initiates AD-specific amyloid and tau cascades.", "subclaim_type": "primacy", "scope": "prespecified AD vascular and proteinopathy settings", "claimed_scope": "prespecified AD vascular and proteinopathy settings", "governing_rubric": "01-neurodegeneration.md", "key_evidence_anchor": "Selective vascular restoration preventing proteinopathy onset", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "GLUT1 and hypoperfusion accelerate pathology in genetically initiated APP models; vascular stress can induce endogenous cis P-tau and cognitive injury without AD tangles. Human BBB prediction is independent of measured protein markers, not a demonstrated path from BBB to proteins. APP/tau can instead injure vessels. No selective pre-onset human or non-protein-initiated natural set establishes the specific two-hit AD sequence. Mechanistic support warrants Γ." }, { "id": "SC4", "statement": "The Two-Hit sequence generalizes to late-life dementia.", "subclaim_type": "generalization", "scope": "late-life dementias and mixed pathologies", "claimed_scope": "late-life dementias and mixed pathologies", "governing_rubric": "01-neurodegeneration.md", "key_evidence_anchor": "Independent disease-separated causal sequencing", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Mixed dementia includes independent infarcts, amyloid/tau, Lewy pathology and variable inherited vascular routes. Multiple clinical prevention contrasts are null or endpoint-dependent; hypoperfusion has opposite protein effects across models. A universal sequence cannot be inferred from its conditional amplification successes." } ], "aggregation_rule": "scope-matched", "aggregation_preregistered": true, "aggregation_rationale": "Use the index Two-Hit proposition. Vascular injury causing cognitive impairment is distinct from vascular initiation of AD-specific pathology. SC3 gates the distinguishing claim; universal dementia extrapolation is separately reported.", "primary_subclaim_id": "SC3", "aggregation_derivation": "Preregistered scope-matched SC3 gives Γ. Vascular cognitive injury reaches Ζ through convergent endogenous perturbations, inherited vasculopathies and randomized human vascular prevention. Those successes do not establish the distinguishing vascular-first AD amyloid/tau sequence. Protein-first injury, rescue without amyloid change, and opposite tau responses remain discriminators.", "aggregation_alternatives": { "weakest_link_would_return": "Β", "primary_subclaim_would_return": "Γ", "scope_matched_would_return": "Γ", "note": "Separate narrow successes do not replace the preregistered gate." }, "index_rule_deviation": "" }, "competing_models": { "models_evaluated": [ { "rank_in_tournament": 1, "model_id": "M3", "is_nominal": false, "name": "Parallel independent pathologies", "core_claim": "Vascular lesions and proteinopathies can injure cognition independently and jointly.", "explains_what_nominal_does_not": "Vascular lesions and proteinopathies can injure cognition independently and jointly.", "strongest_supporting_evidence": [ "Mixed autopsies, APOE4 BBB prediction independent of measured proteins, PTN rescue despite flow deficits and Debio-025 benefit without Aβ change support conditional causal contributions." ], "strongest_contradictory_evidence": [ "Autopsy and independent prediction alone do not prove exclusivity; GLUT1 can modify amyloid clearance." ], "hsef_level_for_this_model": "Ε", "rationale": "Mixed autopsies, APOE4 BBB prediction independent of measured proteins, PTN rescue despite flow deficits and Debio-025 benefit without Aβ change support conditional causal contributions. Autopsy and independent prediction alone do not prove exclusivity; GLUT1 can modify amyloid clearance." }, { "rank_in_tournament": 2, "model_id": "M2", "is_nominal": false, "name": "Proteinopathy-first vascular amplification", "core_claim": "Proteins can impair vessels, which amplify established disease.", "explains_what_nominal_does_not": "Proteins can impair vessels, which amplify established disease.", "strongest_supporting_evidence": [ "Aβ human-slice constriction and APP knock-in vascular abnormalities, tau-peptide endothelial injury and amyloid-model vascular rescue establish this route." ], "strongest_contradictory_evidence": [ "Applied proteins are artificial and vascular injuries can independently impair cognition; it is not every disease initiating pathway." ], "hsef_level_for_this_model": "Ε", "rationale": "Aβ human-slice constriction and APP knock-in vascular abnormalities, tau-peptide endothelial injury and amyloid-model vascular rescue establish this route. Applied proteins are artificial and vascular injuries can independently impair cognition; it is not every disease initiating pathway." }, { "rank_in_tournament": 3, "model_id": "M4", "is_nominal": false, "name": "Amyloid-driven vascular injury", "core_claim": "Amyloid vasculopathy produces cerebrovascular dysfunction and injury.", "explains_what_nominal_does_not": "Amyloid vasculopathy produces cerebrovascular dysfunction and injury.", "strongest_supporting_evidence": [ "Hereditary APP CAA trajectories and model vascular amyloid/hypoperfusion interactions support this defined route." ], "strongest_contradictory_evidence": [ "CAA is not all sporadic AD and many vascular injuries do not require amyloid." ], "hsef_level_for_this_model": "Ε", "rationale": "Hereditary APP CAA trajectories and model vascular amyloid/hypoperfusion interactions support this defined route. CAA is not all sporadic AD and many vascular injuries do not require amyloid." }, { "rank_in_tournament": 4, "model_id": "M1", "is_nominal": true, "name": "Two-Hit vascular initiation", "core_claim": "Vascular dysfunction starts the AD amyloid/tau cascade and dementia.", "explains_what_nominal_does_not": "Vascular dysfunction starts the AD amyloid/tau cascade and dementia.", "strongest_supporting_evidence": [ "Early GLUT1/pericyte lesions and APP-model accelerated deposition provide a coherent mechanism." ], "strongest_contradictory_evidence": [ "The upstream APP lesion, absence of tangles in pure VaD, opposite tau response and retracted landmark reports limit causal primacy." ], "hsef_level_for_this_model": "Γ", "rationale": "Early GLUT1/pericyte lesions and APP-model accelerated deposition provide a coherent mechanism. The upstream APP lesion, absence of tangles in pure VaD, opposite tau response and retracted landmark reports limit causal primacy." }, { "rank_in_tournament": 5, "model_id": "M5", "is_nominal": false, "name": "Shared systemic inflammatory driver", "core_claim": "Systemic exposures produce both vascular and protein injury.", "explains_what_nominal_does_not": "Systemic exposures produce both vascular and protein injury.", "strongest_supporting_evidence": [ "Hepatic APOE and inflammatory/vascular biomarker relationships provide plausible common routes." ], "strongest_contradictory_evidence": [ "Pleiotropy and observational paths do not isolate the shared initiating mediator." ], "hsef_level_for_this_model": "Γ", "rationale": "Hepatic APOE and inflammatory/vascular biomarker relationships provide plausible common routes. Pleiotropy and observational paths do not isolate the shared initiating mediator." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. Perturb vascular and protein processes independently before onset. Parallel injury predicts cognitive improvement without prevention of protein accumulation; vascular-first predicts prevention of new amyloid/tau after engaged vascular protection.", "study_separating_rank1_from_rank2": "Perturb vascular and protein processes independently before onset. Parallel injury predicts cognitive improvement without prevention of protein accumulation; vascular-first predicts prevention of new amyloid/tau after engaged vascular protection.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "21040844", "title": "Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging.", "citation": "Bell RD, Winkler EA, Sagare AP et al. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron. 2010.", "doi": "10.1016/j.neuron.2010.09.043", "pmcid": "PMC3056408", "url": "https://pubmed.ncbi.nlm.nih.gov/21040844/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21040844/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID37797582" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "pericyte-Pdgfrb-platform", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Pdgfrb-deficient adult mice develop vascular dysfunction before general neuronal injury.", "what_it_does_not_show": "Engineered pericyte loss does not establish AD-specific proteinopathy onset; linked correction details unexamined.", "confounders_present": [ "Engineered pericyte loss does not establish AD-specific proteinopathy onset; linked correction details unexamined." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 2, "pmid": "22622580", "title": "Apolipoprotein E controls cerebrovascular integrity via cyclophilin A.", "citation": "Bell RD, Winkler EA, Singh I et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature. 2012.", "doi": "10.1038/nature11087", "pmcid": "PMC4047116", "url": "https://pubmed.ncbi.nlm.nih.gov/22622580/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22622580/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID37142785" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID22622580", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "APOE4 activates pericyte CypA-MMP9 and genetic or pharmacological pathway subtraction protects BBB.", "what_it_does_not_show": "APOE affects multiple compartments; BBB protection is not spontaneous human AD prevention; correction details unexamined.", "confounders_present": [ "APOE affects multiple compartments; BBB protection is not spontaneous human AD prevention; correction details unexamined." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 3, "pmid": "28135240", "title": "Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain.", "citation": "Kisler K, Nelson AR, Rege SV et al. Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain. Nature neuroscience. 2017.", "doi": "10.1038/nn.4489", "pmcid": "PMC5323291", "url": "https://pubmed.ncbi.nlm.nih.gov/28135240/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28135240/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "pericyte-Pdgfrb-platform", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Pericyte-deficient mice lose neurovascular coupling and develop oxygen/metabolic stress.", "what_it_does_not_show": "Shared Pdgfrb platform and physiology do not independently prove amyloid/tau initiation.", "confounders_present": [ "Shared Pdgfrb platform and physiology do not independently prove amyloid/tau initiation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 4, "pmid": "31235908", "title": "Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss.", "citation": "Nikolakopoulou AM, Montagne A, Kisler K et al. Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss. Nature neuroscience. 2019.", "doi": "10.1038/s41593-019-0434-z", "pmcid": "PMC6668719", "url": "https://pubmed.ncbi.nlm.nih.gov/31235908/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31235908/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID31235908", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph2, 1:RESULTS:paragraph3, 1:RESULTS:paragraph4, 1:RESULTS:paragraph10, 1:RESULTS:paragraph12, 1:RESULTS:paragraph13. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [ "M3" ], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Inducible pericyte ablation causes flow/BBB deficits and neuronal/cognitive loss; physiological PTN infusion preserves neurons and cognition despite persistent circulatory defects.", "what_it_does_not_show": "Severe acute dual-promoter ablation is not gradual human disease; amyloid/tau initiation is not tested; PTN depletion alone does not kill neurons.", "confounders_present": [ "Severe acute dual-promoter ablation is not gradual human disease; amyloid/tau initiation is not tested; PTN depletion alone does not kill neurons." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 5, "pmid": "20944625", "title": "Pericytes are required for blood-brain barrier integrity during embryogenesis.", "citation": "Daneman R, Zhou L, Kebede AA et al. Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature. 2010.", "doi": "10.1038/nature09513", "pmcid": "PMC3241506", "url": "https://pubmed.ncbi.nlm.nih.gov/20944625/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20944625/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID20944625", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Developmental pericyte coverage determines BBB permeability before astrocyte development.", "what_it_does_not_show": "Developmental barrier formation is not adult AD etiology or clinical trajectory.", "confounders_present": [ "Developmental barrier formation is not adult AD etiology or clinical trajectory." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 6, "pmid": "32376954", "title": "APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline.", "citation": "Montagne A, Nation DA, Sagare AP et al. APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline. Nature. 2020.", "doi": "10.1038/s41586-020-2247-3", "pmcid": "PMC7250000", "url": "https://pubmed.ncbi.nlm.nih.gov/32376954/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32376954/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID32376954", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Introductory Paragraph:paragraph1, 0:Introductory Paragraph:paragraph3, 0:Introductory Paragraph:paragraph5, 0:Introductory Paragraph:paragraph6, 0:Introductory Paragraph:paragraph9. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Human APOE4-associated BBB disruption and baseline pericyte-injury marker predict subsequent cognitive decline independently of measured amyloid/tau.", "what_it_does_not_show": "No vascular manipulation; cognitively normal APOE4 participants can already have amyloid; baseline marker prediction is not molecular primacy.", "confounders_present": [ "No vascular manipulation; cognitively normal APOE4 participants can already have amyloid; baseline marker prediction is not molecular primacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 7, "pmid": "30643288", "title": "Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction.", "citation": "Nation DA, Sweeney MD, Montagne A et al. Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nature medicine. 2019.", "doi": "10.1038/s41591-018-0297-y", "pmcid": "PMC6367058", "url": "https://pubmed.ncbi.nlm.nih.gov/30643288/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30643288/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID30643288", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Early cognitive dysfunction associates with hippocampal capillary damage irrespective of measured amyloid/tau biomarkers.", "what_it_does_not_show": "Cross-sectional independence does not establish a cascade from vascular injury to proteins.", "confounders_present": [ "Cross-sectional independence does not establish a cascade from vascular injury to proteins." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 8, "pmid": "25611508", "title": "Blood-brain barrier breakdown in the aging human hippocampus.", "citation": "Montagne A, Barnes SR, Sweeney MD et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron. 2015.", "doi": "10.1016/j.neuron.2014.12.032", "pmcid": "PMC4350773", "url": "https://pubmed.ncbi.nlm.nih.gov/25611508/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25611508/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID25611508", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Hippocampal BBB permeability increases with aging and mild cognitive impairment.", "what_it_does_not_show": "Imaging association lacks a selective counterfactual or AD-specific initiating event.", "confounders_present": [ "Imaging association lacks a selective counterfactual or AD-specific initiating event." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 9, "pmid": "25757756", "title": "Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer's disease.", "citation": "Halliday MR, Rege SV, Ma Q et al. Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer's disease. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2016.", "doi": "10.1038/jcbfm.2015.44", "pmcid": "PMC4758554", "url": "https://pubmed.ncbi.nlm.nih.gov/25757756/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25757756/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID25757756", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "APOE4 postmortem brain has pericyte loss and CypA pathway activation.", "what_it_does_not_show": "Terminal tissue cannot order the initiating lesions; genotype is pleiotropic.", "confounders_present": [ "Terminal tissue cannot order the initiating lesions; genotype is pleiotropic." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 10, "pmid": "32514169", "title": "Reconstruction of the human blood-brain barrier in vitro reveals a pathogenic mechanism of APOE4 in pericytes.", "citation": "Blanchard JW, Bula M, Davila-Velderrain J et al. Reconstruction of the human blood-brain barrier in vitro reveals a pathogenic mechanism of APOE4 in pericytes. Nature medicine. 2020.", "doi": "10.1038/s41591-020-0886-4", "pmcid": "PMC7704032", "url": "https://pubmed.ncbi.nlm.nih.gov/32514169/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32514169/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID33514950" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID32514169", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "in vitro", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Human 3D BBB APOE4 models show NFAT-associated cerebral amyloid angiopathy with inhibitor sensitivity.", "what_it_does_not_show": "Culture and accompanying models do not establish BBB failure preceding all proteinopathy; correction details unexamined.", "confounders_present": [ "Culture and accompanying models do not establish BBB failure preceding all proteinopathy; correction details unexamined." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 11, "pmid": "35291561", "title": "APOE4 accelerates advanced-stage vascular and neurodegenerative disorder in old Alzheimer's mice via cyclophilin A independently of amyloid-β.", "citation": "Montagne A, Nikolakopoulou AM, Huuskonen MT et al. APOE4 accelerates advanced-stage vascular and neurodegenerative disorder in old Alzheimer's mice via cyclophilin A independently of amyloid-β. Nature aging. 2021.", "doi": "10.1038/s43587-021-00073-z", "pmcid": "PMC8920485", "url": "https://pubmed.ncbi.nlm.nih.gov/35291561/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35291561/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID37117809" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID35291561", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Results:paragraph11, 0:Results:paragraph12, 0:Results:paragraph15, 0:Results:paragraph16, 0:Results:paragraph18. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [ "M3", "M2" ], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "At 10–12 months Debio-025 improves APOE4 BBB and prevents further neuronal loss and cognitive decline without changing Aβ pathology.", "what_it_does_not_show": "Treatment modifies the APOE4 increment rather than restoring all 5xFAD deficits to wild type; APP mutations precede the vascular insult.", "confounders_present": [ "Treatment modifies the APOE4 increment rather than restoring all 5xFAD deficits to wild type; APP mutations precede the vascular insult." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 12, "pmid": "25730668", "title": "GLUT1 reductions exacerbate Alzheimer's disease vasculo-neuronal dysfunction and degeneration.", "citation": "Winkler EA, Nishida Y, Sagare AP et al. GLUT1 reductions exacerbate Alzheimer's disease vasculo-neuronal dysfunction and degeneration. Nature neuroscience. 2015.", "doi": "10.1038/nn.3966", "pmcid": "PMC4734893", "url": "https://pubmed.ncbi.nlm.nih.gov/25730668/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25730668/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID25730668", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph9, 1:Results:paragraph11, 1:Results:paragraph12, 1:Results:paragraph18, 1:Results:paragraph22, 1:Results:paragraph23. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [ "M1", "M2" ], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Endothelial GLUT1 loss causes early BBB failure; combined Slc2a1 deficiency/APP increases later Aβ and NeuN loss; GLUT1/LRP1 re-expression reduces Aβ.", "what_it_does_not_show": "APP overexpression is present from development; late acceleration and regional clearance rescue are not initiation of spontaneous human AD or whole-animal cognitive reversal.", "confounders_present": [ "APP overexpression is present from development; late acceleration and regional clearance rescue are not initiation of spontaneous human AD or whole-animal cognitive reversal." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 13, "pmid": "31221773", "title": "Amyloid β oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes.", "citation": "Nortley R, Korte N, Izquierdo P et al. Amyloid β oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes. Science (New York, N.Y.). 2019.", "doi": "10.1126/science.aav9518", "pmcid": "PMC6658218", "url": "https://pubmed.ncbi.nlm.nih.gov/31221773/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31221773/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID31221773", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Amyloid β constricts human capillaries at pericytes, 2:Pericytes constrict capillaries in human cognitive decline patients with Aβ deposition, 4:Pericytes constrict capillaries in vivo in AD mice, 6:Reversal of Aβ-evoked capillary constriction. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [ "M2", "M4" ], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Applied Aβ constricts human/rat capillaries; APP knock-in mice show endogenous plaque-region pericyte constriction; CNP reverses acute constriction.", "what_it_does_not_show": "Small human biopsy and mouse samples; thousands of vessel measurements are not independent patients; modeled flow reduction is not measured human flow.", "confounders_present": [ "Small human biopsy and mouse samples; thousands of vessel measurements are not independent patients; modeled flow reduction is not measured human flow." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 14, "pmid": "38420777", "title": "Pathogenic soluble tau peptide disrupts endothelial calcium signaling and vasodilation in the brain microvasculature.", "citation": "Mughal A, Sackheim AM, Koide M et al. Pathogenic soluble tau peptide disrupts endothelial calcium signaling and vasodilation in the brain microvasculature. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2024.", "doi": "10.1177/0271678X241235790", "pmcid": "PMC11197144", "url": "https://pubmed.ncbi.nlm.nih.gov/38420777/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38420777/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID37609200" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID38420777", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "AD-related tau peptides cause endothelial calcium and vasodilatory dysfunction.", "what_it_does_not_show": "Peptide exposure demonstrates a possible protein-to-vessel route, not its prevalence in spontaneous AD.", "confounders_present": [ "Peptide exposure demonstrates a possible protein-to-vessel route, not its prevalence in spontaneous AD." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 15, "pmid": "38475929", "title": "Amyloid β oligomer induces cerebral vasculopathy via pericyte-mediated endothelial dysfunction.", "citation": "Chen S, Guo D, Zhu Y et al. Amyloid β oligomer induces cerebral vasculopathy via pericyte-mediated endothelial dysfunction. Alzheimer's research & therapy. 