{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "Tau Propagation Hypothesis", "entry_form": "phenomenon", "gradeable_restatement": "Pathological tau spreads between anatomically connected neurons by templated seeding, and this cell-to-cell propagation drives the progression of neurodegeneration in tauopathies.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Tau species and conformation, donor and recipient lineage, genotype and expression, disease subtype and stage, exposure route and treatment timing", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "Tau Propagation Hypothesis", "central_claim": "Pathological tau spreads between anatomically connected neurons by templated seeding, and this cell-to-cell propagation drives the progression of neurodegeneration in tauopathies.", "proposed_mechanism": "Pathological tau spreads between anatomically connected neurons by templated seeding, and this cell-to-cell propagation drives the progression of neurodegeneration in tauopathies.", "claimed_scope": "Pathological tau spreads between anatomically connected neurons by templated seeding, and this cell-to-cell propagation drives the progression of neurodegeneration in tauopathies.", "claimed_level": [ "progression" ], "is_conjunctive": true, "conjunctive_note": "Retain the original user wording. Separate spatial pattern, physical transfer, templated conversion and progression causality. All are required by the conjunction. Refresh earlier tau evidence without reading its previous score as a target." }, "rubric_routing": { "primary_rubric": "01-neurodegeneration.md", "secondary_rubrics": [], "index_notes_applied": [ "Retain the original user wording. Separate spatial pattern, physical transfer, templated conversion and progression causality. All are required by the conjunction. Refresh earlier tau evidence without reading its previous score as a target." ], "rubric_fit_note": "Exact archived v5.3 framework. Any stale index empirical framing is rechecked against primary results." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "Tau pathology shows reproducible spatial progression along connected brain systems.", "subclaim_type": "existence", "scope": "defined human tauopathies and staging trajectories", "claimed_scope": "defined human tauopathies and staging trajectories", "governing_rubric": "01-neurodegeneration.md", "key_evidence_anchor": "Longitudinal imaging and anatomical staging", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Longitudinal PET predicts later accumulation along connected systems, supported by anatomical and perturbational models. This is temporal proof beyond static association, but physical propagation is inferred and disease-pattern exceptions remain. The causal explanation of human network progression is Γ." }, { "id": "SC2", "statement": "Pathogenic tau physically transfers between anatomically connected neurons under endogenous conditions.", "subclaim_type": "mechanism", "scope": "spontaneous tauopathy conditions without forced seed delivery", "claimed_scope": "spontaneous tauopathy conditions without forced seed delivery", "governing_rubric": "01-neurodegeneration.md", "key_evidence_anchor": "Donor-specific endogenous lineage tracing", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Donor-restricted models, receptor perturbations and activity experiments establish transport capability. Spontaneous PS19 patterns lack injected seeds but retain widespread mutant tau expression. Direct endogenous lineage transfer under natural disease conditions has not been separated from recipient expression and selective vulnerability." }, { "id": "SC3", "statement": "Transferred tau templates pathological conversion of recipient endogenous tau.", "subclaim_type": "mechanism", "scope": "recipient neurons with physiological tau expression", "claimed_scope": "recipient neurons with physiological tau expression", "governing_rubric": "01-neurodegeneration.md", "key_evidence_anchor": "Recipient-specific conversion with loss and matched rescue", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Wild-type recipients, mouse-specific antibody and tau-null/species-specific comparisons strengthen physiological host-tau conversion after imposed seeds. These establish important bounded capabilities. The registered transferred endogenous pathway remains reliant on forced initiation; host recruitment alone does not prove natural disease necessity." }, { "id": "SC4", "statement": "Cell-to-cell templated propagation causally drives neurodegeneration progression.", "subclaim_type": "necessity", "scope": "tauopathy functional and neuronal-loss trajectories", "claimed_scope": "tauopathy functional and neuronal-loss trajectories", "governing_rubric": "01-neurodegeneration.md", "key_evidence_anchor": "Selective spread inhibition preserving tau functions and cell viability", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Bassoon, exosome-pathway, antibody and source-suppression contrasts affect pathology or function, but also source tau, synaptic physiology, ceramides, clearance or inflammation. Arc loss reduces transmission with early toxicity increased; clinical antibody failures and a mixed LAURIET result constrain progression mediation without proving all tau biology irrelevant." } ], "aggregation_rule": "weakest-link", "aggregation_preregistered": true, "aggregation_rationale": "Retain the original user wording. Separate spatial pattern, physical transfer, templated conversion and progression causality. All are required by the conjunction. Refresh earlier tau evidence without reading its previous score as a target.", "primary_subclaim_id": "SC4", "aggregation_derivation": "The preregistered weakest-link conjunction returns Γ. Longitudinal human network