2024.", "doi": "10.1186/s13195-024-01423-w", "pmcid": "PMC10935813", "url": "https://pubmed.ncbi.nlm.nih.gov/38475929/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38475929/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID38475929", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Aβ exposure injures pericytes and endothelial capillary structure.", "what_it_does_not_show": "Exogenous challenge establishes capacity, not ordinary endogenous initiating direction.", "confounders_present": [ "Exogenous challenge establishes capacity, not ordinary endogenous initiating direction." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 16, "pmid": "36922879", "title": "Astrocytic APOE4 removal confers cerebrovascular protection despite increased cerebral amyloid angiopathy.", "citation": "Xiong M, Wang C, Gratuze M et al. Astrocytic APOE4 removal confers cerebrovascular protection despite increased cerebral amyloid angiopathy. Molecular neurodegeneration. 2023.", "doi": "10.1186/s13024-023-00610-x", "pmcid": "PMC10018855", "url": "https://pubmed.ncbi.nlm.nih.gov/36922879/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36922879/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID36922879", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Early astrocytic APOE4 removal in 5xFAD reduces vascular injury despite increased vascular amyloid.", "what_it_does_not_show": "Genetic APP proteinopathy persists and cell-specific APOE effects are not a vessel-only intervention.", "confounders_present": [ "Genetic APP proteinopathy persists and cell-specific APOE effects are not a vessel-only intervention." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 17, "pmid": "30742116", "title": "Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer's disease mouse models.", "citation": "Cruz Hernández JC, Bracko O, Kersbergen CJ et al. Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer's disease mouse models. Nature neuroscience. 2019.", "doi": "10.1038/s41593-018-0329-4", "pmcid": "PMC6508667", "url": "https://pubmed.ncbi.nlm.nih.gov/30742116/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30742116/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID30742116", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Anti-Ly6G relieves neutrophil capillary stalls and rapidly improves flow and memory in APP/PS1 and 5xFAD mice.", "what_it_does_not_show": "Acute functional rescue occurs after engineered proteinopathy and is not prevention of AD onset.", "confounders_present": [ "Acute functional rescue occurs after engineered proteinopathy and is not prevention of AD onset." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 18, "pmid": "32876357", "title": "Denser brain capillary network with preserved pericytes in Alzheimer's disease.", "citation": "Fernandez-Klett F, Brandt L, Fernández-Zapata C et al. Denser brain capillary network with preserved pericytes in Alzheimer's disease. Brain pathology (Zurich, Switzerland). 2020.", "doi": "10.1111/bpa.12897", "pmcid": "PMC8018033", "url": "https://pubmed.ncbi.nlm.nih.gov/32876357/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32876357/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID32876357", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "null", "what_it_shows": "Two human frontal-cortex cohorts show preserved pericytes and increased capillary density in AD.", "what_it_does_not_show": "Regional postmortem counterexample does not rule out hippocampal or functional vascular injury.", "confounders_present": [ "Regional postmortem counterexample does not rule out hippocampal or functional vascular injury." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 19, "pmid": "35173711", "title": "Multifocal Cerebral Microinfarcts Modulate Early Alzheimer's Disease Pathology in a Sex-Dependent Manner.", "citation": "Lecordier S, Pons V, Rivest S et al. Multifocal Cerebral Microinfarcts Modulate Early Alzheimer's Disease Pathology in a Sex-Dependent Manner. Frontiers in immunology. 2021.", "doi": "10.3389/fimmu.2021.813536", "pmcid": "PMC8841345", "url": "https://pubmed.ncbi.nlm.nih.gov/35173711/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35173711/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID35173711", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Microinfarcts produce sex-dependent cognitive injury while decreasing plaques without changing soluble Aβ in APP/PS1 mice.", "what_it_does_not_show": "Surgical infarcts and strain/sex differences constrain generalization; lower plaques are not lower overall injury.", "confounders_present": [ "Surgical infarcts and strain/sex differences constrain generalization; lower plaques are not lower overall injury." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 20, "pmid": "39621511", "title": "Cerebral hypoperfusion reduces tau accumulation.", "citation": "Gheni G, Shinohara M, Masuda-Suzukake M et al. Cerebral hypoperfusion reduces tau accumulation. Annals of clinical and translational neurology. 2025.", "doi": "10.1002/acn3.52247", "pmcid": "PMC11752094", "url": "https://pubmed.ncbi.nlm.nih.gov/39621511/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39621511/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID39621511", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph0, 2:Results:paragraph11, 2:Results:paragraph13, 2:Results:paragraph14, 2:Results:paragraph18. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [ "M3" ], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "BCAS performed two months after tau seeding reduces accumulated tau while worsening white matter; NACC remote stroke associates with less AD pathology.", "what_it_does_not_show": "Seeded tau is imposed first; CTSD colocalization/upregulation is a candidate mediator without necessity subtraction; autopsy associations retain survival and diagnosis biases.", "confounders_present": [ "Seeded tau is imposed first; CTSD colocalization/upregulation is a candidate mediator without necessity subtraction; autopsy associations retain survival and diagnosis biases." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 21, "pmid": "27314529", "title": "Chronic Cerebral Hypoperfusion Accelerates Alzheimer's Disease Pathology with Cerebrovascular Remodeling in a Novel Mouse Model.", "citation": "Zhai Y, Yamashita T, Nakano Y et al. Chronic Cerebral Hypoperfusion Accelerates Alzheimer's Disease Pathology with Cerebrovascular Remodeling in a Novel Mouse Model. Journal of Alzheimer's disease : JAD. 2016.", "doi": "10.3233/JAD-160345", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/27314529/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27314529/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID27314529", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Hypoperfusion in APP23 exacerbates amyloid/cognitive abnormalities and galantamine ameliorates phenotypes.", "what_it_does_not_show": "APP is genetically upstream; galantamine has nonvascular neuronal actions.", "confounders_present": [ "APP is genetically upstream; galantamine has nonvascular neuronal actions." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 22, "pmid": "27050297", "title": "Chronic cerebral hypoperfusion enhances Tau hyperphosphorylation and reduces autophagy in Alzheimer's disease mice.", "citation": "Qiu L, Ng G, Tan EK et al. Chronic cerebral hypoperfusion enhances Tau hyperphosphorylation and reduces autophagy in Alzheimer's disease mice. Scientific reports. 2016.", "doi": "10.1038/srep23964", "pmcid": "PMC4822118", "url": "https://pubmed.ncbi.nlm.nih.gov/27050297/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27050297/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID27050297", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Unilateral occlusion raises selected phospho-tau epitopes in aged wild-type/3xTg mice without changing Aβ42.", "what_it_does_not_show": "Age/genotype-specific phosphorylation is not a complete AD amyloid/tau initiating cascade.", "confounders_present": [ "Age/genotype-specific phosphorylation is not a complete AD amyloid/tau initiating cascade." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 23, "pmid": "19646974", "title": "Chronic cerebral hypoperfusion accelerates amyloid beta deposition in APPSwInd transgenic mice.", "citation": "Kitaguchi H, Tomimoto H, Ihara M et al. Chronic cerebral hypoperfusion accelerates amyloid beta deposition in APPSwInd transgenic mice. Brain research. 2009.", "doi": "10.1016/j.brainres.2009.07.078", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/19646974/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19646974/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID19646974", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "BCAS in APP-transgenic mice increases intracellular and fibrillar Aβ deposits.", "what_it_does_not_show": "Transgenic APP is upstream, and accelerated deposition does not identify sporadic onset.", "confounders_present": [ "Transgenic APP is upstream, and accelerated deposition does not identify sporadic onset." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 24, "pmid": "22170742", "title": "Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts.", "citation": "Okamoto Y, Yamamoto T, Kalaria RN et al. Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts. Acta neuropathologica. 2012.", "doi": "10.1007/s00401-011-0925-9", "pmcid": "PMC3282897", "url": "https://pubmed.ncbi.nlm.nih.gov/22170742/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22170742/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID22170742", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "BCAS augments vascular amyloid and microinfarcts in CAA mice; human postmortem observations agree.", "what_it_does_not_show": "Amyloid vasculopathy is pre-existing; terminal association and hypoperfusion amplification are not vascular-first AD initiation.", "confounders_present": [ "Amyloid vasculopathy is pre-existing; terminal association and hypoperfusion amplification are not vascular-first AD initiation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 25, "pmid": "20961660", "title": "Selective white matter pathology induces a specific impairment in spatial working memory.", "citation": "Coltman R, Spain A, Tsenkina Y et al. Selective white matter pathology induces a specific impairment in spatial working memory. Neurobiology of aging. 2011.", "doi": "10.1016/j.neurobiolaging.2010.09.005", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/20961660/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20961660/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID20961660", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Chronic hypoperfusion produces white-matter injury and selective spatial working-memory deficits.", "what_it_does_not_show": "Excluding mice with neuronal perikaryal injury conditions analysis on an outcome; impairment is not necessarily AD dementia.", "confounders_present": [ "Excluding mice with neuronal perikaryal injury conditions analysis on an outcome; impairment is not necessarily AD dementia." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 26, "pmid": "34078745", "title": "Cis P-tau underlies vascular contribution to cognitive impairment and dementia and can be effectively targeted by immunotherapy in mice.", "citation": "Qiu C, Albayram O, Kondo A et al. Cis P-tau underlies vascular contribution to cognitive impairment and dementia and can be effectively targeted by immunotherapy in mice. Science translational medicine. 2021.", "doi": "10.1126/scitranslmed.aaz7615", "pmcid": "PMC8272885", "url": "https://pubmed.ncbi.nlm.nih.gov/34078745/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34078745/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "cis-tau-BCAS-htau-platform", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph0, 1:RESULTS:paragraph1, 1:RESULTS:paragraph2, 1:RESULTS:paragraph6, 1:RESULTS:paragraph7, 1:RESULTS:paragraph8. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [ "M3" ], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "BCAS induces endogenous cis P-tau; cis antibody and DAPK1 loss preserve white matter and executive function; separate htau mice respond to treatment.", "what_it_does_not_show": "Human VaD brains lack overt NFTs; htau AD-like tangles arise in a separate model, so BCAS-to-classic-AD initiation is not demonstrated.", "confounders_present": [ "Human VaD brains lack overt NFTs; htau AD-like tangles arise in a separate model, so BCAS-to-classic-AD initiation is not demonstrated." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 27, "pmid": "33215083", "title": "Cerebrovascular disease promotes tau pathology in Alzheimer's disease.", "citation": "Laing KK, Simoes S, Baena-Caldas GP et al. Cerebrovascular disease promotes tau pathology in Alzheimer's disease. Brain communications. 2020.", "doi": "10.1093/braincomms/fcaa132", "pmcid": "PMC7660042", "url": "https://pubmed.ncbi.nlm.nih.gov/33215083/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33215083/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID33215083", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "White-matter vascular pathology associates with total tau/Braak measures; aged MCAO produces phospho-tau.", "what_it_does_not_show": "Mixed observational/ischemic evidence does not show onset of the specific amyloid/tau cascade or exclude injury-related tau release.", "confounders_present": [ "Mixed observational/ischemic evidence does not show onset of the specific amyloid/tau cascade or exclude injury-related tau release." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 28, "pmid": "34957486", "title": "APOE4 derived from astrocytes leads to blood-brain barrier impairment.", "citation": "Jackson RJ, Meltzer JC, Nguyen H et al. APOE4 derived from astrocytes leads to blood-brain barrier impairment. Brain : a journal of neurology. 2022.", "doi": "10.1093/brain/awab478", "pmcid": "PMC9586546", "url": "https://pubmed.ncbi.nlm.nih.gov/34957486/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34957486/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID34957486", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Astrocytic APOE4 deletion ameliorates BBB impairment relative to matched APOE3 designs.", "what_it_does_not_show": "APOE has nonvascular effects; barrier rescue does not establish that amyloid/tau initiation depends on barrier failure.", "confounders_present": [ "APOE has nonvascular effects; barrier rescue does not establish that amyloid/tau initiation depends on barrier failure." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 29, "pmid": "35915180", "title": "Peripheral apoE4 enhances Alzheimer's pathology and impairs cognition by compromising cerebrovascular function.", "citation": "Liu CC, Zhao J, Fu Y et al. Peripheral apoE4 enhances Alzheimer's pathology and impairs cognition by compromising cerebrovascular function. Nature neuroscience. 2022.", "doi": "10.1038/s41593-022-01127-0", "pmcid": "PMC10009873", "url": "https://pubmed.ncbi.nlm.nih.gov/35915180/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35915180/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID35915180", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Liver-only APOE4 causes vascular/synaptic/cognitive abnormalities and exacerbates APP-model amyloid; APOE3 plasma improves aged phenotypes.", "what_it_does_not_show": "Systemic pleiotropy and APP crossing distinguish vascular contribution from AD-specific primacy.", "confounders_present": [ "Systemic pleiotropy and APP crossing distinguish vascular contribution from AD-specific primacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 30, "pmid": "35165441", "title": "A human brain vascular atlas reveals diverse mediators of Alzheimer's risk.", "citation": "Yang AC, Vest RT, Kern F et al. A human brain vascular atlas reveals diverse mediators of Alzheimer's risk. Nature. 2022.", "doi": "10.1038/s41586-021-04369-3", "pmcid": "PMC9635042", "url": "https://pubmed.ncbi.nlm.nih.gov/35165441/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35165441/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID35165441", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Single-nucleus human vascular atlas identifies AD-associated cellular changes and risk-gene expression.", "what_it_does_not_show": "Risk-gene expression is not a causal vascular instrument; terminal transcriptomes cannot order events.", "confounders_present": [ "Risk-gene expression is not a causal vascular instrument; terminal transcriptomes cannot order events." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 31, "pmid": "30688979", "title": "Effect of Intensive vs Standard Blood Pressure Control on Probable Dementia: A Randomized Clinical Trial.", "citation": " , Williamson JD, Pajewski NM et al. Effect of Intensive vs Standard Blood Pressure Control on Probable Dementia: A Randomized Clinical Trial. JAMA. 2019.", "doi": "10.1001/jama.2018.21442", "pmcid": "PMC6439590", "url": "https://pubmed.ncbi.nlm.nih.gov/30688979/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30688979/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "SPRINT-cognitive-cohort", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "SPRINT intensive blood-pressure treatment reduces MCI and combined cognitive endpoints.", "what_it_does_not_show": "Primary probable-dementia contrast is nonsignificant; early cardiovascular stopping and exclusion of diabetes/stroke limit scope; no AD biomarker-onset endpoint.", "confounders_present": [ "Primary probable-dementia contrast is nonsignificant; early cardiovascular stopping and exclusion of diabetes/stroke limit scope; no AD biomarker-onset endpoint." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 32, "pmid": "39819096", "title": "Long-Term Effect of Intensive vs Standard Blood Pressure Control on Mild Cognitive Impairment and Probable Dementia in SPRINT.", "citation": "Reboussin DM, Gaussoin SA, Pajewski NM et al. Long-Term Effect of Intensive vs Standard Blood Pressure Control on Mild Cognitive Impairment and Probable Dementia in SPRINT. Neurology. 2025.", "doi": "10.1212/WNL.0000000000213334", "pmcid": "PMC11737843", "url": "https://pubmed.ncbi.nlm.nih.gov/39819096/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39819096/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "ErratumIn: PMID40315397" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "SPRINT-cognitive-cohort", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "SPRINT extended follow-up retains MCI/composite benefit.", "what_it_does_not_show": "Probable dementia remains nonsignificant; only 59% of eligible participants were ascertained; same randomized cohort and unexamined correction do not add independent replication.", "confounders_present": [ "Probable dementia remains nonsignificant; only 59% of eligible participants were ascertained; same randomized cohort and unexamined correction do not add independent replication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 33, "pmid": "40258956", "title": "Blood pressure reduction and all-cause dementia in people with uncontrolled hypertension: an open-label, blinded-endpoint, cluster-randomized trial.", "citation": "He J, Zhao C, Zhong S et al. Blood pressure reduction and all-cause dementia in people with uncontrolled hypertension: an open-label, blinded-endpoint, cluster-randomized trial. Nature medicine. 2025.", "doi": "10.1038/s41591-025-03616-8", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/40258956/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40258956/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID40258956", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [ "M3" ], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Rural-China cluster randomization of 33995 adults in 326 villages lowers 48-month incident all-cause dementia with provider-led blood-pressure treatment.", "what_it_does_not_show": "Bundled care is not a selective BBB/pericyte intervention; all-cause dementia benefit does not demonstrate prevention of AD-specific amyloid/tau; abstract/status depth only.", "confounders_present": [ "Bundled care is not a selective BBB/pericyte intervention; all-cause dementia benefit does not demonstrate prevention of AD-specific amyloid/tau; abstract/status depth only." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 34, "pmid": "18614402", "title": "Incident dementia and blood pressure lowering in the Hypertension in the Very Elderly Trial cognitive function assessment (HYVET-COG): a double-blind, placebo controlled trial.", "citation": "Peters R, Beckett N, Forette F et al. Incident dementia and blood pressure lowering in the Hypertension in the Very Elderly Trial cognitive function assessment (HYVET-COG): a double-blind, placebo controlled trial. The Lancet. Neurology. 2008.", "doi": "10.1016/S1474-4422(08)70143-1", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/18614402/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18614402/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID18614402", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "null", "what_it_shows": "HYVET-COG randomized antihypertensive treatment in adults over 80 and measured incident dementia.", "what_it_does_not_show": "Short follow-up primary dementia contrast is nonsignificant; meta-analysis pooling is not a positive primary trial result.", "confounders_present": [ "Short follow-up primary dementia contrast is nonsignificant; meta-analysis pooling is not a positive primary trial result." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 35, "pmid": "9802273", "title": "Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial.", "citation": "Forette F, Seux ML, Staessen JA et al. Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet (London, England). 1998.", "doi": "10.1016/s0140-6736(98)03086-4", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/9802273/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/9802273/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "Syst-Eur-cohort", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Syst-Eur randomized antihypertensive therapy yields fewer clinical dementia cases over two years.", "what_it_does_not_show": "Only 32 events and borderline significance; clinical classification does not establish biomarker-defined AD prevention.", "confounders_present": [ "Only 32 events and borderline significance; clinical classification does not establish biomarker-defined AD prevention." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 36, "pmid": "12374512", "title": "The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study.", "citation": "Forette F, Seux ML, Staessen JA et al. The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study. Archives of internal medicine. 2002.", "doi": "10.1001/archinte.162.18.2046", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/12374512/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/12374512/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "Syst-Eur-cohort", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Syst-Eur extended follow-up reports continued dementia incidence difference including clinical AD cases.", "what_it_does_not_show": "Control participants were offered active treatment after blinded phase; same initial cohort, not an independent randomized trial or proof of molecular onset prevention.", "confounders_present": [ "Control participants were offered active treatment after blinded phase; same initial cohort, not an independent randomized trial or proof of molecular onset prevention." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 37, "pmid": "31607143", "title": "Effects of Intensive Versus Standard Ambulatory Blood Pressure Control on Cerebrovascular Outcomes in Older People (INFINITY).", "citation": "White WB, Wakefield DB, Moscufo N et al. Effects of Intensive Versus Standard Ambulatory Blood Pressure Control on Cerebrovascular Outcomes in Older People (INFINITY). Circulation. 2019.", "doi": "10.1161/CIRCULATIONAHA.119.041603", "pmcid": "PMC6848792", "url": "https://pubmed.ncbi.nlm.nih.gov/31607143/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31607143/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID31607143", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "null", "what_it_shows": "INFINITY lowers white-matter hyperintensity accumulation with intensive ambulatory blood-pressure control.", "what_it_does_not_show": "Gait and cognition contrasts are null despite MRI effects; biomarkers cannot stand for preserved clinical trajectory.", "confounders_present": [ "Gait and cognition contrasts are null despite MRI effects; biomarkers cannot stand for preserved clinical trajectory." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 38, "pmid": "27474376", "title": "Effectiveness of a 6-year multidomain vascular care intervention to prevent dementia (preDIVA): a cluster-randomised controlled trial.", "citation": "Moll van Charante EP, Richard E, Eurelings LS et al. Effectiveness of a 6-year multidomain vascular care intervention to prevent dementia (preDIVA): a cluster-randomised controlled trial. Lancet (London, England). 2016.", "doi": "10.1016/S0140-6736(16)30950-3", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/27474376/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27474376/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID27474376", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "null", "what_it_shows": "preDIVA vascular-care cluster trial shows no overall incident dementia or disability reduction.", "what_it_does_not_show": "Low baseline risk and strong usual care reduce intervention contrast; null bundled care is not selective pathway falsification.", "confounders_present": [ "Low baseline risk and strong usual care reduce intervention contrast; null bundled care is not selective pathway falsification." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 39, "pmid": "12742805", "title": "Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease.", "citation": "Tzourio C, Anderson C, Chapman N et al. Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Archives of internal medicine. 2003.", "doi": "10.1001/archinte.163.9.1069", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/12742805/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/12742805/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID12742805", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "PROGRESS reduces cognitive decline with perindopril-based therapy after stroke/TIA; dementia benefit concentrates with recurrent stroke.", "what_it_does_not_show": "Overall dementia contrast is null and benefit without recurrent stroke is not established; this supports stroke-related injury prevention rather than obligatory AD cascade interruption.", "confounders_present": [ "Overall dementia contrast is null and benefit without recurrent stroke is not established; this supports stroke-related injury prevention rather than obligatory AD cascade interruption." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 40, "pmid": "37863608", "title": "Effect of blood pressure-lowering agents on microvascular function in people with small vessel diseases (TREAT-SVDs): a multicentre, open-label, randomised, crossover trial.", "citation": "Kopczak A, Stringer MS, van den Brink H et al. Effect of blood pressure-lowering agents on microvascular function in people with small vessel diseases (TREAT-SVDs): a multicentre, open-label, randomised, crossover trial. The Lancet. Neurology. 2023.", "doi": "10.1016/S1474-4422(23)00293-4", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/37863608/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37863608/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID37863608", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "null", "what_it_shows": "TREAT-SVD crossover compares cerebrovascular reactivity under three drugs; CADASIL shows differential physiological effects.", "what_it_does_not_show": "No drug difference in sporadic SVD; four-week physiology is not functional or dementia prevention; small analyzed subgroups.", "confounders_present": [ "No drug difference in sporadic SVD; four-week physiology is not functional or dementia prevention; small analyzed subgroups." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 41, "pmid": "25771249", "title": "A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial.", "citation": "Ngandu T, Lehtisalo J, Solomon A et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet (London, England). 2015.", "doi": "10.1016/S0140-6736(15)60461-5", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/25771249/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25771249/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID25771249", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "FINGER multidomain intervention improves a neuropsychological composite over two years.", "what_it_does_not_show": "Diet, exercise and cognitive training accompany vascular monitoring; benefit cannot be assigned to vascular correction or AD onset prevention.", "confounders_present": [ "Diet, exercise and cognitive training accompany vascular monitoring; benefit cannot be assigned to vascular correction or AD onset prevention." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 42, "pmid": "35732594", "title": "Associations of Vascular Risk and Amyloid Burden with Subsequent Dementia.", "citation": "Gottesman RF, Wu A, Coresh J et al. Associations of Vascular Risk and Amyloid Burden with Subsequent Dementia. Annals of neurology. 2022.", "doi": "10.1002/ana.26447", "pmcid": "PMC11412067", "url": "https://pubmed.ncbi.nlm.nih.gov/35732594/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35732594/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "ARIC-PET-overlap", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "ARIC hypertension and amyloid independently predict dementia without detected multiplicative synergy.", "what_it_does_not_show": "Absence of multiplicative interaction is not absence of additive interaction; observational hazards cannot order the pathology.", "confounders_present": [ "Absence of multiplicative interaction is not absence of additive interaction; observational hazards cannot order the pathology." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 43, "pmid": "28399252", "title": "Association Between Midlife Vascular Risk Factors and Estimated Brain Amyloid Deposition.", "citation": "Gottesman RF, Schneider AL, Zhou Y et al. Association Between Midlife Vascular Risk Factors and Estimated Brain Amyloid Deposition. JAMA. 2017.", "doi": "10.1001/jama.2017.3090", "pmcid": "PMC5921896", "url": "https://pubmed.ncbi.nlm.nih.gov/28399252/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28399252/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "ARIC-PET-overlap", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Multiple midlife vascular risks associate with later brain amyloid while late-life risks do not.", "what_it_does_not_show": "Long interval supports prediction but not an unconfounded vascular-to-amyloid initiating mechanism; same ARIC platform.", "confounders_present": [ "Long interval supports prediction but not an unconfounded vascular-to-amyloid initiating mechanism; same ARIC platform." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 44, "pmid": "38711107", "title": "Association between retinal microvascular abnormalities and late-life brain amyloid-β deposition: the ARIC-PET study.", "citation": "Egle M, Deal JA, Walker KA et al. Association between retinal microvascular abnormalities and late-life brain amyloid-β deposition: the ARIC-PET study. Alzheimer's research & therapy. 2024.", "doi": "10.1186/s13195-024-01461-4", "pmcid": "PMC11071225", "url": "https://pubmed.ncbi.nlm.nih.gov/38711107/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38711107/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "ARIC-PET-overlap", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "null", "what_it_shows": "ARIC retinal features at midlife do not predict amyloid; late-life continuous SUVr association differs from binary positivity.", "what_it_does_not_show": "Retinal proxies and endpoint definitions constrain inference; same cohort is not independent replication.", "confounders_present": [ "Retinal proxies and endpoint definitions constrain inference; same cohort is not independent replication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 45, "pmid": "9052711", "title": "Brain infarction and the clinical expression of Alzheimer disease. The Nun Study.", "citation": "Snowdon DA, Greiner LH, Mortimer JA et al. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA. 1997.", "doi": "", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/9052711/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/9052711/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID9052711", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Nun Study infarcts lower the burden of AD lesions associated with clinical dementia.", "what_it_does_not_show": "Small autopsy sample and wide intervals; interaction in clinical expression does not imply infarcts initiated plaques/tangles.", "confounders_present": [ "Small autopsy sample and wide intervals; interaction in clinical expression does not imply infarcts initiated plaques/tangles." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 46, "pmid": "17568013", "title": "Mixed brain pathologies account for most dementia cases in community-dwelling older persons.", "citation": "Schneider JA, Arvanitakis Z, Bang W et al. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology. 2007.", "doi": "10.1212/01.wnl.0000271090.28148.24", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/17568013/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17568013/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID17568013", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Rush autopsies show mixed pathologies increase probability of clinical dementia.", "what_it_does_not_show": "Postmortem mixture supports additive injury but cannot establish chronological initiation.", "confounders_present": [ "Postmortem mixture supports additive injury but cannot establish chronological initiation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 47, "pmid": "17879383", "title": "Pathological correlates of dementia in a longitudinal, population-based sample of aging.", "citation": "Sonnen JA, Larson EB, Crane PK et al. Pathological correlates of dementia in a longitudinal, population-based sample of aging. Annals of neurology. 2007.", "doi": "10.1002/ana.21208", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/17879383/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17879383/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID17879383", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "ACT autopsies identify independent contributions of microinfarcts, Braak pathology and Lewy bodies to dementia.", "what_it_does_not_show": "Selected autopsy fraction and weighting retain possible selection/confounding; independent association is not random intervention.", "confounders_present": [ "Selected autopsy fraction and weighting retain possible selection/confounding; independent association is not random intervention." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 48, "pmid": "19521084", "title": "Large vessel cerebral atherosclerosis is not in direct association with neuropathological lesions of Alzheimer's disease.", "citation": "Luoto TM, Haikonen S, Haapasalo H et al. Large vessel cerebral atherosclerosis is not in direct association with neuropathological lesions of Alzheimer's disease. European neurology. 2009.", "doi": "10.1159/000222779", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/19521084/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19521084/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID19521084", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [ "M3" ], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "null", "what_it_shows": "Large-artery atherosclerosis in 466 autopsies does not associate with AD plaques/tangles.", "what_it_does_not_show": "Large-vessel pathology differs from BBB microvascular dysfunction; negative subtype result does not exclude all vascular contributions.", "confounders_present": [ "Large-vessel pathology differs from BBB microvascular dysfunction; negative subtype result does not exclude all vascular contributions." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 49, "pmid": "39288341", "title": "Association of Vascular Risk Factors and Cerebrovascular Pathology With Alzheimer Disease Pathologic Changes in Individuals Without Dementia.", "citation": "Lorenzini L, Maranzano A, Ingala S et al. Association of Vascular Risk Factors and Cerebrovascular Pathology With Alzheimer Disease Pathologic Changes in Individuals Without Dementia. Neurology. 2024.", "doi": "10.1212/WNL.0000000000209801", "pmcid": "PMC11450612", "url": "https://pubmed.ncbi.nlm.nih.gov/39288341/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39288341/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID39288341", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "EPAD structural-equation analysis fits vascular risk/SVD/amyloid/tau/cognitive pathways in nondemented participants.", "what_it_does_not_show": "Statistical mediation and fitted ordering do not establish causality, temporal precedence, or absence of alternative models.", "confounders_present": [ "Statistical mediation and fitted ordering do not establish causality, temporal precedence, or absence of alternative models." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 50, "pmid": "16914401", "title": "Risk score for the prediction of dementia risk in 20 years among middle aged people: a longitudinal, population-based study.", "citation": "Kivipelto M, Ngandu T, Laatikainen T et al. Risk score for the prediction of dementia risk in 20 years among middle aged people: a longitudinal, population-based study. The Lancet. Neurology. 2006.", "doi": "10.1016/S1474-4422(06)70537-3", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/16914401/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16914401/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID16914401", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Midlife CAIDE factors predict late-life dementia over about 20 years.", "what_it_does_not_show": "Predictive discrimination is not causal mediation or a validated preventable fraction.", "confounders_present": [ "Predictive discrimination is not causal mediation or a validated preventable fraction." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 51, "pmid": "29901708", "title": "Association between systolic blood pressure and dementia in the Whitehall II cohort study: role of age, duration, and threshold used to define hypertension.", "citation": "Abell JG, Kivimäki M, Dugravot A et al. Association between systolic blood pressure and dementia in the Whitehall II cohort study: role of age, duration, and threshold used to define hypertension. European heart journal. 2018.", "doi": "10.1093/eurheartj/ehy288", "pmcid": "PMC6122131", "url": "https://pubmed.ncbi.nlm.nih.gov/29901708/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29901708/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "Whitehall-II", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Whitehall II blood pressure at age 50 predicts dementia, unlike measurements at 60 or 70.", "what_it_does_not_show": "Age-dependent association retains reverse causation and selection; CVD-free association is not a selective vascular instrument.", "confounders_present": [ "Age-dependent association retains reverse causation and selection; CVD-free association is not a selective vascular instrument." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 52, "pmid": "25497301", "title": "Lifetime hypertension as a predictor of brain structure in older adults: cohort study with a 28-year follow-up.", "citation": "Allan CL, Zsoldos E, Filippini N et al. Lifetime hypertension as a predictor of brain structure in older adults: cohort study with a 28-year follow-up. The British journal of psychiatry : the journal of mental science. 2015.", "doi": "10.1192/bjp.bp.114.153536", "pmcid": "PMC4381190", "url": "https://pubmed.ncbi.nlm.nih.gov/25497301/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25497301/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "Whitehall-II", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Longitudinal midlife blood pressure relates to later white-matter lesions.", "what_it_does_not_show": "Hippocampal/global atrophy associations are not established; tissue injury proxy is not molecular AD initiation.", "confounders_present": [ "Hippocampal/global atrophy associations are not established; tissue injury proxy is not molecular AD initiation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 53, "pmid": "40455489", "title": "Contribution of Modifiable Midlife and Late-Life Vascular Risk Factors to Incident Dementia.", "citation": "Smith JR, Pike JR, Gottesman RF et al. Contribution of Modifiable Midlife and Late-Life Vascular Risk Factors to Incident Dementia. JAMA neurology. 2025.", "doi": "10.1001/jamaneurol.2025.1495", "pmcid": "PMC12131178", "url": "https://pubmed.ncbi.nlm.nih.gov/40455489/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40455489/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID40455489", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "ARIC estimates substantial vascular-risk-associated dementia fractions before age 80 and smaller fractions at older ages.", "what_it_does_not_show": "Population-attributable fractions assume causal and intervention relationships; they are not demonstrated preventable percentages.", "confounders_present": [ "Population-attributable fractions assume causal and intervention relationships; they are not demonstrated preventable percentages." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 54, "pmid": "32955960", "title": "Brain amyloid and vascular risk are related to distinct white matter hyperintensity patterns.", "citation": "Pålhaugen L, Sudre CH, Tecelao S et al. Brain amyloid and vascular risk are related to distinct white matter hyperintensity patterns. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2021.", "doi": "10.1177/0271678X20957604", "pmcid": "PMC8054718", "url": "https://pubmed.ncbi.nlm.nih.gov/32955960/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32955960/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID32955960", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Amyloid-related and vascular-risk-related white-matter patterns differ topographically.", "what_it_does_not_show": "Cross-sectional topography cannot order cause and effect or validate a universal two-hit sequence.", "confounders_present": [ "Cross-sectional topography cannot order cause and effect or validate a universal two-hit sequence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 55, "pmid": "35695802", "title": "Evidence of beta amyloid independent small vessel disease in familial Alzheimer's disease.", "citation": "Littau JL, Velilla L, Hase Y et al. Evidence of beta amyloid independent small vessel disease in familial Alzheimer's disease. Brain pathology (Zurich, Switzerland). 2022.", "doi": "10.1111/bpa.13097", "pmcid": "PMC9616091", "url": "https://pubmed.ncbi.nlm.nih.gov/35695802/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35695802/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID35695802", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "PSEN1 familial AD has SVD changes that are not explained solely by CAA and can be covert on MRI.", "what_it_does_not_show": "Known PSEN1 lesion precedes the vascular phenotype; familial tissue does not establish sporadic vascular initiation.", "confounders_present": [ "Known PSEN1 lesion precedes the vascular phenotype; familial tissue does not establish sporadic vascular initiation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 56, "pmid": "32732295", "title": "Broad phenotype of cysteine-altering NOTCH3 variants in UK Biobank: CADASIL to nonpenetrance.", "citation": "Rutten JW, Hack RJ, Duering M et al. Broad phenotype of cysteine-altering NOTCH3 variants in UK Biobank: CADASIL to nonpenetrance. Neurology. 2020.", "doi": "10.1212/WNL.0000000000010525", "pmcid": "PMC7682826", "url": "https://pubmed.ncbi.nlm.nih.gov/32732295/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32732295/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID32732295", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "natural experiment", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "NOTCH3 variants produce heterogeneous SVD/vascular phenotypes in population carriers.", "what_it_does_not_show": "Many imaged carriers remain normal into late life; penetrance and selection prevent universal dementia inference.", "confounders_present": [ "Many imaged carriers remain normal into late life; penetrance and selection prevent universal dementia inference." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 57, "pmid": "36535904", "title": "Three-tiered EGFr domain risk stratification for individualized NOTCH3-small vessel disease prediction.", "citation": "Hack RJ, Gravesteijn G, Cerfontaine MN et al. Three-tiered EGFr domain risk stratification for individualized NOTCH3-small vessel disease prediction. Brain : a journal of neurology. 2023.", "doi": "10.1093/brain/awac486", "pmcid": "PMC10316769", "url": "https://pubmed.ncbi.nlm.nih.gov/36535904/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36535904/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID36535904", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "natural experiment", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "NOTCH3 domain location stratifies CADASIL stroke/SVD risk across clinical and population samples.", "what_it_does_not_show": "Genetic risk strata are not intervention outcomes; phenotype/penetrance varies and AD amyloid/tau onset is not tested.", "confounders_present": [ "Genetic risk strata are not intervention outcomes; phenotype/penetrance varies and AD amyloid/tau onset is not tested." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 58, "pmid": "27604306", "title": "Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations.", "citation": "Stam AH, Kothari PH, Shaikh A et al. Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations. Brain : a journal of neurology. 2016.", "doi": "10.1093/brain/aww217", "pmcid": "PMC5091044", "url": "https://pubmed.ncbi.nlm.nih.gov/27604306/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27604306/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID27604306", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "natural experiment", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "TREX1 families develop systemic retinal/cerebral vasculopathy with cognitive decline in a substantial subset.", "what_it_does_not_show": "Rare familial systemic disease is a distinct vascular cause, not universal AD dementia or a vessel-only mediator instrument.", "confounders_present": [ "Rare familial systemic disease is a distinct vascular cause, not universal AD dementia or a vessel-only mediator instrument." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 59, "pmid": "31680059", "title": "Patient-Specific iPSC Model of a Genetic Vascular Dementia Syndrome Reveals Failure of Mural Cells to Stabilize Capillary Structures.", "citation": "Kelleher J, Dickinson A, Cain S et al. Patient-Specific iPSC Model of a Genetic Vascular Dementia Syndrome Reveals Failure of Mural Cells to Stabilize Capillary Structures. Stem cell reports. 