progression, recipient-host conversion experiments and causal modifiers make the claim more than association alone. None of the assembled lines selectively establishes that spontaneous templated neuronal propagation is necessary for the neuronal-loss trajectory across tauopathies. Defined laboratory capability is credited, while selective propagation mediation is the remaining gate.", "aggregation_alternatives": { "weakest_link_would_return": "Γ", "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": "M2", "is_nominal": false, "name": "Cell-autonomous selective vulnerability", "core_claim": "Intrinsic neuronal type, synaptic tau binding and proteostasis help determine which cells degenerate.", "explains_what_nominal_does_not": "Intrinsic neuronal type, synaptic tau binding and proteostasis help determine which cells degenerate.", "strongest_supporting_evidence": [ "Synaptogyrin-3 perturbation rescues synaptic function and memory; identical seeds affect different human neuronal subtypes differently." ], "strongest_contradictory_evidence": [ "This does not exclude transfer as an additional contributor, and familial/organoid scope is limited." ], "hsef_level_for_this_model": "Ε", "rationale": "Synaptogyrin-3 perturbation rescues synaptic function and memory; identical seeds affect different human neuronal subtypes differently. This does not exclude transfer as an additional contributor, and familial/organoid scope is limited." }, { "rank_in_tournament": 2, "model_id": "M1", "is_nominal": true, "name": "Templated neuronal propagation", "core_claim": "Donor tau transfer recruits recipient substrate and helps advance pathology.", "explains_what_nominal_does_not": "Donor tau transfer recruits recipient substrate and helps advance pathology.", "strongest_supporting_evidence": [ "Wild-type host conversion, mouse-tau-specific neutralization, temporal seed detection and connected-region models support capability." ], "strongest_contradictory_evidence": [ "A selective natural propagation-to-neuron-loss dependency is unresolved; Arc and clinical outcome contrasts prevent automatic mediation." ], "hsef_level_for_this_model": "Γ", "rationale": "Wild-type host conversion, mouse-tau-specific neutralization, temporal seed detection and connected-region models support capability. A selective natural propagation-to-neuron-loss dependency is unresolved; Arc and clinical outcome contrasts prevent automatic mediation." }, { "rank_in_tournament": 3, "model_id": "M3", "is_nominal": false, "name": "Transfer without neurotoxicity", "core_claim": "Transferred material can move independently of recipient templating or lethal consequences.", "explains_what_nominal_does_not": "Transferred material can move independently of recipient templating or lethal consequences.", "strongest_supporting_evidence": [ "Human donor tau transfers in a mouse-tau-null recipient model and seeding occurs in neurologically normal brains." ], "strongest_contradictory_evidence": [ "Healthy seeds differ from AD seeds; pathogenic seed exposure causes dysfunction in specified recipient models." ], "hsef_level_for_this_model": "Γ", "rationale": "Human donor tau transfers in a mouse-tau-null recipient model and seeding occurs in neurologically normal brains. Healthy seeds differ from AD seeds; pathogenic seed exposure causes dysfunction in specified recipient models." }, { "rank_in_tournament": 4, "model_id": "M4", "is_nominal": false, "name": "Upstream proteostatic failure", "core_claim": "Endolysosomal escape and cellular clearance determine tau competence and intrinsic toxicity.", "explains_what_nominal_does_not": "Endolysosomal escape and cellular clearance determine tau competence and intrinsic toxicity.", "strongest_supporting_evidence": [ "RAB7 assays, human-neuron CRISPR proteostasis screens and organoid rescue support relevant mechanisms." ], "strongest_contradictory_evidence": [ "Cultured-cell and engineered systems do not establish a common upstream initiator of all tauopathies." ], "hsef_level_for_this_model": "Γ", "rationale": "RAB7 assays, human-neuron CRISPR proteostasis screens and organoid rescue support relevant mechanisms. Cultured-cell and engineered systems do not establish a common upstream initiator of all tauopathies." }, { "rank_in_tournament": 5, "model_id": "M5", "is_nominal": false, "name": "Shared microenvironment pseudo-spread", "core_claim": "Network activity and glial environments create correlated pathology without obligatory neuron-to-neuron transfer.", "explains_what_nominal_does_not": "Network activity and glial environments create correlated pathology without obligatory neuron-to-neuron transfer.", "strongest_supporting_evidence": [ "Connectivity covariance, glial injury and intrinsic susceptibility are compatible with this route." ], "strongest_contradictory_evidence": [ "Compatibility alone does not prove it, and direct laboratory donor transfer cannot be explained as covariance alone." ], "hsef_level_for_this_model": "Β", "rationale": "Connectivity covariance, glial injury and intrinsic susceptibility are compatible with this route. Compatibility alone does not prove it, and direct laboratory donor transfer cannot be explained as covariance alone." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. Compare transfer-selective loss and matched rescue with source-tau- and recipient-viability-matched controls, measuring both recipient conversion and blinded neuronal loss. Intrinsic toxicity may coexist; an epistasis design must test mediation rather than rank mutually compatible stories as exclusive.", "study_separating_rank1_from_rank2": "Compare transfer-selective loss and matched rescue with source-tau- and recipient-viability-matched controls, measuring both recipient conversion and blinded neuronal loss. Intrinsic toxicity may coexist; an epistasis design must test mediation rather than rank mutually compatible stories as exclusive.