2019.", "doi": "10.1016/j.stemcr.2019.10.004", "pmcid": "PMC6893064", "url": "https://pubmed.ncbi.nlm.nih.gov/31680059/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31680059/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID31680059", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "in vitro", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "CADASIL patient-derived mural cells destabilize capillary networks with VEGF-sensitive rescue.", "what_it_does_not_show": "In vitro networks do not establish organismal cognitive trajectory or specific endogenous human rescue.", "confounders_present": [ "In vitro networks do not establish organismal cognitive trajectory or specific endogenous human rescue." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 60, "pmid": "41622715", "title": "Impairment of hippocampal gamma oscillations, mitochondria and neurovascular function in CADASIL.", "citation": "Shao W, Oliveira DV, Naia L et al. Impairment of hippocampal gamma oscillations, mitochondria and neurovascular function in CADASIL. Brain : a journal of neurology. 2026.", "doi": "10.1093/brain/awag033", "pmcid": "PMC13548857", "url": "https://pubmed.ncbi.nlm.nih.gov/41622715/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41622715/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID41622715", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "NOTCH3 R182C mice and human tissue show vascular-smooth-muscle metabolic and neuronal activity abnormalities.", "what_it_does_not_show": "Mechanism-associated physiology without selective rescue or AD-specific protein onset cannot close the nominal chain.", "confounders_present": [ "Mechanism-associated physiology without selective rescue or AD-specific protein onset cannot close the nominal chain." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 61, "pmid": "32043162", "title": "Identification of early pericyte loss and vascular amyloidosis in Alzheimer's disease retina.", "citation": "Shi H, Koronyo Y, Rentsendorj A et al. Identification of early pericyte loss and vascular amyloidosis in Alzheimer's disease retina. Acta neuropathologica. 2020.", "doi": "10.1007/s00401-020-02134-w", "pmcid": "PMC7181564", "url": "https://pubmed.ncbi.nlm.nih.gov/32043162/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32043162/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID32043162", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "AD retinal tissue shows pericyte loss related to amyloid.", "what_it_does_not_show": "Retinal pathology is not interchangeable with brain BBB function or chronological AD origin.", "confounders_present": [ "Retinal pathology is not interchangeable with brain BBB function or chronological AD origin." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 62, "pmid": "34041783", "title": "Blood-Brain Barrier Breakdown in Relationship to Alzheimer and Vascular Disease.", "citation": "Lin Z, Sur S, Liu P et al. Blood-Brain Barrier Breakdown in Relationship to Alzheimer and Vascular Disease. Annals of neurology. 2021.", "doi": "10.1002/ana.26134", "pmcid": "PMC8805295", "url": "https://pubmed.ncbi.nlm.nih.gov/34041783/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34041783/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID34041783", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Water-permeability BBB measures associate with AD biomarkers while albumin permeability tracks vascular risks.", "what_it_does_not_show": "Assays measure different transport/barrier properties; association cannot assign a common causal mechanism.", "confounders_present": [ "Assays measure different transport/barrier properties; association cannot assign a common causal mechanism." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 63, "pmid": "41052375", "title": "Alzheimer Disease, Vascular Disease, and Blood-Brain Barrier Permeability Biomarkers in Middle-Aged Adults.", "citation": "Edwards NC, Lao P, Alshikho MJ et al. Alzheimer Disease, Vascular Disease, and Blood-Brain Barrier Permeability Biomarkers in Middle-Aged Adults. Neurology. 2025.", "doi": "10.1212/WNL.0000000000214220", "pmcid": "PMC12591055", "url": "https://pubmed.ncbi.nlm.nih.gov/41052375/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41052375/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID41052375", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Midlife vascular/VEGF biomarker paths associate with AD-related measures.", "what_it_does_not_show": "Cross-sectional path analysis cannot validate the article's proposed causal ordering.", "confounders_present": [ "Cross-sectional path analysis cannot validate the article's proposed causal ordering." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 64, "pmid": "39085945", "title": "Assessing blood-brain barrier dysfunction and its association with Alzheimer's pathology, cognitive impairment and neuroinflammation.", "citation": "Preis L, Villringer K, Brosseron F et al. Assessing blood-brain barrier dysfunction and its association with Alzheimer's pathology, cognitive impairment and neuroinflammation. Alzheimer's research & therapy. 2024.", "doi": "10.1186/s13195-024-01529-1", "pmcid": "PMC11290219", "url": "https://pubmed.ncbi.nlm.nih.gov/39085945/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39085945/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID39085945", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "null", "what_it_shows": "DELCODE BBB permeability increases in dementia but not MCI; sPDGFRβ has no overall diagnostic/APOE difference.", "what_it_does_not_show": "Small sample and divergent permeability/injury assays; age/inflammation associations and null amyloid/tau-positivity relations limit a general initiating claim.", "confounders_present": [ "Small sample and divergent permeability/injury assays; age/inflammation associations and null amyloid/tau-positivity relations limit a general initiating claim." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 65, "pmid": "11402113", "title": "Presenilin-1-associated abnormalities in regional cerebral perfusion.", "citation": "Johnson KA, Lopera F, Jones K et al. Presenilin-1-associated abnormalities in regional cerebral perfusion. Neurology. 2001.", "doi": "10.1212/wnl.56.11.1545", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/11402113/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/11402113/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID11402113", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Presymptomatic PS1 mutation carriers have cerebral perfusion abnormalities.", "what_it_does_not_show": "Presymptomatic means before clinical symptoms, not before molecular proteinopathy; genotype is already an initiating lesion.", "confounders_present": [ "Presymptomatic means before clinical symptoms, not before molecular proteinopathy; genotype is already an initiating lesion." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 66, "pmid": "9539411", "title": "Brain volumes and regional cerebral blood flow in carriers of the Swedish Alzheimer amyloid protein mutation.", "citation": "Julin P, Almkvist O, Basun H et al. Brain volumes and regional cerebral blood flow in carriers of the Swedish Alzheimer amyloid protein mutation. Alzheimer disease and associated disorders. 1998.", "doi": "10.1097/00002093-199803000-00008", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/9539411/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/9539411/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID9539411", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Small APP Swedish family shows flow changes before marked atrophy in some carriers.", "what_it_does_not_show": "Five carriers with youngest participants normal; no demonstration that vascular change precedes amyloid production.", "confounders_present": [ "Five carriers with youngest participants normal; no demonstration that vascular change precedes amyloid production." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 67, "pmid": "41052971", "title": "Rapid amyloid-β clearance and cognitive recovery through multivalent modulation of blood-brain barrier transport.", "citation": "Chen J, Xiang P, Duro-Castano A et al. Rapid amyloid-β clearance and cognitive recovery through multivalent modulation of blood-brain barrier transport. Signal transduction and targeted therapy. 2025.", "doi": "10.1038/s41392-025-02426-1", "pmcid": "PMC12500928", "url": "https://pubmed.ncbi.nlm.nih.gov/41052971/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41052971/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID41052971", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "LRP1-targeted transport therapy clears amyloid and improves cognition in AD models.", "what_it_does_not_show": "Treatment after existing pathology tests clearance and delivery, not whether vascular failure initiated AD.", "confounders_present": [ "Treatment after existing pathology tests clearance and delivery, not whether vascular failure initiated AD." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 68, "pmid": "41529684", "title": "Angiopoietin-2 aggravates Alzheimer's disease by promoting blood-brain barrier dysfunction and neuroinflammation.", "citation": "Lee E, Kim S, Zhu CL et al. Angiopoietin-2 aggravates Alzheimer's disease by promoting blood-brain barrier dysfunction and neuroinflammation. Cell reports. 2026.", "doi": "10.1016/j.celrep.2025.116621", "pmcid": "PMC13058827", "url": "https://pubmed.ncbi.nlm.nih.gov/41529684/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41529684/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID41529684", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Endothelial ANGPT2 loss reduces amyloid, while overexpression worsens BBB/inflammatory/memory phenotypes in 5xFAD.", "what_it_does_not_show": "Genetic APP/PS1 pathology is upstream; expression/phenotype rescue does not demonstrate ordinary human vascular-first onset.", "confounders_present": [ "Genetic APP/PS1 pathology is upstream; expression/phenotype rescue does not demonstrate ordinary human vascular-first onset." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 69, "pmid": "35360926", "title": "Longitudinal Progression of Magnetic Resonance Imaging Markers and Cognition in Dutch-Type Hereditary Cerebral Amyloid Angiopathy.", "citation": "van Dijk SE, van der Grond J, Lak J et al. Longitudinal Progression of Magnetic Resonance Imaging Markers and Cognition in Dutch-Type Hereditary Cerebral Amyloid Angiopathy. Stroke. 2022.", "doi": "10.1161/STROKEAHA.121.035826", "pmcid": "PMC9126261", "url": "https://pubmed.ncbi.nlm.nih.gov/35360926/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35360926/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID35605042" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID35360926", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [ "M4" ], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Longitudinal hereditary CAA shows progressive vascular-reactivity change before clinical symptoms.", "what_it_does_not_show": "Mutant APP is upstream; no parallel CBF/cognitive change in presymptomatic carriers, and clinical timing does not equal pre-proteinopathy timing.", "confounders_present": [ "Mutant APP is upstream; no parallel CBF/cognitive change in presymptomatic carriers, and clinical timing does not equal pre-proteinopathy timing." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] } ], "verification_summary": { "load_bearing_claims_checked": 74, "verified": 74, "unverified": 0, "contradicted": 0, "note": "Verified attribution is distinct from mechanism truth or complete body access." }, "factual_issues_found": [], "cap_rules_applied": [ { "subclaim_id": "SC1", "cap": "Β", "cap_source": "universal", "triggered": true, "trigger_text_quoted": "Pure association evidence — however large, however replicated — cannot exceed Β.", "specific_trigger": "Midlife risks, imaging and mixed autopsy lesions predict dementia, with substantial age, region and assay dependence. The descriptive association claim is Β; intervention evidence is assigned to SC2 rather than silently changing SC1.", "resulting_ceiling": "Β" }, { "subclaim_id": "SC3", "cap": "Γ", "cap_source": "rubric", "triggered": true, "trigger_text_quoted": "Maximum if mechanism is biologically plausible, supported by in vitro or simplified animal paradigms, but no disease-relevant necessity is shown in vivo.", "specific_trigger": "GLUT1 and hypoperfusion accelerate pathology in genetically initiated APP models; vascular stress can induce endogenous cis P-tau and cognitive injury without AD tangles. Human BBB prediction is independent of measured protein markers, not a demonstrated path from BBB to proteins. APP/tau can instead injure vessels. No selective pre-onset human or non-protein-initiated natural set establishes the specific two-hit AD sequence. Mechanistic support warrants Γ.", "resulting_ceiling": "Γ" }, { "subclaim_id": "SC4", "cap": "Γ", "cap_source": "rubric", "triggered": true, "trigger_text_quoted": "Maximum if mechanism is biologically plausible, supported by in vitro or simplified animal paradigms, but no disease-relevant necessity is shown in vivo.", "specific_trigger": "Mixed dementia includes independent infarcts, amyloid/tau, Lewy pathology and variable inherited vascular routes. Multiple clinical prevention contrasts are null or endpoint-dependent; hypoperfusion has opposite protein effects across models. A universal sequence cannot be inferred from its conditional amplification successes.", "resulting_ceiling": "Γ" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Cerebrovascular dysfunction, including blood–brain barrier breakdown, pericyte loss and chronic hypoperfusion, initiates the Alzheimer amyloid and tau cascades and thereby dementia.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "SC2 endogenous injury and rescue plus human clinical trajectories form a convergent causal set; associative legs do not re-cap the set at Β. SC3 separately asks AD-specific initiation and remains Γ because genetically imposed proteins, injury-related tau and independent BBB prediction do not establish it. Model contribution is preserved rather than transferred to broad etiology.", "note": "Convergent lines are assessed as a set; one weak leg is not re-capped over the assembled case." } ], "boundary_check_BGD": [ { "subclaim_id": "SC1", "field_valid_perturbation_quote": "\n- Endogenous genetic deletion, suppression, or degron depletion of the proposed mediator in vivo\n- Selective pathway inhibition that changes onset/progression while preserving broader viability\n- Vagotomy-type natural experiment, only if confounding is rigorously controlled AND effect is disease-initiation relevant rather than merely associated", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "PMID30688979, PMID39819096, PMID40258956, PMID18614402, PMID9802273, PMID12374512, PMID27474376, PMID12742805, PMID25771249", "gamma_hard_rules_triggered": [ "In vitro toxicity or barrier networks do not establish human AD onset.", "Exogenous Aβ/tau challenge or APP overexpression does not establish spontaneous vascular-first etiology.", "Biomarker, MRI and fitted mediation changes are not incident AD-specific proteinopathy prevention.", "Presymptomatic inherited APP/PS1 perfusion change is not demonstrated pre-proteinopathy change." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Midlife risks, imaging and mixed autopsy lesions predict dementia, with substantial age, region and assay dependence. The descriptive association claim is Β; intervention evidence is assigned to SC2 rather than silently changing SC1.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC2", "field_valid_perturbation_quote": "\n- Endogenous genetic deletion, suppression, or degron depletion of the proposed mediator in vivo\n- Selective pathway inhibition that changes onset/progression while preserving broader viability\n- Vagotomy-type natural experiment, only if confounding is rigorously controlled AND effect is disease-initiation relevant rather than merely associated", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID21040844, PMID22622580, PMID31235908, PMID20944625, PMID35291561, PMID25730668, PMID36922879, PMID30742116, PMID35173711, PMID39621511, PMID27314529, PMID22170742, PMID20961660, PMID34078745, PMID34957486, PMID35915180, PMID30688979, PMID39819096, PMID40258956, PMID18614402, PMID9802273, PMID12374512, PMID31607143, PMID27474376, PMID12742805, PMID37863608, PMID25771249, PMID32732295, PMID36535904, PMID27604306, PMID41052971, PMID41529684", "gamma_hard_rules_triggered": [ "In vitro toxicity or barrier networks do not establish human AD onset.", "Exogenous Aβ/tau challenge or APP overexpression does not establish spontaneous vascular-first etiology.", "Biomarker, MRI and fitted mediation changes are not incident AD-specific proteinopathy prevention.", "Presymptomatic inherited APP/PS1 perfusion change is not demonstrated pre-proteinopathy change." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Adult pericyte ablation with PTN rescue, endogenous ischemia/cis-tau subtraction, rare genetic vasculopathies and randomized blood-pressure treatment converge on vascular cognitive injury across different failure structures. China incident dementia and PROGRESS stroke-linked cognitive benefit add human functional evidence. SPRINT primary dementia, preDIVA and INFINITY cognitive nulls limit universal therapeutic efficacy but do not negate the assembled causal set. Ζ applies to defined vascular injury, not an AD-specific initiating cascade or universal Η trajectory.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC3", "field_valid_perturbation_quote": "\n- Endogenous genetic deletion, suppression, or degron depletion of the proposed mediator in vivo\n- Selective pathway inhibition that changes onset/progression while preserving broader viability\n- Vagotomy-type natural experiment, only if confounding is rigorously controlled AND effect is disease-initiation relevant rather than merely associated", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "PMID21040844, PMID22622580, PMID31235908, PMID35291561, PMID25730668, PMID31221773, PMID38420777, PMID38475929, PMID36922879, PMID30742116, PMID35173711, PMID39621511, PMID27314529, PMID27050297, PMID19646974, PMID22170742, PMID34078745, PMID34957486, PMID35915180, PMID40258956, PMID41052971, PMID41529684", "gamma_hard_rules_triggered": [ "In vitro toxicity or barrier networks do not establish human AD onset.", "Exogenous Aβ/tau challenge or APP overexpression does not establish spontaneous vascular-first etiology.", "Biomarker, MRI and fitted mediation changes are not incident AD-specific proteinopathy prevention.", "Presymptomatic inherited APP/PS1 perfusion change is not demonstrated pre-proteinopathy change." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "GLUT1 and hypoperfusion accelerate pathology in genetically initiated APP models; vascular stress can induce endogenous cis P-tau and cognitive injury without AD tangles. Human BBB prediction is independent of measured protein markers, not a demonstrated path from BBB to proteins. APP/tau can instead injure vessels. No selective pre-onset human or non-protein-initiated natural set establishes the specific two-hit AD sequence. Mechanistic support warrants Γ.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC4", "field_valid_perturbation_quote": "\n- Endogenous genetic deletion, suppression, or degron depletion of the proposed mediator in vivo\n- Selective pathway inhibition that changes onset/progression while preserving broader viability\n- Vagotomy-type natural experiment, only if confounding is rigorously controlled AND effect is disease-initiation relevant rather than merely associated", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "PMID32732295, PMID36535904, PMID27604306", "gamma_hard_rules_triggered": [ "In vitro toxicity or barrier networks do not establish human AD onset.", "Exogenous Aβ/tau challenge or APP overexpression does not establish spontaneous vascular-first etiology.", "Biomarker, MRI and fitted mediation changes are not incident AD-specific proteinopathy prevention.", "Presymptomatic inherited APP/PS1 perfusion change is not demonstrated pre-proteinopathy change." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Mixed dementia includes independent infarcts, amyloid/tau, Lewy pathology and variable inherited vascular routes. Multiple clinical prevention contrasts are null or endpoint-dependent; hypoperfusion has opposite protein effects across models. A universal sequence cannot be inferred from its conditional amplification successes.", "ceiling_from_boundary_check": "Γ" } ], "thresholds_tested": [ { "subclaim_id": "SC1", "threshold": "Δ", "requirement_quoted": "Requires at least one genuine causal perturbation in a disease-relevant in vivo system, or equivalent human natural experiment that materially supports the mechanism.", "satisfied": "no", "supporting_evidence": [ "[31] SPRINT intensive blood-pressure treatment reduces MCI and combined cognitive endpoints.", "[32] SPRINT extended follow-up retains MCI/composite benefit.", "[33] Rural-China cluster randomization of 33995 adults in 326 villages lowers 48-month incident all-cause dementia with provider-led blood-pressure treatment.", "[34] HYVET-COG randomized antihypertensive treatment in adults over 80 and measured incident dementia.", "[35] Syst-Eur randomized antihypertensive therapy yields fewer clinical dementia cases over two years.", "[36] Syst-Eur extended follow-up reports continued dementia incidence difference including clinical AD cases.", "[38] preDIVA vascular-care cluster trial shows no overall incident dementia or disability reduction.", "[39] PROGRESS reduces cognitive decline with perindopril-based therapy after stroke/TIA; dementia benefit concentrates with recurrent stroke.", "[41] FINGER multidomain intervention improves a neuropsychological composite over two years." ], "what_would_cross_it": "Keep prediction as descriptive and test intervention in a distinct causal subclaim." }, { "subclaim_id": "SC2", "threshold": "Δ", "requirement_quoted": "Requires at least one genuine causal perturbation in a disease-relevant in vivo system, or equivalent human natural experiment that materially supports the mechanism.", "satisfied": "yes", "supporting_evidence": [ "[1] Pdgfrb-deficient adult mice develop vascular dysfunction before general neuronal injury.", "[2] APOE4 activates pericyte CypA-MMP9 and genetic or pharmacological pathway subtraction protects BBB.", "[4] Inducible pericyte ablation causes flow/BBB deficits and neuronal/cognitive loss; physiological PTN infusion preserves neurons and cognition despite persistent circulatory defects.", "[5] Developmental pericyte coverage determines BBB permeability before astrocyte development.", "[11] At 10–12 months Debio-025 improves APOE4 BBB and prevents further neuronal loss and cognitive decline without changing Aβ pathology.", "[12] Endothelial GLUT1 loss causes early BBB failure; combined Slc2a1 deficiency/APP increases later Aβ and NeuN loss; GLUT1/LRP1 re-expression reduces Aβ.", "[16] Early astrocytic APOE4 removal in 5xFAD reduces vascular injury despite increased vascular amyloid.", "[17] Anti-Ly6G relieves neutrophil capillary stalls and rapidly improves flow and memory in APP/PS1 and 5xFAD mice.", "[19] Microinfarcts produce sex-dependent cognitive injury while decreasing plaques without changing soluble Aβ in APP/PS1 mice.", "[20] BCAS performed two months after tau seeding reduces accumulated tau while worsening white matter; NACC remote stroke associates with less AD pathology.", "[21] Hypoperfusion in APP23 exacerbates amyloid/cognitive abnormalities and galantamine ameliorates phenotypes.", "[24] BCAS augments vascular amyloid and microinfarcts in CAA mice; human postmortem observations agree.", "[25] Chronic hypoperfusion produces white-matter injury and selective spatial working-memory deficits.", "[26] BCAS induces endogenous cis P-tau; cis antibody and DAPK1 loss preserve white matter and executive function; separate htau mice respond to treatment.", "[28] Astrocytic APOE4 deletion ameliorates BBB impairment relative to matched APOE3 designs.", "[29] Liver-only APOE4 causes vascular/synaptic/cognitive abnormalities and exacerbates APP-model amyloid; APOE3 plasma improves aged phenotypes.", "[31] SPRINT intensive blood-pressure treatment reduces MCI and combined cognitive endpoints.", "[32] SPRINT extended follow-up retains MCI/composite benefit.", "[33] Rural-China cluster randomization of 33995 adults in 326 villages lowers 48-month incident all-cause dementia with provider-led blood-pressure treatment.", "[34] HYVET-COG randomized antihypertensive treatment in adults over 80 and measured incident dementia.", "[35] Syst-Eur randomized antihypertensive therapy yields fewer clinical dementia cases over two years.", "[36] Syst-Eur extended follow-up reports continued dementia incidence difference including clinical AD cases.", "[37] INFINITY lowers white-matter hyperintensity accumulation with intensive ambulatory blood-pressure control.", "[38] preDIVA vascular-care cluster trial shows no overall incident dementia or disability reduction.", "[39] PROGRESS reduces cognitive decline with perindopril-based therapy after stroke/TIA; dementia benefit concentrates with recurrent stroke.", "[40] TREAT-SVD crossover compares cerebrovascular reactivity under three drugs; CADASIL shows differential physiological effects.", "[41] FINGER multidomain intervention improves a neuropsychological composite over two years.", "[56] NOTCH3 variants produce heterogeneous SVD/vascular phenotypes in population carriers.", "[57] NOTCH3 domain location stratifies CADASIL stroke/SVD risk across clinical and population samples.", "[58] TREX1 families develop systemic retinal/cerebral vasculopathy with cognitive decline in a substantial subset.", "[67] LRP1-targeted transport therapy clears amyloid and improves cognition in AD models.", "[68] Endothelial ANGPT2 loss reduces amyloid, while overexpression worsens BBB/inflammatory/memory phenotypes in 5xFAD." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ε", "requirement_quoted": "Requires causal support in a defined context, but with clear restriction by subtype, disease stage, model, or tissue.\n\nUse Ε when there is a real causal contribution, but generalization to the entire disease class fails.", "satisfied": "yes", "supporting_evidence": [ "[1] Pdgfrb-deficient adult mice develop vascular dysfunction before general neuronal injury.", "[2] APOE4 activates pericyte CypA-MMP9 and genetic or pharmacological pathway subtraction protects BBB.", "[4] Inducible pericyte ablation causes flow/BBB deficits and neuronal/cognitive loss; physiological PTN infusion preserves neurons and cognition despite persistent circulatory defects.", "[5] Developmental pericyte coverage determines BBB permeability before astrocyte development.", "[11] At 10–12 months Debio-025 improves APOE4 BBB and prevents further neuronal loss and cognitive decline without changing Aβ pathology.", "[12] Endothelial GLUT1 loss causes early BBB failure; combined Slc2a1 deficiency/APP increases later Aβ and NeuN loss; GLUT1/LRP1 re-expression reduces Aβ.", "[16] Early astrocytic APOE4 removal in 5xFAD reduces vascular injury despite increased vascular amyloid.", "[17] Anti-Ly6G relieves neutrophil capillary stalls and rapidly improves flow and memory in APP/PS1 and 5xFAD mice.", "[19] Microinfarcts produce sex-dependent cognitive injury while decreasing plaques without changing soluble Aβ in APP/PS1 mice.", "[20] BCAS performed two months after tau seeding reduces accumulated tau while worsening white matter; NACC remote stroke associates with less AD pathology.", "[21] Hypoperfusion in APP23 exacerbates amyloid/cognitive abnormalities and galantamine ameliorates phenotypes.", "[24] BCAS augments vascular amyloid and microinfarcts in CAA mice; human postmortem observations agree.", "[25] Chronic hypoperfusion produces white-matter injury and selective spatial working-memory deficits.", "[26] BCAS induces endogenous cis P-tau; cis antibody and DAPK1 loss preserve white matter and executive function; separate htau mice respond to treatment.", "[28] Astrocytic APOE4 deletion ameliorates BBB impairment relative to matched APOE3 designs.", "[29] Liver-only APOE4 causes vascular/synaptic/cognitive abnormalities and exacerbates APP-model amyloid; APOE3 plasma improves aged phenotypes.", "[31] SPRINT intensive blood-pressure treatment reduces MCI and combined cognitive endpoints.", "[32] SPRINT extended follow-up retains MCI/composite benefit.", "[33] Rural-China cluster randomization of 33995 adults in 326 villages lowers 48-month incident all-cause dementia with provider-led blood-pressure treatment.", "[34] HYVET-COG randomized antihypertensive treatment in adults over 80 and measured incident dementia.", "[35] Syst-Eur randomized antihypertensive therapy yields fewer clinical dementia cases over two years.", "[36] Syst-Eur extended follow-up reports continued dementia incidence difference including clinical AD cases.", "[37] INFINITY lowers white-matter hyperintensity accumulation with intensive ambulatory blood-pressure control.", "[38] preDIVA vascular-care cluster trial shows no overall incident dementia or disability reduction.", "[39] PROGRESS reduces cognitive decline with perindopril-based therapy after stroke/TIA; dementia benefit concentrates with recurrent stroke.", "[40] TREAT-SVD crossover compares cerebrovascular reactivity under three drugs; CADASIL shows differential physiological effects.", "[41] FINGER multidomain intervention improves a neuropsychological composite over two years.", "[56] NOTCH3 variants produce heterogeneous SVD/vascular phenotypes in population carriers.", "[57] NOTCH3 domain location stratifies CADASIL stroke/SVD risk across clinical and population samples.", "[58] TREX1 families develop systemic retinal/cerebral vasculopathy with cognitive decline in a substantial subset.", "[67] LRP1-targeted transport therapy clears amyloid and improves cognition in AD models.", "[68] Endothelial ANGPT2 loss reduces amyloid, while overexpression worsens BBB/inflammatory/memory phenotypes in 5xFAD." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Multiple independent causal lines in vivo\n- Replication across at least two relevant systems\n- Narrowing of major alternative models", "satisfied": "yes", "supporting_evidence": [ "[1] Pdgfrb-deficient adult mice develop vascular dysfunction before general neuronal injury.", "[2] APOE4 activates pericyte CypA-MMP9 and genetic or pharmacological pathway subtraction protects BBB.", "[4] Inducible pericyte ablation causes flow/BBB deficits and neuronal/cognitive loss; physiological PTN infusion preserves neurons and cognition despite persistent circulatory defects.", "[5] Developmental pericyte coverage determines BBB permeability before astrocyte development.", "[11] At 10–12 months Debio-025 improves APOE4 BBB and prevents further neuronal loss and cognitive decline without changing Aβ pathology.", "[12] Endothelial GLUT1 loss causes early BBB failure; combined Slc2a1 deficiency/APP increases later Aβ and NeuN loss; GLUT1/LRP1 re-expression reduces Aβ.", "[16] Early astrocytic APOE4 removal in 5xFAD reduces vascular injury despite increased vascular amyloid.", "[17] Anti-Ly6G relieves neutrophil capillary stalls and rapidly improves flow and memory in APP/PS1 and 5xFAD mice.", "[19] Microinfarcts produce sex-dependent cognitive injury while decreasing plaques without changing soluble Aβ in APP/PS1 mice.", "[20] BCAS performed two months after tau seeding reduces accumulated tau while worsening white matter; NACC remote stroke associates with less AD pathology.", "[21] Hypoperfusion in APP23 exacerbates amyloid/cognitive abnormalities and galantamine ameliorates phenotypes.", "[24] BCAS augments vascular amyloid and microinfarcts in CAA mice; human postmortem observations agree.", "[25] Chronic hypoperfusion produces white-matter injury and selective spatial working-memory deficits.", "[26] BCAS induces endogenous cis P-tau; cis antibody and DAPK1 loss preserve white matter and executive function; separate htau mice respond to treatment.", "[28] Astrocytic APOE4 deletion ameliorates BBB impairment relative to matched APOE3 designs.", "[29] Liver-only APOE4 causes vascular/synaptic/cognitive abnormalities and exacerbates APP-model amyloid; APOE3 plasma improves aged phenotypes.", "[31] SPRINT intensive blood-pressure treatment reduces MCI and combined cognitive endpoints.", "[32] SPRINT extended follow-up retains MCI/composite benefit.", "[33] Rural-China cluster randomization of 33995 adults in 326 villages lowers 48-month incident all-cause dementia with provider-led blood-pressure treatment.", "[34] HYVET-COG randomized antihypertensive treatment in adults over 80 and measured incident dementia.", "[35] Syst-Eur randomized antihypertensive therapy yields fewer clinical dementia cases over two years.", "[36] Syst-Eur extended follow-up reports continued dementia incidence difference including clinical AD cases.", "[37] INFINITY lowers white-matter hyperintensity accumulation with intensive ambulatory blood-pressure control.", "[38] preDIVA vascular-care cluster trial shows no overall incident dementia or disability reduction.", "[39] PROGRESS reduces cognitive decline with perindopril-based therapy after stroke/TIA; dementia benefit concentrates with recurrent stroke.", "[40] TREAT-SVD crossover compares cerebrovascular reactivity under three drugs; CADASIL shows differential physiological effects.", "[41] FINGER multidomain intervention improves a neuropsychological composite over two years.", "[56] NOTCH3 variants produce heterogeneous SVD/vascular phenotypes in population carriers.", "[57] NOTCH3 domain location stratifies CADASIL stroke/SVD risk across clinical and population samples.", "[58] TREX1 families develop systemic retinal/cerebral vasculopathy with cognitive decline in a substantial subset.", "[67] LRP1-targeted transport therapy clears amyloid and improves cognition in AD models.", "[68] Endothelial ANGPT2 loss reduces amyloid, while overexpression worsens BBB/inflammatory/memory phenotypes in 5xFAD." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Η", "requirement_quoted": "Requires:\n- Strong convergent causal evidence across systems\n- Intervention-sensitive change in trajectory\n- No major unresolved contradiction about whether the mechanism is upstream versus downstream", "satisfied": "no", "supporting_evidence": [ "[1] Pdgfrb-deficient adult mice develop vascular dysfunction before general neuronal injury.", "[2] APOE4 activates pericyte CypA-MMP9 and genetic or pharmacological pathway subtraction protects BBB.", "[4] Inducible pericyte ablation causes flow/BBB deficits and neuronal/cognitive loss; physiological PTN infusion preserves neurons and cognition despite persistent circulatory defects.", "[5] Developmental pericyte coverage determines BBB permeability before astrocyte development.", "[11] At 10–12 months Debio-025 improves APOE4 BBB and prevents further neuronal loss and cognitive decline without changing Aβ pathology.", "[12] Endothelial GLUT1 loss causes early BBB failure; combined Slc2a1 deficiency/APP increases later Aβ and NeuN loss; GLUT1/LRP1 re-expression reduces Aβ.", "[16] Early astrocytic APOE4 removal in 5xFAD reduces vascular injury despite increased vascular amyloid.", "[17] Anti-Ly6G relieves neutrophil capillary stalls and rapidly improves flow and memory in APP/PS1 and 5xFAD mice.", "[19] Microinfarcts produce sex-dependent cognitive injury while decreasing plaques without changing soluble Aβ in APP/PS1 mice.", "[20] BCAS performed two months after tau seeding reduces accumulated tau while worsening white matter; NACC remote stroke associates with less AD pathology.", "[21] Hypoperfusion in APP23 exacerbates amyloid/cognitive abnormalities and galantamine ameliorates phenotypes.", "[24] BCAS augments vascular amyloid and microinfarcts in CAA mice; human postmortem observations agree.", "[25] Chronic hypoperfusion produces white-matter injury and selective spatial working-memory deficits.", "[26] BCAS induces endogenous cis P-tau; cis antibody and DAPK1 loss preserve white matter and executive function; separate htau mice respond to treatment.", "[28] Astrocytic APOE4 deletion ameliorates BBB impairment relative to matched APOE3 designs.", "[29] Liver-only APOE4 causes vascular/synaptic/cognitive abnormalities and exacerbates APP-model amyloid; APOE3 plasma improves aged phenotypes.", "[31] SPRINT intensive blood-pressure treatment reduces MCI and combined cognitive endpoints.", "[32] SPRINT extended follow-up retains MCI/composite benefit.", "[33] Rural-China cluster randomization of 33995 adults in 326 villages lowers 48-month incident all-cause dementia with provider-led blood-pressure treatment.", "[34] HYVET-COG randomized antihypertensive treatment in adults over 80 and measured incident dementia.", "[35] Syst-Eur randomized antihypertensive therapy yields fewer clinical dementia cases over two years.", "[36] Syst-Eur extended follow-up reports continued dementia incidence difference including clinical AD cases.", "[37] INFINITY lowers white-matter hyperintensity accumulation with intensive ambulatory blood-pressure control.", "[38] preDIVA vascular-care cluster trial shows no overall incident dementia or disability reduction.", "[39] PROGRESS reduces cognitive decline with perindopril-based therapy after stroke/TIA; dementia benefit concentrates with recurrent stroke.", "[40] TREAT-SVD crossover compares cerebrovascular reactivity under three drugs; CADASIL shows differential physiological effects.", "[41] FINGER multidomain intervention improves a neuropsychological composite over two years.", "[56] NOTCH3 variants produce heterogeneous SVD/vascular phenotypes in population carriers.", "[57] NOTCH3 domain location stratifies CADASIL stroke/SVD risk across clinical and population samples.", "[58] TREX1 families develop systemic retinal/cerebral vasculopathy with cognitive decline in a substantial subset.", "[67] LRP1-targeted transport therapy clears amyloid and improves cognition in AD models.", "[68] Endothelial ANGPT2 loss reduces amyloid, while overexpression worsens BBB/inflammatory/memory phenotypes in 5xFAD." ], "what_would_cross_it": "Reconcile late-life prevention nulls with adequate exposure and baseline risk, demonstrate sustained functional trajectories and replicate mechanistically matched vascular restoration." }, { "subclaim_id": "SC3", "threshold": "Δ", "requirement_quoted": "Requires at least one genuine causal perturbation in a disease-relevant in vivo system, or equivalent human natural experiment that materially supports the mechanism.", "satisfied": "no", "supporting_evidence": [ "[1] Pdgfrb-deficient adult mice develop vascular dysfunction before general neuronal injury.", "[2] APOE4 activates pericyte CypA-MMP9 and genetic or pharmacological pathway subtraction protects BBB.", "[4] Inducible pericyte ablation causes flow/BBB deficits and neuronal/cognitive loss; physiological PTN infusion preserves neurons and cognition despite persistent circulatory defects.", "[11] At 10–12 months Debio-025 improves APOE4 BBB and prevents further neuronal loss and cognitive decline without changing Aβ pathology.", "[12] Endothelial GLUT1 loss causes early BBB failure; combined Slc2a1 deficiency/APP increases later Aβ and NeuN loss; GLUT1/LRP1 re-expression reduces Aβ.", "[13] Applied Aβ constricts human/rat capillaries; APP knock-in mice show endogenous plaque-region pericyte constriction; CNP reverses acute constriction.", "[14] AD-related tau peptides cause endothelial calcium and vasodilatory dysfunction.", "[15] Aβ exposure injures pericytes and endothelial capillary structure.", "[16] Early astrocytic APOE4 removal in 5xFAD reduces vascular injury despite increased vascular amyloid.", "[17] Anti-Ly6G relieves neutrophil capillary stalls and rapidly improves flow and memory in APP/PS1 and 5xFAD mice.", "[19] Microinfarcts produce sex-dependent cognitive injury while decreasing plaques without changing soluble Aβ in APP/PS1 mice.", "[20] BCAS performed two months after tau seeding reduces accumulated tau while worsening white matter; NACC remote stroke associates with less AD pathology.", "[21] Hypoperfusion in APP23 exacerbates amyloid/cognitive abnormalities and galantamine ameliorates phenotypes.", "[22] Unilateral occlusion raises selected phospho-tau epitopes in aged wild-type/3xTg mice without changing Aβ42.", "[23] BCAS in APP-transgenic mice increases intracellular and fibrillar Aβ deposits.", "[24] BCAS augments vascular amyloid and microinfarcts in CAA mice; human postmortem observations agree.", "[26] BCAS induces endogenous cis P-tau; cis antibody and DAPK1 loss preserve white matter and executive function; separate htau mice respond to treatment.", "[28] Astrocytic APOE4 deletion ameliorates BBB impairment relative to matched APOE3 designs.", "[29] Liver-only APOE4 causes vascular/synaptic/cognitive abnormalities and exacerbates APP-model amyloid; APOE3 plasma improves aged phenotypes.", "[33] Rural-China cluster randomization of 33995 adults in 326 villages lowers 48-month incident all-cause dementia with provider-led blood-pressure treatment.", "[67] LRP1-targeted transport therapy clears amyloid and improves cognition in AD models.", "[68] Endothelial ANGPT2 loss reduces amyloid, while overexpression worsens BBB/inflammatory/memory phenotypes in 5xFAD." ], "what_would_cross_it": "Before proteinopathy, selectively preserve BBB/pericyte/flow function in a prospectively defined non-APP-initiated setting and show prevention of new amyloid/tau plus cognitive disease, with reverse-direction protein intervention and mediator reinstatement controls." }, { "subclaim_id": "SC4", "threshold": "Δ", "requirement_quoted": "Requires at least one genuine causal perturbation in a disease-relevant in vivo system, or equivalent human natural experiment that materially supports the mechanism.", "satisfied": "no", "supporting_evidence": [ "[56] NOTCH3 variants produce heterogeneous SVD/vascular phenotypes in population carriers.", "[57] NOTCH3 domain location stratifies CADASIL stroke/SVD risk across clinical and population samples.", "[58] TREX1 families develop systemic retinal/cerebral vasculopathy with cognitive decline in a substantial subset." ], "what_would_cross_it": "Map baseline vascular/protein/genetic strata prospectively and establish the ordering in independent disease-separated populations rather than pooled late-life syndromes." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "PTN rescues neurons and cognition without restoring the ablated-pericyte flow/BBB defects; PTN depletion alone is insufficient for neuron death.", "Debio-025 improves the APOE4 component while Aβ remains unchanged and 5xFAD outcomes do not fully reach wild type.", "GLUT1 endothelial versus astrocytic deletion separates barrier mechanisms.", "Aβ scrambled-sequence and wild-type/cerebellar comparisons constrain protein-to-capillary injury.", "Hypoperfusion after tau seeding reduces tau; microinfarcts can reduce plaques while injuring cognition.", "VaD human brains in cis-tau work lack obvious NFTs.", "INFINITY MRI benefit coexists with cognitive/gait nulls; preDIVA and HYVET primary dementia contrasts are null.", "SPRINT primary probable-dementia contrasts are nonsignificant despite MCI/composite benefit.", "NOTCH3 population carriers can lack MRI disease; late-life risk effects differ from midlife." ], "note": "Define vascular lesion, region, age, genotype, measured protein baseline and exposure before outcomes. Severe ablation, carotid surgery and APP mutations are not ordinary late-life sporadic onset. No post-hoc responder subset is used. Different BBB assays, retina versus brain, clinical AD versus biomarker AD and clinical presymptomatic versus molecular pre-onset are kept separate." }, "falsification_patterns_met": [ { "pattern": "The nominal causal ordering can run in reverse or fail to generate proteins", "evidence": "Aβ/tau injure vessels, BCAS after tau seeding lowers accumulation and pure VaD cis-tau brains lack overt NFTs.", "downgrade_applied": false }, { "pattern": "Engaged vascular benefit can decouple from amyloid", "evidence": "Debio-025 neuronal/cognitive protection occurs without Aβ change, and PTN preserves neurons despite persistent circulatory defects.", "downgrade_applied": false } ], "pitfalls_flagged": [ { "pitfall": "Retracted pericyte studies inflate convergence", "where": "PMID24336108 and PMID29400711 excluded with publisher notices." }, { "pitfall": "All-cause dementia prevention becomes AD molecular prevention", "where": "China trial and stroke-related PROGRESS outcomes." }, { "pitfall": "Thousands of vessels counted as independent humans", "where": "Nortley human biopsy and mouse sampling." }, { "pitfall": "Statistical mediation establishes temporal causality", "where": "EPAD and VEGF path models." }, { "pitfall": "Presymptomatic inherited disease means vascular-first", "where": "APP/PS1 and hereditary CAA." }, { "pitfall": "Provider Moderate initiation label becomes framework score", "where": "Consensus broad table unsupported human initiation claim rejected." }, { "pitfall": "Partial body retrieval called whole-paper validation", "where": "Seven selected Results bodies; clinical papers abstract/status only." } ], "causal_tally_audit": { "tally_claimed_by_document": 37, "tally_after_audit": 37, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "Shared cohorts, experimental platforms, transgenic lineages and repeated outcomes do not constitute fully independent causal lines." ] }, "steelman": { "case_one_rung_higher": "The strongest higher-level case combines early endothelial GLUT1 deficiency, clearance rescue, APOE4 barrier prediction and incident dementia prevention. These establish more than passive vascular association, and SC2 receives Ζ. APP already precedes the model vascular insult, independent human BBB prediction does not lead to proteins, and clinical endpoints are not molecular onset, so the same set does not cross SC3 Δ.", "case_one_rung_lower": "A Β-only account misses adult pericyte loss/rescue, endogenous ischemic mediator subtraction, human slice perturbation and randomized prevention. The AD-initiation chain has credible mechanistic support even though primacy is unestablished.", "which_rejected": "Γ is retained for the distinguishing AD-specific claim, with Ζ for defined vascular cognitive injury. Neither vascular injury as passive response nor universal vascular-first AD fits the full evidence.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: Enroll baseline vascular-risk and molecularly amyloid/tau-negative strata, then selectively correct the implicated endothelial/pericyte lesion with verified brain engagement. Combine with orthogonal protein-directed comparison and a non-APP-initiated endogenous model using mediator reinstatement. Follow new biomarker conversion, adjudicated disease and cognitive trajectory, with independent replication." }, "final_score": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "69 primary reports with 7 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "Preregistered scope-matched SC3 gives Γ. Vascular cognitive injury reaches Ζ through convergent endogenous perturbations, inherited vasculopathies and randomized human vascular prevention. Those successes do not establish the distinguishing vascular-first AD amyloid/tau sequence. Protein-first injury, rescue without amyloid change, and opposite tau responses remain discriminators." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": 5, "derivation": "In AD the vascular pathway can amplify proteinopathy and cognitive injury; removing it can improve function without removing proteins. Defined vascular injury can independently initiate non-AD cognitive disease. No common rate-limiting AD initiating step is demonstrated.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "2025 incident dementia prevention and 2026 endothelial ANGPT2 model perturbations refine clinical contribution and molecular amplification. No currently recruiting decisive onset trial is asserted.", "justification": "2025 incident dementia prevention and 2026 endothelial ANGPT2 model perturbations refine clinical contribution and molecular amplification. No currently recruiting decisive onset trial is asserted." }, "stability": { "value": "Stable", "trigger": "No verified named pending result is identified as likely to change SC3 imminently; pre-onset selective molecular prevention would do so.", "justification": "No verified named pending result is identified as likely to change SC3 imminently; pre-onset selective molecular prevention would do so." }, "divergence": { "implied_level": null, "implied_level_basis": "No single field-implied level is defensible from conflicting framings.", "assessed_level": "Γ", "gap_in_rungs": null, "value": "Contested", "justification": "No manufactured field consensus or arithmetic gap." }, "calibration_note": "M/S/D never modify HSEF level or confidence." }, "change_record": { "applies": false, "prior_level": "Ranking categorical verdict visible; no prior letter used as a target", "prior_confidence": null, "prior_source": null, "derived_before_consulting_prior": false, "new_level": "Γ", "direction": "newly assigned", "what_moved_it": "Fresh primary evidence appraisal; not blinded.", "divergence_from_other_reviewers": null }, "proposed_decisive_experiments": [ { "name": "Registered boundary experiment", "experiment": "Enroll baseline vascular-risk and molecularly amyloid/tau-negative strata, then selectively correct the implicated endothelial/pericyte lesion with verified brain engagement. Combine with orthogonal protein-directed comparison and a non-APP-initiated endogenous model using mediator reinstatement. Follow new biomarker conversion, adjudicated disease and cognitive trajectory, with independent replication.", "readout": "Incident amyloid/tau conversion, neuronal/white-matter integrity, dementia subtype and sustained cognition", "critical_control": "Baseline genotype/proteins, age, stroke, vascular lesion, BBB assay specificity, general hemodynamics, bundled care, mortality and attrition", "supporting_result": "Engaged vascular preservation prevents new AD-specific proteins and disease, and matched lesion reinstatement reverses that protection in predicted strata", "falsifying_result": "Adequate early vascular correction preserves cognition without changing protein onset, or protein-directed correction prevents vascular injury instead" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Distinguish clinical presymptomatic from pre-proteinopathy timing.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Test AD-specific conversion after engaged vascular prevention, not merely all-cause dementia.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Replicate pericyte/GLUT1 pathways on independent platforms after report-specific retractions.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Separate pericyte trophic support from flow and barrier failure with factorial rescues.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Reconcile increased cis/phospho-tau with reduced seeded tau under hypoperfusion.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 6", "statement": "Map brain region, sex, genotype and baseline vascular burden prospectively.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 7", "statement": "Validate BBB assay identity and keep retinal proxies separate.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 8", "statement": "Resolve clinical prevention heterogeneity, adequate exposure and selective mediation.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-07", "reviewer": "Codex", "evidence_base_note": "69 primary reports; literature cutoff 2026-10-07; source examination UTC date 2026-10-07; bounded critical review, not exhaustive systematic review.", "literature_tools_available": true, "literature_tools_note": "Life Sciences Literature PubMed/Entrez; attempted Europe PMC XML and successful public NCBI PMC direct HTTPS access are separately logged. Signed-in Consensus browser discovery and targeted indexed full-text checks are reconciled with original sections; failed matches and source substitutions remain explicit. Zero Consensus API calls. SciSpace discovery was also used; matched primary leads were resolved to original records before counting. See scispace-leads.json.", "skill_version": "5.3", "validator_run": "exact archived v5.3 validator 2.3; see validator.txt", "validator_warnings_addressed": "Phenomenon entry was restated as the preregistered causal claim. No real phenomenon is labelled refuted; warning is explicitly justified.", "consensus_consistency_audit": "2026-10-09; supplementary provenance/source reconciliation; original grading retained; prior grades visible." }, "is_calibration_entry": { "value": false, "entry_role": "not_calibration", "blind_graded": null, "completed_blinded_calibration": false, "expected_band_sealed_at": "", "target_sha256": "", "target_authorship": "not applicable", "target_author_saw_review": null, "future_run_status": "not prepared", "unblinded_reason": "Ranking categorical verdict and index guidance were visible. No completed blinded calibration claimed." }, "upper_ladder_check": { "final_level_below_zeta": true, "equivalents_considered": [ { "kind": "mendelian_randomization", "available": false, "why_not_sufficient": "Randomized China, PROGRESS, SPRINT and other clinical endpoints and NOTCH3/TREX1 natural experiments are live upper-level evidence for vascular injury. No unethical randomized induction of human vascular damage is required. Existing convergent instruments reach SC2 Ζ but neither incident all-cause dementia nor familial SVD tests AD-specific proteinopathy initiation. Molecular sequencing and selective engagement are the remaining scope-specific requirements." }, { "kind": "natural_experiment", "available": true, "why_not_sufficient": "Randomized China, PROGRESS, SPRINT and other clinical endpoints and NOTCH3/TREX1 natural experiments are live upper-level evidence for vascular injury. No unethical randomized induction of human vascular damage is required. Existing convergent instruments reach SC2 Ζ but neither incident all-cause dementia nor familial SVD tests AD-specific proteinopathy initiation. Molecular sequencing and selective engagement are the remaining scope-specific requirements." }, { "kind": "dose_response_across_populations", "available": true, "why_not_sufficient": "Randomized China, PROGRESS, SPRINT and other clinical endpoints and NOTCH3/TREX1 natural experiments are live upper-level evidence for vascular injury. No unethical randomized induction of human vascular damage is required. Existing convergent instruments reach SC2 Ζ but neither incident all-cause dementia nor familial SVD tests AD-specific proteinopathy initiation. Molecular sequencing and selective engagement are the remaining scope-specific requirements." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Randomized China, PROGRESS, SPRINT and other clinical endpoints and NOTCH3/TREX1 natural experiments are live upper-level evidence for vascular injury. No unethical randomized induction of human vascular damage is required. Existing convergent instruments reach SC2 Ζ but neither incident all-cause dementia nor familial SVD tests AD-specific proteinopathy initiation. Molecular sequencing and selective engagement are the remaining scope-specific requirements." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": true, "why_not_sufficient": "Randomized China, PROGRESS, SPRINT and other clinical endpoints and NOTCH3/TREX1 natural experiments are live upper-level evidence for vascular injury. No unethical randomized induction of human vascular damage is required. Existing convergent instruments reach SC2 Ζ but neither incident all-cause dementia nor familial SVD tests AD-specific proteinopathy initiation. Molecular sequencing and selective engagement are the remaining scope-specific requirements." } ], "convergence_present": true, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 69, "claims_total": 74, "claims_verified": 74, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 69, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "Pdgfrb-deficient adult mice develop vascular dysfunction before general neuronal injury. Engineered pericyte loss does not establish AD-specific proteinopathy onset; linked correction details unexamined.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C2", "text": "APOE4 activates pericyte CypA-MMP9 and genetic or pharmacological pathway subtraction protects BBB. APOE affects multiple compartments; BBB protection is not spontaneous human AD prevention; correction details unexamined.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C3", "text": "Pericyte-deficient mice lose neurovascular coupling and develop oxygen/metabolic stress. Shared Pdgfrb platform and physiology do not independently prove amyloid/tau initiation.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C4", "text": "Inducible pericyte ablation causes flow/BBB deficits and neuronal/cognitive loss; physiological PTN infusion preserves neurons and cognition despite persistent circulatory defects. Severe acute dual-promoter ablation is not gradual human disease; amyloid/tau initiation is not tested; PTN depletion alone does not kill neurons.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph2, 1:RESULTS:paragraph3, 1:RESULTS:paragraph4, 1:RESULTS:paragraph10, 1:RESULTS:paragraph12, 1:RESULTS:paragraph13. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C5", "text": "Developmental pericyte coverage determines BBB permeability before astrocyte development. Developmental barrier formation is not adult AD etiology or clinical trajectory.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C6", "text": "Human APOE4-associated BBB disruption and baseline pericyte-injury marker predict subsequent cognitive decline independently of measured amyloid/tau. No vascular manipulation; cognitively normal APOE4 participants can already have amyloid; baseline marker prediction is not molecular primacy.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Introductory Paragraph:paragraph1, 0:Introductory Paragraph:paragraph3, 0:Introductory Paragraph:paragraph5, 0:Introductory Paragraph:paragraph6, 0:Introductory Paragraph:paragraph9. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C7", "text": "Early cognitive dysfunction associates with hippocampal capillary damage irrespective of measured amyloid/tau biomarkers. Cross-sectional independence does not establish a cascade from vascular injury to proteins.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C8", "text": "Hippocampal BBB permeability increases with aging and mild cognitive impairment. Imaging association lacks a selective counterfactual or AD-specific initiating event.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C9", "text": "APOE4 postmortem brain has pericyte loss and CypA pathway activation. Terminal tissue cannot order the initiating lesions; genotype is pleiotropic.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C10", "text": "Human 3D BBB APOE4 models show NFAT-associated cerebral amyloid angiopathy with inhibitor sensitivity. Culture and accompanying models do not establish BBB failure preceding all proteinopathy; correction details unexamined.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C11", "text": "At 10–12 months Debio-025 improves APOE4 BBB and prevents further neuronal loss and cognitive decline without changing Aβ pathology. Treatment modifies the APOE4 increment rather than restoring all 5xFAD deficits to wild type; APP mutations precede the vascular insult.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Results:paragraph11, 0:Results:paragraph12, 0:Results:paragraph15, 0:Results:paragraph16, 0:Results:paragraph18. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C12", "text": "Endothelial GLUT1 loss causes early BBB failure; combined Slc2a1 deficiency/APP increases later Aβ and NeuN loss; GLUT1/LRP1 re-expression reduces Aβ. APP overexpression is present from development; late acceleration and regional clearance rescue are not initiation of spontaneous human AD or whole-animal cognitive reversal.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph9, 1:Results:paragraph11, 1:Results:paragraph12, 1:Results:paragraph18, 1:Results:paragraph22, 1:Results:paragraph23. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C13", "text": "Applied Aβ constricts human/rat capillaries; APP knock-in mice show endogenous plaque-region pericyte constriction; CNP reverses acute constriction. Small human biopsy and mouse samples; thousands of vessel measurements are not independent patients; modeled flow reduction is not measured human flow.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Amyloid β constricts human capillaries at pericytes, 2:Pericytes constrict capillaries in human cognitive decline patients with Aβ deposition, 4:Pericytes constrict capillaries in vivo in AD mice, 6:Reversal of Aβ-evoked capillary constriction. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C14", "text": "AD-related tau peptides cause endothelial calcium and vasodilatory dysfunction. Peptide exposure demonstrates a possible protein-to-vessel route, not its prevalence in spontaneous AD.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C15", "text": "Aβ exposure injures pericytes and endothelial capillary structure. Exogenous challenge establishes capacity, not ordinary endogenous initiating direction.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C16", "text": "Early astrocytic APOE4 removal in 5xFAD reduces vascular injury despite increased vascular amyloid. Genetic APP proteinopathy persists and cell-specific APOE effects are not a vessel-only intervention.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C17", "text": "Anti-Ly6G relieves neutrophil capillary stalls and rapidly improves flow and memory in APP/PS1 and 5xFAD mice. Acute functional rescue occurs after engineered proteinopathy and is not prevention of AD onset.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C18", "text": "Two human frontal-cortex cohorts show preserved pericytes and increased capillary density in AD. Regional postmortem counterexample does not rule out hippocampal or functional vascular injury.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 18 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C19", "text": "Microinfarcts produce sex-dependent cognitive injury while decreasing plaques without changing soluble Aβ in APP/PS1 mice. Surgical infarcts and strain/sex differences constrain generalization; lower plaques are not lower overall injury.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C20", "text": "BCAS performed two months after tau seeding reduces accumulated tau while worsening white matter; NACC remote stroke associates with less AD pathology. Seeded tau is imposed first; CTSD colocalization/upregulation is a candidate mediator without necessity subtraction; autopsy associations retain survival and diagnosis biases.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph0, 2:Results:paragraph11, 2:Results:paragraph13, 2:Results:paragraph14, 2:Results:paragraph18. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C21", "text": "Hypoperfusion in APP23 exacerbates amyloid/cognitive abnormalities and galantamine ameliorates phenotypes. APP is genetically upstream; galantamine has nonvascular neuronal actions.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C22", "text": "Unilateral occlusion raises selected phospho-tau epitopes in aged wild-type/3xTg mice without changing Aβ42. Age/genotype-specific phosphorylation is not a complete AD amyloid/tau initiating cascade.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C23", "text": "BCAS in APP-transgenic mice increases intracellular and fibrillar Aβ deposits. Transgenic APP is upstream, and accelerated deposition does not identify sporadic onset.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C24", "text": "BCAS augments vascular amyloid and microinfarcts in CAA mice; human postmortem observations agree. Amyloid vasculopathy is pre-existing; terminal association and hypoperfusion amplification are not vascular-first AD initiation.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C25", "text": "Chronic hypoperfusion produces white-matter injury and selective spatial working-memory deficits. Excluding mice with neuronal perikaryal injury conditions analysis on an outcome; impairment is not necessarily AD dementia.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C26", "text": "BCAS induces endogenous cis P-tau; cis antibody and DAPK1 loss preserve white matter and executive function; separate htau mice respond to treatment. Human VaD brains lack overt NFTs; htau AD-like tangles arise in a separate model, so BCAS-to-classic-AD initiation is not demonstrated.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph0, 1:RESULTS:paragraph1, 1:RESULTS:paragraph2, 1:RESULTS:paragraph6, 1:RESULTS:paragraph7, 1:RESULTS:paragraph8. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C27", "text": "White-matter vascular pathology associates with total tau/Braak measures; aged MCAO produces phospho-tau. Mixed observational/ischemic evidence does not show onset of the specific amyloid/tau cascade or exclude injury-related tau release.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C28", "text": "Astrocytic APOE4 deletion ameliorates BBB impairment relative to matched APOE3 designs. APOE has nonvascular effects; barrier rescue does not establish that amyloid/tau initiation depends on barrier failure.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C29", "text": "Liver-only APOE4 causes vascular/synaptic/cognitive abnormalities and exacerbates APP-model amyloid; APOE3 plasma improves aged phenotypes. Systemic pleiotropy and APP crossing distinguish vascular contribution from AD-specific primacy.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C30", "text": "Single-nucleus human vascular atlas identifies AD-associated cellular changes and risk-gene expression. Risk-gene expression is not a causal vascular instrument; terminal transcriptomes cannot order events.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C31", "text": "SPRINT intensive blood-pressure treatment reduces MCI and combined cognitive endpoints. Primary probable-dementia contrast is nonsignificant; early cardiovascular stopping and exclusion of diabetes/stroke limit scope; no AD biomarker-onset endpoint.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C32", "text": "SPRINT extended follow-up retains MCI/composite benefit. Probable dementia remains nonsignificant; only 59% of eligible participants were ascertained; same randomized cohort and unexamined correction do not add independent replication.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C33", "text": "Rural-China cluster randomization of 33995 adults in 326 villages lowers 48-month incident all-cause dementia with provider-led blood-pressure treatment. Bundled care is not a selective BBB/pericyte intervention; all-cause dementia benefit does not demonstrate prevention of AD-specific amyloid/tau; abstract/status depth only.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C34", "text": "HYVET-COG randomized antihypertensive treatment in adults over 80 and measured incident dementia. Short follow-up primary dementia contrast is nonsignificant; meta-analysis pooling is not a positive primary trial result.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C35", "text": "Syst-Eur randomized antihypertensive therapy yields fewer clinical dementia cases over two years. Only 32 events and borderline significance; clinical classification does not establish biomarker-defined AD prevention.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C36", "text": "Syst-Eur extended follow-up reports continued dementia incidence difference including clinical AD cases. Control participants were offered active treatment after blinded phase; same initial cohort, not an independent randomized trial or proof of molecular onset prevention.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C37", "text": "INFINITY lowers white-matter hyperintensity accumulation with intensive ambulatory blood-pressure control. Gait and cognition contrasts are null despite MRI effects; biomarkers cannot stand for preserved clinical trajectory.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C38", "text": "preDIVA vascular-care cluster trial shows no overall incident dementia or disability reduction. Low baseline risk and strong usual care reduce intervention contrast; null bundled care is not selective pathway falsification.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C39", "text": "PROGRESS reduces cognitive decline with perindopril-based therapy after stroke/TIA; dementia benefit concentrates with recurrent stroke. Overall dementia contrast is null and benefit without recurrent stroke is not established; this supports stroke-related injury prevention rather than obligatory AD cascade interruption.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C40", "text": "TREAT-SVD crossover compares cerebrovascular reactivity under three drugs; CADASIL shows differential physiological effects. No drug difference in sporadic SVD; four-week physiology is not functional or dementia prevention; small analyzed subgroups.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C41", "text": "FINGER multidomain intervention improves a neuropsychological composite over two years. Diet, exercise and cognitive training accompany vascular monitoring; benefit cannot be assigned to vascular correction or AD onset prevention.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C42", "text": "ARIC hypertension and amyloid independently predict dementia without detected multiplicative synergy. Absence of multiplicative interaction is not absence of additive interaction; observational hazards cannot order the pathology.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C43", "text": "Multiple midlife vascular risks associate with later brain amyloid while late-life risks do not. Long interval supports prediction but not an unconfounded vascular-to-amyloid initiating mechanism; same ARIC platform.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C44", "text": "ARIC retinal features at midlife do not predict amyloid; late-life continuous SUVr association differs from binary positivity. Retinal proxies and endpoint definitions constrain inference; same cohort is not independent replication.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 44 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C45", "text": "Nun Study infarcts lower the burden of AD lesions associated with clinical dementia. Small autopsy sample and wide intervals; interaction in clinical expression does not imply infarcts initiated plaques/tangles.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C46", "text": "Rush autopsies show mixed pathologies increase probability of clinical dementia. Postmortem mixture supports additive injury but cannot establish chronological initiation.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C47", "text": "ACT autopsies identify independent contributions of microinfarcts, Braak pathology and Lewy bodies to dementia. Selected autopsy fraction and weighting retain possible selection/confounding; independent association is not random intervention.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C48", "text": "Large-artery atherosclerosis in 466 autopsies does not associate with AD plaques/tangles. Large-vessel pathology differs from BBB microvascular dysfunction; negative subtype result does not exclude all vascular contributions.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C49", "text": "EPAD structural-equation analysis fits vascular risk/SVD/amyloid/tau/cognitive pathways in nondemented participants. Statistical mediation and fitted ordering do not establish causality, temporal precedence, or absence of alternative models.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C50", "text": "Midlife CAIDE factors predict late-life dementia over about 20 years. Predictive discrimination is not causal mediation or a validated preventable fraction.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C51", "text": "Whitehall II blood pressure at age 50 predicts dementia, unlike measurements at 60 or 70. Age-dependent association retains reverse causation and selection; CVD-free association is not a selective vascular instrument.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C52", "text": "Longitudinal midlife blood pressure relates to later white-matter lesions. Hippocampal/global atrophy associations are not established; tissue injury proxy is not molecular AD initiation.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C53", "text": "ARIC estimates substantial vascular-risk-associated dementia fractions before age 80 and smaller fractions at older ages. Population-attributable fractions assume causal and intervention relationships; they are not demonstrated preventable percentages.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C54", "text": "Amyloid-related and vascular-risk-related white-matter patterns differ topographically. Cross-sectional topography cannot order cause and effect or validate a universal two-hit sequence.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C55", "text": "PSEN1 familial AD has SVD changes that are not explained solely by CAA and can be covert on MRI. Known PSEN1 lesion precedes the vascular phenotype; familial tissue does not establish sporadic vascular initiation.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C56", "text": "NOTCH3 variants produce heterogeneous SVD/vascular phenotypes in population carriers. Many imaged carriers remain normal into late life; penetrance and selection prevent universal dementia inference.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C57", "text": "NOTCH3 domain location stratifies CADASIL stroke/SVD risk across clinical and population samples. Genetic risk strata are not intervention outcomes; phenotype/penetrance varies and AD amyloid/tau onset is not tested.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C58", "text": "TREX1 families develop systemic retinal/cerebral vasculopathy with cognitive decline in a substantial subset. Rare familial systemic disease is a distinct vascular cause, not universal AD dementia or a vessel-only mediator instrument.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C59", "text": "CADASIL patient-derived mural cells destabilize capillary networks with VEGF-sensitive rescue. In vitro networks do not establish organismal cognitive trajectory or specific endogenous human rescue.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 59 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C60", "text": "NOTCH3 R182C mice and human tissue show vascular-smooth-muscle metabolic and neuronal activity abnormalities. Mechanism-associated physiology without selective rescue or AD-specific protein onset cannot close the nominal chain.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C61", "text": "AD retinal tissue shows pericyte loss related to amyloid. Retinal pathology is not interchangeable with brain BBB function or chronological AD origin.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 61 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C62", "text": "Water-permeability BBB measures associate with AD biomarkers while albumin permeability tracks vascular risks. Assays measure different transport/barrier properties; association cannot assign a common causal mechanism.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 62 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C63", "text": "Midlife vascular/VEGF biomarker paths associate with AD-related measures. Cross-sectional path analysis cannot validate the article's proposed causal ordering.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 63 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C64", "text": "DELCODE BBB permeability increases in dementia but not MCI; sPDGFRβ has no overall diagnostic/APOE difference. Small sample and divergent permeability/injury assays; age/inflammation associations and null amyloid/tau-positivity relations limit a general initiating claim.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 64 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C65", "text": "Presymptomatic PS1 mutation carriers have cerebral perfusion abnormalities. Presymptomatic means before clinical symptoms, not before molecular proteinopathy; genotype is already an initiating lesion.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 65 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C66", "text": "Small APP Swedish family shows flow changes before marked atrophy in some carriers. Five carriers with youngest participants normal; no demonstration that vascular change precedes amyloid production.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 66 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C67", "text": "LRP1-targeted transport therapy clears amyloid and improves cognition in AD models. Treatment after existing pathology tests clearance and delivery, not whether vascular failure initiated AD.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 67 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C68", "text": "Endothelial ANGPT2 loss reduces amyloid, while overexpression worsens BBB/inflammatory/memory phenotypes in 5xFAD. Genetic APP/PS1 pathology is upstream; expression/phenotype rescue does not demonstrate ordinary human vascular-first onset.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 68 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "C69", "text": "Longitudinal hereditary CAA shows progressive vascular-reactivity change before clinical symptoms. Mutant APP is upstream; no parallel CBF/cognitive change in presymptomatic carriers, and clinical timing does not equal pre-proteinopathy timing.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 69 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-07", "note": "" }, { "id": "CSC1", "text": "Midlife risks, imaging and mixed autopsy lesions predict dementia, with substantial age, region and assay dependence. The descriptive association claim is Β; intervention evidence is assigned to SC2 rather than silently changing SC1.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 6, 7, 8, 9, 18, 27, 30, 31, 32, 33, 34, 35, 36, 38, 39, 41, 42, 43, 44, 48, 49, 50, 51, 52, 53, 54, 61, 62, 63, 64, 65, 66, 69 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-07", "note": "" }, { "id": "CSC2", "text": "Adult pericyte ablation with PTN rescue, endogenous ischemia/cis-tau subtraction, rare genetic vasculopathies and randomized blood-pressure treatment converge on vascular cognitive injury across different failure structures. China incident dementia and PROGRESS stroke-linked cognitive benefit add human functional evidence. SPRINT primary dementia, preDIVA and INFINITY cognitive nulls limit universal therapeutic efficacy but do not negate the assembled causal set. Ζ applies to defined vascular injury, not an AD-specific initiating cascade or universal Η trajectory.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 1, 2, 3, 4, 5, 11, 12, 16, 17, 19, 20, 21, 24, 25, 26, 28, 29, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 45, 46, 47, 53, 55, 56, 57, 58, 59, 60, 67, 68 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-07", "note": "" }, { "id": "CSC3", "text": "GLUT1 and hypoperfusion accelerate pathology in genetically initiated APP models; vascular stress can induce endogenous cis P-tau and cognitive injury without AD tangles. Human BBB prediction is independent of measured protein markers, not a demonstrated path from BBB to proteins. APP/tau can instead injure vessels. No selective pre-onset human or non-protein-initiated natural set establishes the specific two-hit AD sequence. Mechanistic support warrants Γ.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 1, 2, 4, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 27, 28, 29, 30, 33, 42, 43, 44, 45, 46, 47, 48, 49, 54, 55, 62, 63, 64, 65, 66, 67, 68, 69 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-07", "note": "" }, { "id": "CSC4", "text": "Mixed dementia includes independent infarcts, amyloid/tau, Lewy pathology and variable inherited vascular routes. Multiple clinical prevention contrasts are null or endpoint-dependent; hypoperfusion has opposite protein effects across models. A universal sequence cannot be inferred from its conditional amplification successes.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 56, 57, 58 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-07", "note": "" }, { "id": "CH", "text": "Vascular injury can cause cognitive impairment and amplify Alzheimer disease, but vascular initiation of its amyloid/tau cascade is not established.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 4, 12, 11, 20, 33 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-07", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Bell RD, Winkler EA, Sagare AP et al. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron. 2010.", "tier": "A", "kind": "primary", "pmid": "21040844", "doi": "10.1016/j.neuron.2010.09.043", "url": "https://pubmed.ncbi.nlm.nih.gov/21040844/", "status_flags": [ "ErratumIn: PMID37797582" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "pericyte-Pdgfrb-platform", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C1", "CSC2", "CSC3" ] }, { "n": 2, "citation": "Bell RD, Winkler EA, Singh I et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature. 2012.", "tier": "A", "kind": "primary", "pmid": "22622580", "doi": "10.1038/nature11087", "url": "https://pubmed.ncbi.nlm.nih.gov/22622580/", "status_flags": [ "ErratumIn: PMID37142785" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID22622580", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C2", "CSC2", "CSC3" ] }, { "n": 3, "citation": "Kisler K, Nelson AR, Rege SV et al. Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain. Nature neuroscience. 2017.", "tier": "A", "kind": "primary", "pmid": "28135240", "doi": "10.1038/nn.4489", "url": "https://pubmed.ncbi.nlm.nih.gov/28135240/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "pericyte-Pdgfrb-platform", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C3", "CSC2" ] }, { "n": 4, "citation": "Nikolakopoulou AM, Montagne A, Kisler K et al. Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss. Nature neuroscience. 2019.", "tier": "A", "kind": "primary", "pmid": "31235908", "doi": "10.1038/s41593-019-0434-z", "url": "https://pubmed.ncbi.nlm.nih.gov/31235908/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID31235908", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph2, 1:RESULTS:paragraph3, 1:RESULTS:paragraph4, 1:RESULTS:paragraph10, 1:RESULTS:paragraph12, 1:RESULTS:paragraph13. No complete-paper or supplement audit claimed.", "carries_claims": [ "C4", "CSC2", "CSC3", "CH" ] }, { "n": 5, "citation": "Daneman R, Zhou L, Kebede AA et al. Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature. 2010.", "tier": "A", "kind": "primary", "pmid": "20944625", "doi": "10.1038/nature09513", "url": "https://pubmed.ncbi.nlm.nih.gov/20944625/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID20944625", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C5", "CSC2" ] }, { "n": 6, "citation": "Montagne A, Nation DA, Sagare AP et al. APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline. Nature. 2020.", "tier": "A", "kind": "primary", "pmid": "32376954", "doi": "10.1038/s41586-020-2247-3", "url": "https://pubmed.ncbi.nlm.nih.gov/32376954/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID32376954", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Introductory Paragraph:paragraph1, 0:Introductory Paragraph:paragraph3, 0:Introductory Paragraph:paragraph5, 0:Introductory Paragraph:paragraph6, 0:Introductory Paragraph:paragraph9. No complete-paper or supplement audit claimed.", "carries_claims": [ "C6", "CSC1", "CSC3" ] }, { "n": 7, "citation": "Nation DA, Sweeney MD, Montagne A et al. Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nature medicine. 2019.", "tier": "A", "kind": "primary", "pmid": "30643288", "doi": "10.1038/s41591-018-0297-y", "url": "https://pubmed.ncbi.nlm.nih.gov/30643288/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID30643288", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C7", "CSC1", "CSC3" ] }, { "n": 8, "citation": "Montagne A, Barnes SR, Sweeney MD et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron. 2015.", "tier": "A", "kind": "primary", "pmid": "25611508", "doi": "10.1016/j.neuron.2014.12.032", "url": "https://pubmed.ncbi.nlm.nih.gov/25611508/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID25611508", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C8", "CSC1" ] }, { "n": 9, "citation": "Halliday MR, Rege SV, Ma Q et al. Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer's disease. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2016.", "tier": "A", "kind": "primary", "pmid": "25757756", "doi": "10.1038/jcbfm.2015.44", "url": "https://pubmed.ncbi.nlm.nih.gov/25757756/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID25757756", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C9", "CSC1", "CSC3" ] }, { "n": 10, "citation": "Blanchard JW, Bula M, Davila-Velderrain J et al. Reconstruction of the human blood-brain barrier in vitro reveals a pathogenic mechanism of APOE4 in pericytes. Nature medicine. 2020.", "tier": "A", "kind": "primary", "pmid": "32514169", "doi": "10.1038/s41591-020-0886-4", "url": "https://pubmed.ncbi.nlm.nih.gov/32514169/", "status_flags": [ "ErratumIn: PMID33514950" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID32514169", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C10", "CSC3" ] }, { "n": 11, "citation": "Montagne A, Nikolakopoulou AM, Huuskonen MT et al. APOE4 accelerates advanced-stage vascular and neurodegenerative disorder in old Alzheimer's mice via cyclophilin A independently of amyloid-β. Nature aging. 2021.", "tier": "A", "kind": "primary", "pmid": "35291561", "doi": "10.1038/s43587-021-00073-z", "url": "https://pubmed.ncbi.nlm.nih.gov/35291561/", "status_flags": [ "ErratumIn: PMID37117809" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID35291561", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Results:paragraph11, 0:Results:paragraph12, 0:Results:paragraph15, 0:Results:paragraph16, 0:Results:paragraph18. No complete-paper or supplement audit claimed.", "carries_claims": [ "C11", "CSC2", "CSC3", "CH" ] }, { "n": 12, "citation": "Winkler EA, Nishida Y, Sagare AP et al. GLUT1 reductions exacerbate Alzheimer's disease vasculo-neuronal dysfunction and degeneration. Nature neuroscience. 2015.", "tier": "A", "kind": "primary", "pmid": "25730668", "doi": "10.1038/nn.3966", "url": "https://pubmed.ncbi.nlm.nih.gov/25730668/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID25730668", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph9, 1:Results:paragraph11, 1:Results:paragraph12, 1:Results:paragraph18, 1:Results:paragraph22, 1:Results:paragraph23. No complete-paper or supplement audit claimed.", "carries_claims": [ "C12", "CSC2", "CSC3", "CH" ] }, { "n": 13, "citation": "Nortley R, Korte N, Izquierdo P et al. Amyloid β oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes. Science (New York, N.Y.). 2019.", "tier": "A", "kind": "primary", "pmid": "31221773", "doi": "10.1126/science.aav9518", "url": "https://pubmed.ncbi.nlm.nih.gov/31221773/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID31221773", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Amyloid β constricts human capillaries at pericytes, 2:Pericytes constrict capillaries in human cognitive decline patients with Aβ deposition, 4:Pericytes constrict capillaries in vivo in AD mice, 6:Reversal of Aβ-evoked capillary constriction. No complete-paper or supplement audit claimed.", "carries_claims": [ "C13", "CSC3" ] }, { "n": 14, "citation": "Mughal A, Sackheim AM, Koide M et al. Pathogenic soluble tau peptide disrupts endothelial calcium signaling and vasodilation in the brain microvasculature. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2024.", "tier": "A", "kind": "primary", "pmid": "38420777", "doi": "10.1177/0271678X241235790", "url": "https://pubmed.ncbi.nlm.nih.gov/38420777/", "status_flags": [ "UpdateOf: PMID37609200" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID38420777", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C14", "CSC3" ] }, { "n": 15, "citation": "Chen S, Guo D, Zhu Y et al. Amyloid β oligomer induces cerebral vasculopathy via pericyte-mediated endothelial dysfunction. Alzheimer's research & therapy. 2024.", "tier": "A", "kind": "primary", "pmid": "38475929", "doi": "10.1186/s13195-024-01423-w", "url": "https://pubmed.ncbi.nlm.nih.gov/38475929/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID38475929", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C15", "CSC3" ] }, { "n": 16, "citation": "Xiong M, Wang C, Gratuze M et al. Astrocytic APOE4 removal confers cerebrovascular protection despite increased cerebral amyloid angiopathy. Molecular neurodegeneration. 2023.", "tier": "A", "kind": "primary", "pmid": "36922879", "doi": "10.1186/s13024-023-00610-x", "url": "https://pubmed.ncbi.nlm.nih.gov/36922879/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID36922879", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C16", "CSC2", "CSC3" ] }, { "n": 17, "citation": "Cruz Hernández JC, Bracko O, Kersbergen CJ et al. Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer's disease mouse models. Nature neuroscience. 2019.", "tier": "A", "kind": "primary", "pmid": "30742116", "doi": "10.1038/s41593-018-0329-4", "url": "https://pubmed.ncbi.nlm.nih.gov/30742116/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID30742116", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C17", "CSC2", "CSC3" ] }, { "n": 18, "citation": "Fernandez-Klett F, Brandt L, Fernández-Zapata C et al. Denser brain capillary network with preserved pericytes in Alzheimer's disease. Brain pathology (Zurich, Switzerland). 2020.", "tier": "A", "kind": "primary", "pmid": "32876357", "doi": "10.1111/bpa.12897", "url": "https://pubmed.ncbi.nlm.nih.gov/32876357/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID32876357", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C18", "CSC1", "CSC3" ] }, { "n": 19, "citation": "Lecordier S, Pons V, Rivest S et al. Multifocal Cerebral Microinfarcts Modulate Early Alzheimer's Disease Pathology in a Sex-Dependent Manner. Frontiers in immunology. 2021.", "tier": "A", "kind": "primary", "pmid": "35173711", "doi": "10.3389/fimmu.2021.813536", "url": "https://pubmed.ncbi.nlm.nih.gov/35173711/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID35173711", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C19", "CSC2", "CSC3" ] }, { "n": 20, "citation": "Gheni G, Shinohara M, Masuda-Suzukake M et al. Cerebral hypoperfusion reduces tau accumulation. Annals of clinical and translational neurology. 2025.", "tier": "A", "kind": "primary", "pmid": "39621511", "doi": "10.1002/acn3.52247", "url": "https://pubmed.ncbi.nlm.nih.gov/39621511/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID39621511", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph0, 2:Results:paragraph11, 2:Results:paragraph13, 2:Results:paragraph14, 2:Results:paragraph18. No complete-paper or supplement audit claimed.", "carries_claims": [ "C20", "CSC2", "CSC3", "CH" ] }, { "n": 21, "citation": "Zhai Y, Yamashita T, Nakano Y et al. Chronic Cerebral Hypoperfusion Accelerates Alzheimer's Disease Pathology with Cerebrovascular Remodeling in a Novel Mouse Model. Journal of Alzheimer's disease : JAD. 2016.", "tier": "A", "kind": "primary", "pmid": "27314529", "doi": "10.3233/JAD-160345", "url": "https://pubmed.ncbi.nlm.nih.gov/27314529/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID27314529", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C21", "CSC2", "CSC3" ] }, { "n": 22, "citation": "Qiu L, Ng G, Tan EK et al. Chronic cerebral hypoperfusion enhances Tau hyperphosphorylation and reduces autophagy in Alzheimer's disease mice. Scientific reports. 2016.", "tier": "A", "kind": "primary", "pmid": "27050297", "doi": "10.1038/srep23964", "url": "https://pubmed.ncbi.nlm.nih.gov/27050297/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID27050297", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C22", "CSC3" ] }, { "n": 23, "citation": "Kitaguchi H, Tomimoto H, Ihara M et al. Chronic cerebral hypoperfusion accelerates amyloid beta deposition in APPSwInd transgenic mice. Brain research. 2009.", "tier": "A", "kind": "primary", "pmid": "19646974", "doi": "10.1016/j.brainres.2009.07.078", "url": "https://pubmed.ncbi.nlm.nih.gov/19646974/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID19646974", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C23", "CSC3" ] }, { "n": 24, "citation": "Okamoto Y, Yamamoto T, Kalaria RN et al. Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts. Acta neuropathologica. 2012.", "tier": "A", "kind": "primary", "pmid": "22170742", "doi": "10.1007/s00401-011-0925-9", "url": "https://pubmed.ncbi.nlm.nih.gov/22170742/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID22170742", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C24", "CSC2", "CSC3" ] }, { "n": 25, "citation": "Coltman R, Spain A, Tsenkina Y et al. Selective white matter pathology induces a specific impairment in spatial working memory. Neurobiology of aging. 2011.", "tier": "A", "kind": "primary", "pmid": "20961660", "doi": "10.1016/j.neurobiolaging.2010.09.005", "url": "https://pubmed.ncbi.nlm.nih.gov/20961660/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID20961660", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C25", "CSC2" ] }, { "n": 26, "citation": "Qiu C, Albayram O, Kondo A et al. Cis P-tau underlies vascular contribution to cognitive impairment and dementia and can be effectively targeted by immunotherapy in mice. Science translational medicine. 2021.", "tier": "A", "kind": "primary", "pmid": "34078745", "doi": "10.1126/scitranslmed.aaz7615", "url": "https://pubmed.ncbi.nlm.nih.gov/34078745/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "cis-tau-BCAS-htau-platform", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph0, 1:RESULTS:paragraph1, 1:RESULTS:paragraph2, 1:RESULTS:paragraph6, 1:RESULTS:paragraph7, 1:RESULTS:paragraph8. No complete-paper or supplement audit claimed.", "carries_claims": [ "C26", "CSC2", "CSC3" ] }, { "n": 27, "citation": "Laing KK, Simoes S, Baena-Caldas GP et al. Cerebrovascular disease promotes tau pathology in Alzheimer's disease. Brain communications. 2020.", "tier": "A", "kind": "primary", "pmid": "33215083", "doi": "10.1093/braincomms/fcaa132", "url": "https://pubmed.ncbi.nlm.nih.gov/33215083/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID33215083", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C27", "CSC1", "CSC3" ] }, { "n": 28, "citation": "Jackson RJ, Meltzer JC, Nguyen H et al. APOE4 derived from astrocytes leads to blood-brain barrier impairment. Brain : a journal of neurology. 2022.", "tier": "A", "kind": "primary", "pmid": "34957486", "doi": "10.1093/brain/awab478", "url": "https://pubmed.ncbi.nlm.nih.gov/34957486/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID34957486", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C28", "CSC2", "CSC3" ] }, { "n": 29, "citation": "Liu CC, Zhao J, Fu Y et al. Peripheral apoE4 enhances Alzheimer's pathology and impairs cognition by compromising cerebrovascular function. Nature neuroscience. 2022.", "tier": "A", "kind": "primary", "pmid": "35915180", "doi": "10.1038/s41593-022-01127-0", "url": "https://pubmed.ncbi.nlm.nih.gov/35915180/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID35915180", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C29", "CSC2", "CSC3" ] }, { "n": 30, "citation": "Yang AC, Vest RT, Kern F et al. A human brain vascular atlas reveals diverse mediators of Alzheimer's risk. Nature. 2022.", "tier": "A", "kind": "primary", "pmid": "35165441", "doi": "10.1038/s41586-021-04369-3", "url": "https://pubmed.ncbi.nlm.nih.gov/35165441/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID35165441", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C30", "CSC1", "CSC3" ] }, { "n": 31, "citation": " , Williamson JD, Pajewski NM et al. Effect of Intensive vs Standard Blood Pressure Control on Probable Dementia: A Randomized Clinical Trial. JAMA. 2019.", "tier": "A", "kind": "rct", "pmid": "30688979", "doi": "10.1001/jama.2018.21442", "url": "https://pubmed.ncbi.nlm.nih.gov/30688979/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "SPRINT-cognitive-cohort", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C31", "CSC1", "CSC2" ] }, { "n": 32, "citation": "Reboussin DM, Gaussoin SA, Pajewski NM et al. Long-Term Effect of Intensive vs Standard Blood Pressure Control on Mild Cognitive Impairment and Probable Dementia in SPRINT. Neurology. 2025.", "tier": "A", "kind": "rct", "pmid": "39819096", "doi": "10.1212/WNL.0000000000213334", "url": "https://pubmed.ncbi.nlm.nih.gov/39819096/", "status_flags": [ "ErratumIn: PMID40315397" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "SPRINT-cognitive-cohort", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C32", "CSC1", "CSC2" ] }, { "n": 33, "citation": "He J, Zhao C, Zhong S et al. Blood pressure reduction and all-cause dementia in people with uncontrolled hypertension: an open-label, blinded-endpoint, cluster-randomized trial. Nature medicine. 2025.", "tier": "A", "kind": "rct", "pmid": "40258956", "doi": "10.1038/s41591-025-03616-8", "url": "https://pubmed.ncbi.nlm.nih.gov/40258956/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID40258956", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C33", "CSC1", "CSC2", "CSC3", "CH" ] }, { "n": 34, "citation": "Peters R, Beckett N, Forette F et al. Incident dementia and blood pressure lowering in the Hypertension in the Very Elderly Trial cognitive function assessment (HYVET-COG): a double-blind, placebo controlled trial. The Lancet. Neurology. 2008.", "tier": "A", "kind": "rct", "pmid": "18614402", "doi": "10.1016/S1474-4422(08)70143-1", "url": "https://pubmed.ncbi.nlm.nih.gov/18614402/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID18614402", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C34", "CSC1", "CSC2" ] }, { "n": 35, "citation": "Forette F, Seux ML, Staessen JA et al. Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet (London, England). 1998.", "tier": "A", "kind": "rct", "pmid": "9802273", "doi": "10.1016/s0140-6736(98)03086-4", "url": "https://pubmed.ncbi.nlm.nih.gov/9802273/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "Syst-Eur-cohort", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C35", "CSC1", "CSC2" ] }, { "n": 36, "citation": "Forette F, Seux ML, Staessen JA et al. The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study. Archives of internal medicine. 2002.", "tier": "A", "kind": "rct", "pmid": "12374512", "doi": "10.1001/archinte.162.18.2046", "url": "https://pubmed.ncbi.nlm.nih.gov/12374512/", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "Syst-Eur-cohort", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C36", "CSC1", "CSC2" ] }, { "n": 37, "citation": "White WB, Wakefield DB, Moscufo N et al. Effects of Intensive Versus Standard Ambulatory Blood Pressure Control on Cerebrovascular Outcomes in Older People (INFINITY). Circulation. 2019.", "tier": "A", "kind": "rct", "pmid": "31607143", "doi": "10.1161/CIRCULATIONAHA.119.041603", "url": "https://pubmed.ncbi.nlm.nih.gov/31607143/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID31607143", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C37", "CSC2" ] }, { "n": 38, "citation": "Moll van Charante EP, Richard E, Eurelings LS et al. Effectiveness of a 6-year multidomain vascular care intervention to prevent dementia (preDIVA): a cluster-randomised controlled trial. Lancet (London, England). 2016.", "tier": "A", "kind": "rct", "pmid": "27474376", "doi": "10.1016/S0140-6736(16)30950-3", "url": "https://pubmed.ncbi.nlm.nih.gov/27474376/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID27474376", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C38", "CSC1", "CSC2" ] }, { "n": 39, "citation": "Tzourio C, Anderson C, Chapman N et al. Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Archives of internal medicine. 2003.", "tier": "A", "kind": "rct", "pmid": "12742805", "doi": "10.1001/archinte.163.9.1069", "url": "https://pubmed.ncbi.nlm.nih.gov/12742805/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID12742805", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C39", "CSC1", "CSC2" ] }, { "n": 40, "citation": "Kopczak A, Stringer MS, van den Brink H et al. Effect of blood pressure-lowering agents on microvascular function in people with small vessel diseases (TREAT-SVDs): a multicentre, open-label, randomised, crossover trial. The Lancet. Neurology. 2023.", "tier": "A", "kind": "rct", "pmid": "37863608", "doi": "10.1016/S1474-4422(23)00293-4", "url": "https://pubmed.ncbi.nlm.nih.gov/37863608/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID37863608", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C40", "CSC2" ] }, { "n": 41, "citation": "Ngandu T, Lehtisalo J, Solomon A et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet (London, England). 2015.", "tier": "A", "kind": "rct", "pmid": "25771249", "doi": "10.1016/S0140-6736(15)60461-5", "url": "https://pubmed.ncbi.nlm.nih.gov/25771249/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID25771249", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C41", "CSC1", "CSC2" ] }, { "n": 42, "citation": "Gottesman RF, Wu A, Coresh J et al. Associations of Vascular Risk and Amyloid Burden with Subsequent Dementia. Annals of neurology. 2022.", "tier": "A", "kind": "primary", "pmid": "35732594", "doi": "10.1002/ana.26447", "url": "https://pubmed.ncbi.nlm.nih.gov/35732594/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "ARIC-PET-overlap", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C42", "CSC1", "CSC3" ] }, { "n": 43, "citation": "Gottesman RF, Schneider AL, Zhou Y et al. Association Between Midlife Vascular Risk Factors and Estimated Brain Amyloid Deposition. JAMA. 2017.", "tier": "A", "kind": "primary", "pmid": "28399252", "doi": "10.1001/jama.2017.3090", "url": "https://pubmed.ncbi.nlm.nih.gov/28399252/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "ARIC-PET-overlap", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C43", "CSC1", "CSC3" ] }, { "n": 44, "citation": "Egle M, Deal JA, Walker KA et al. Association between retinal microvascular abnormalities and late-life brain amyloid-β deposition: the ARIC-PET study. Alzheimer's research & therapy. 2024.", "tier": "A", "kind": "primary", "pmid": "38711107", "doi": "10.1186/s13195-024-01461-4", "url": "https://pubmed.ncbi.nlm.nih.gov/38711107/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "ARIC-PET-overlap", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C44", "CSC1", "CSC3" ] }, { "n": 45, "citation": "Snowdon DA, Greiner LH, Mortimer JA et al. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA. 1997.", "tier": "A", "kind": "primary", "pmid": "9052711", "doi": "", "url": "https://pubmed.ncbi.nlm.nih.gov/9052711/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID9052711", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C45", "CSC2", "CSC3" ] }, { "n": 46, "citation": "Schneider JA, Arvanitakis Z, Bang W et al. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology. 2007.", "tier": "A", "kind": "primary", "pmid": "17568013", "doi": "10.1212/01.wnl.0000271090.28148.24", "url": "https://pubmed.ncbi.nlm.nih.gov/17568013/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID17568013", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C46", "CSC2", "CSC3" ] }, { "n": 47, "citation": "Sonnen JA, Larson EB, Crane PK et al. Pathological correlates of dementia in a longitudinal, population-based sample of aging. Annals of neurology. 2007.", "tier": "A", "kind": "primary", "pmid": "17879383", "doi": "10.1002/ana.21208", "url": "https://pubmed.ncbi.nlm.nih.gov/17879383/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID17879383", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C47", "CSC2", "CSC3" ] }, { "n": 48, "citation": "Luoto TM, Haikonen S, Haapasalo H et al. Large vessel cerebral atherosclerosis is not in direct association with neuropathological lesions of Alzheimer's disease. European neurology. 2009.", "tier": "A", "kind": "primary", "pmid": "19521084", "doi": "10.1159/000222779", "url": "https://pubmed.ncbi.nlm.nih.gov/19521084/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID19521084", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C48", "CSC1", "CSC3" ] }, { "n": 49, "citation": "Lorenzini L, Maranzano A, Ingala S et al. Association of Vascular Risk Factors and Cerebrovascular Pathology With Alzheimer Disease Pathologic Changes in Individuals Without Dementia. Neurology. 2024.", "tier": "A", "kind": "primary", "pmid": "39288341", "doi": "10.1212/WNL.0000000000209801", "url": "https://pubmed.ncbi.nlm.nih.gov/39288341/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID39288341", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C49", "CSC1", "CSC3" ] }, { "n": 50, "citation": "Kivipelto M, Ngandu T, Laatikainen T et al. Risk score for the prediction of dementia risk in 20 years among middle aged people: a longitudinal, population-based study. The Lancet. Neurology. 2006.", "tier": "A", "kind": "primary", "pmid": "16914401", "doi": "10.1016/S1474-4422(06)70537-3", "url": "https://pubmed.ncbi.nlm.nih.gov/16914401/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID16914401", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C50", "CSC1" ] }, { "n": 51, "citation": "Abell JG, Kivimäki M, Dugravot A et al. Association between systolic blood pressure and dementia in the Whitehall II cohort study: role of age, duration, and threshold used to define hypertension. European heart journal. 2018.", "tier": "A", "kind": "primary", "pmid": "29901708", "doi": "10.1093/eurheartj/ehy288", "url": "https://pubmed.ncbi.nlm.nih.gov/29901708/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "Whitehall-II", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C51", "CSC1" ] }, { "n": 52, "citation": "Allan CL, Zsoldos E, Filippini N et al. Lifetime hypertension as a predictor of brain structure in older adults: cohort study with a 28-year follow-up. The British journal of psychiatry : the journal of mental science. 2015.", "tier": "A", "kind": "primary", "pmid": "25497301", "doi": "10.1192/bjp.bp.114.153536", "url": "https://pubmed.ncbi.nlm.nih.gov/25497301/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "Whitehall-II", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C52", "CSC1" ] }, { "n": 53, "citation": "Smith JR, Pike JR, Gottesman RF et al. Contribution of Modifiable Midlife and Late-Life Vascular Risk Factors to Incident Dementia. JAMA neurology. 2025.", "tier": "A", "kind": "primary", "pmid": "40455489", "doi": "10.1001/jamaneurol.2025.1495", "url": "https://pubmed.ncbi.nlm.nih.gov/40455489/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID40455489", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C53", "CSC1", "CSC2" ] }, { "n": 54, "citation": "Pålhaugen L, Sudre CH, Tecelao S et al. Brain amyloid and vascular risk are related to distinct white matter hyperintensity patterns. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2021.", "tier": "A", "kind": "primary", "pmid": "32955960", "doi": "10.1177/0271678X20957604", "url": "https://pubmed.ncbi.nlm.nih.gov/32955960/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID32955960", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C54", "CSC1", "CSC3" ] }, { "n": 55, "citation": "Littau JL, Velilla L, Hase Y et al. Evidence of beta amyloid independent small vessel disease in familial Alzheimer's disease. Brain pathology (Zurich, Switzerland). 2022.", "tier": "A", "kind": "primary", "pmid": "35695802", "doi": "10.1111/bpa.13097", "url": "https://pubmed.ncbi.nlm.nih.gov/35695802/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID35695802", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C55", "CSC2", "CSC3" ] }, { "n": 56, "citation": "Rutten JW, Hack RJ, Duering M et al. Broad phenotype of cysteine-altering NOTCH3 variants in UK Biobank: CADASIL to nonpenetrance. Neurology. 2020.", "tier": "A", "kind": "primary", "pmid": "32732295", "doi": "10.1212/WNL.0000000000010525", "url": "https://pubmed.ncbi.nlm.nih.gov/32732295/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID32732295", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C56", "CSC2", "CSC4" ] }, { "n": 57, "citation": "Hack RJ, Gravesteijn G, Cerfontaine MN et al. Three-tiered EGFr domain risk stratification for individualized NOTCH3-small vessel disease prediction. Brain : a journal of neurology. 2023.", "tier": "A", "kind": "primary", "pmid": "36535904", "doi": "10.1093/brain/awac486", "url": "https://pubmed.ncbi.nlm.nih.gov/36535904/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID36535904", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C57", "CSC2", "CSC4" ] }, { "n": 58, "citation": "Stam AH, Kothari PH, Shaikh A et al. Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations. Brain : a journal of neurology. 2016.", "tier": "A", "kind": "primary", "pmid": "27604306", "doi": "10.1093/brain/aww217", "url": "https://pubmed.ncbi.nlm.nih.gov/27604306/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID27604306", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C58", "CSC2", "CSC4" ] }, { "n": 59, "citation": "Kelleher J, Dickinson A, Cain S et al. Patient-Specific iPSC Model of a Genetic Vascular Dementia Syndrome Reveals Failure of Mural Cells to Stabilize Capillary Structures. Stem cell reports. 2019.", "tier": "A", "kind": "primary", "pmid": "31680059", "doi": "10.1016/j.stemcr.2019.10.004", "url": "https://pubmed.ncbi.nlm.nih.gov/31680059/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID31680059", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C59", "CSC2" ] }, { "n": 60, "citation": "Shao W, Oliveira DV, Naia L et al. Impairment of hippocampal gamma oscillations, mitochondria and neurovascular function in CADASIL. Brain : a journal of neurology. 2026.", "tier": "A", "kind": "primary", "pmid": "41622715", "doi": "10.1093/brain/awag033", "url": "https://pubmed.ncbi.nlm.nih.gov/41622715/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID41622715", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C60", "CSC2" ] }, { "n": 61, "citation": "Shi H, Koronyo Y, Rentsendorj A et al. Identification of early pericyte loss and vascular amyloidosis in Alzheimer's disease retina. Acta neuropathologica. 2020.", "tier": "A", "kind": "primary", "pmid": "32043162", "doi": "10.1007/s00401-020-02134-w", "url": "https://pubmed.ncbi.nlm.nih.gov/32043162/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID32043162", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C61", "CSC1" ] }, { "n": 62, "citation": "Lin Z, Sur S, Liu P et al. Blood-Brain Barrier Breakdown in Relationship to Alzheimer and Vascular Disease. Annals of neurology. 2021.", "tier": "A", "kind": "primary", "pmid": "34041783", "doi": "10.1002/ana.26134", "url": "https://pubmed.ncbi.nlm.nih.gov/34041783/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID34041783", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C62", "CSC1", "CSC3" ] }, { "n": 63, "citation": "Edwards NC, Lao P, Alshikho MJ et al. Alzheimer Disease, Vascular Disease, and Blood-Brain Barrier Permeability Biomarkers in Middle-Aged Adults. Neurology. 2025.", "tier": "A", "kind": "primary", "pmid": "41052375", "doi": "10.1212/WNL.0000000000214220", "url": "https://pubmed.ncbi.nlm.nih.gov/41052375/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID41052375", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C63", "CSC1", "CSC3" ] }, { "n": 64, "citation": "Preis L, Villringer K, Brosseron F et al. Assessing blood-brain barrier dysfunction and its association with Alzheimer's pathology, cognitive impairment and neuroinflammation. Alzheimer's research & therapy. 2024.", "tier": "A", "kind": "primary", "pmid": "39085945", "doi": "10.1186/s13195-024-01529-1", "url": "https://pubmed.ncbi.nlm.nih.gov/39085945/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID39085945", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C64", "CSC1", "CSC3" ] }, { "n": 65, "citation": "Johnson KA, Lopera F, Jones K et al. Presenilin-1-associated abnormalities in regional cerebral perfusion. Neurology. 2001.", "tier": "A", "kind": "primary", "pmid": "11402113", "doi": "10.1212/wnl.56.11.1545", "url": "https://pubmed.ncbi.nlm.nih.gov/11402113/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID11402113", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C65", "CSC1", "CSC3" ] }, { "n": 66, "citation": "Julin P, Almkvist O, Basun H et al. Brain volumes and regional cerebral blood flow in carriers of the Swedish Alzheimer amyloid protein mutation. Alzheimer disease and associated disorders. 1998.", "tier": "A", "kind": "primary", "pmid": "9539411", "doi": "10.1097/00002093-199803000-00008", "url": "https://pubmed.ncbi.nlm.nih.gov/9539411/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID9539411", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C66", "CSC1", "CSC3" ] }, { "n": 67, "citation": "Chen J, Xiang P, Duro-Castano A et al. Rapid amyloid-β clearance and cognitive recovery through multivalent modulation of blood-brain barrier transport. Signal transduction and targeted therapy. 2025.", "tier": "A", "kind": "primary", "pmid": "41052971", "doi": "10.1038/s41392-025-02426-1", "url": "https://pubmed.ncbi.nlm.nih.gov/41052971/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID41052971", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C67", "CSC2", "CSC3" ] }, { "n": 68, "citation": "Lee E, Kim S, Zhu CL et al. Angiopoietin-2 aggravates Alzheimer's disease by promoting blood-brain barrier dysfunction and neuroinflammation. Cell reports. 2026.", "tier": "A", "kind": "primary", "pmid": "41529684", "doi": "10.1016/j.celrep.2025.116621", "url": "https://pubmed.ncbi.nlm.nih.gov/41529684/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID41529684", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C68", "CSC2", "CSC3" ] }, { "n": 69, "citation": "van Dijk SE, van der Grond J, Lak J et al. Longitudinal Progression of Magnetic Resonance Imaging Markers and Cognition in Dutch-Type Hereditary Cerebral Amyloid Angiopathy. Stroke. 2022.", "tier": "A", "kind": "primary", "pmid": "35360926", "doi": "10.1161/STROKEAHA.121.035826", "url": "https://pubmed.ncbi.nlm.nih.gov/35360926/", "status_flags": [ "ErratumIn: PMID35605042" ], "opened": true, "opened_on": "2026-10-07", "status_checked_on": "2026-10-07", "study_id": "PMID35360926", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C69", "CSC1", "CSC3" ] } ], "independence_basis": { "required": true, "lines": [ { "label": "Inducible cell loss and neurotroph rescue", "sources": [ 4 ], "excludes_error": "Adult cell ablation and PTN rescue distinguish cell-derived neuronal support from persistent flow loss." }, { "label": "Ischemic mediator subtraction", "sources": [ 26 ], "excludes_error": "Endogenous cis-tau/DAPK1 subtraction after BCAS tests injury mediation through a different molecular instrument." }, { "label": "Randomized clinical vascular prevention", "sources": [ 33, 39 ], "excludes_error": "Human incident dementia/cognitive endpoints test intervention-sensitive trajectories rather than animal marker expression." }, { "label": "Inherited non-AD vasculopathies", "sources": [ 58, 56 ], "excludes_error": "Independent familial vascular routes exclude APP overexpression as a required cause of vascular cognitive injury, while retaining penetrance and pleiotropy limits." } ], "shared_failure_mode_checked": true, "note": "Distinct adult cell ablation, ischemic mediator subtraction, clinical randomization and rare vasculopathy routes converge on defined vascular cognitive injury. Several pericyte/GLUT1/APOE4 reports share a laboratory platform and possible assay vulnerabilities. SPRINT and Syst-Eur follow-ups, ARIC and Whitehall reports are not independent cohorts. These lines do not converge on vascular initiation of human AD-specific proteins. Report-specific retractions remove two landmarks from the positive corpus; other reports are not invalidated by affiliation alone." }, "consensus_validation": { "completed": true, "status": "documented_historical_discovery_and_reconciliation", "provider": "Consensus", "provider_mode": "Historical browser/connector use as recorded in the source artifacts", "local_audit_date": "2026-10-09", "primary_comparison_count": null, "reported_usage": [], "grade_changed": false, "score_before": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "69 primary reports with 7 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "Preregistered scope-matched SC3 gives Γ. Vascular cognitive injury reaches Ζ through convergent endogenous perturbations, inherited vasculopathies and randomized human vascular prevention. Those successes do not establish the distinguishing vascular-first AD amyloid/tau sequence. Protein-first injury, rescue without amyloid change, and opposite tau responses remain discriminators." }, "score_after": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "69 primary reports with 7 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "Preregistered scope-matched SC3 gives Γ. Vascular cognitive injury reaches Ζ through convergent endogenous perturbations, inherited vasculopathies and randomized human vascular prevention. Those successes do not establish the distinguishing vascular-first AD amyloid/tau sequence. Protein-first injury, rescue without amyloid change, and opposite tau responses remain discriminators." }, "independent_blinded_audit": false, "raw_receipts": [ { "path": "deliverables\\hsef_v53_popularity_ranks_26_30_2026-10-07\\two-hit-vascular-dementia\\consensus-leads-search-log.json", "sha256": "f646238c90db41dd1e8679c56c46ad2532aa18ad9756371331ebd2af6ee9295b" }, { "path": "deliverables\\hsef_v53_popularity_ranks_26_30_2026-10-07\\two-hit-vascular-dementia\\consensus-leads.json", "sha256": "99d33bc0e64015556d54dbc0282cd7c105b118fc3c0798f6c54ea1faa0f0f27c" }, { "path": "deliverables\\hsef_v53_popularity_ranks_26_30_2026-10-07\\two-hit-vascular-dementia\\consensus\\broad-browser-snapshot.txt", "sha256": "58f6c2b6e2dbaf89aefa72a2bbff70c66c5619a086918eeac63cecd825cd7d7a" }, { "path": "deliverables\\hsef_v53_popularity_ranks_26_30_2026-10-07\\two-hit-vascular-dementia\\consensus\\query-ledger.json", "sha256": "9e5ba69cb666b4f6694e3eaec4314ee263d2fe52031ad6fb629e8cf326002ddc" }, { "path": "deliverables\\hsef_v53_popularity_ranks_26_30_2026-10-07\\two-hit-vascular-dementia\\consensus\\reconciliation.md", "sha256": "252f487cc209040ba4e172853939cddef1d2a58979bed36f117066a444327c68" } ], "limitations": "This verifies documented historical use and links the record to the final edition. It adds no primary-source, full-text, independence or verification credit. Original access remains limited to the source-specific record." } }