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "26436904", "title": "Depletion of microglia and inhibition of exosome synthesis halt tau propagation.", "citation": "Asai H, Ikezu S, Tsunoda S et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nature neuroscience. 2015.", "doi": "10.1038/nn.4132", "pmcid": "PMC4694577", "url": "https://pubmed.ncbi.nlm.nih.gov/26436904/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26436904/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID26436904", "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": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Microglial depletion and exosome-synthesis inhibition reduced tau propagation in an AAV entorhinal-to-dentate model and changed dentate excitability.", "what_it_does_not_show": "AAV expression and broad microglial/exosome effects do not isolate spontaneous tau templating as the mediator of neuron death.", "confounders_present": [ "AAV expression and broad microglial/exosome effects do not isolate spontaneous tau templating as the mediator of neuron death." ], "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": "39736627", "title": "Distinct regulation of Tau Monomer and aggregate uptake and intracellular accumulation in human neurons.", "citation": "Marvian AT, Strauss T, Tang Q et al. Distinct regulation of Tau Monomer and aggregate uptake and intracellular accumulation in human neurons. Molecular neurodegeneration. 2024.", "doi": "10.1186/s13024-024-00786-w", "pmcid": "PMC11686972", "url": "https://pubmed.ncbi.nlm.nih.gov/39736627/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39736627/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID39736627", "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": "Weak", "system": "cell culture", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Human neuron assays distinguished aggregate uptake through HSPG-related mechanisms from largely LRP1-dependent monomer accumulation.", "what_it_does_not_show": "Recombinant protein exposure and uptake assays do not demonstrate recipient conversion or endogenous human disease progression; the abstract's leading-cause framing exceeds its experiment.", "confounders_present": [ "Recombinant protein exposure and uptake assays do not demonstrate recipient conversion or endogenous human disease progression; the abstract's leading-cause framing exceeds its experiment." ], "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": "42372723", "title": "Arc mediates intercellular tau transmission via extracellular vesicles.", "citation": "Tyagi M, de Hoog E, Grega M et al. Arc mediates intercellular tau transmission via extracellular vesicles. Cell. 2026.", "doi": "10.1016/j.cell.2026.06.008", "pmcid": "PMC13315601", "url": "https://pubmed.ncbi.nlm.nih.gov/42372723/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42372723/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID39484489" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID42372723", "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": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Arc knockout nearly abolished intercellular transmission in mutant-tau mice while reducing EV tau and increasing intracellular accumulation with modest early toxicity.", "what_it_does_not_show": "Transmission reduction did not yield uniform neuroprotection; developmental Arc functions and mutant transgenic expression complicate selective spread mediation. UpdateOf links the preceding version, not a separate replication.", "confounders_present": [ "Transmission reduction did not yield uniform neuroprotection; developmental Arc functions and mutant transgenic expression complicate selective spread mediation. UpdateOf links the preceding version, not a separate 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": 4, "pmid": "37192625", "title": "Synaptic oligomeric tau in Alzheimer's disease - A potential culprit in the spread of tau pathology through the brain.", "citation": "Colom-Cadena M, Davies C, Sirisi S et al. Synaptic oligomeric tau in Alzheimer's disease - A potential culprit in the spread of tau pathology through the brain. Neuron. 2023.", "doi": "10.1016/j.neuron.2023.04.020", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/37192625/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37192625/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID37192625", "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": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Postmortem subdiffraction microscopy detected oligomeric tau in human pre- and postsynaptic terminals, including regions with little fibrillar deposition.", "what_it_does_not_show": "Static terminal colocalization does not trace transfer direction, recipient templating or an early causal sequence in living people.", "confounders_present": [ "Static terminal colocalization does not trace transfer direction, recipient templating or an early causal sequence in living people." ], "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": "32296178", "title": "LRP1 is a master regulator of tau uptake and spread.", "citation": "Rauch JN, Luna G, Guzman E et al. LRP1 is a master regulator of tau uptake and spread. Nature. 2020.", "doi": "10.1038/s41586-020-2156-5", "pmcid": "PMC7687380", "url": "https://pubmed.ncbi.nlm.nih.gov/32296178/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32296178/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID32296178", "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": false, "direction": "supports", "what_it_shows": "LRP1 knockdown reduced tau uptake in human-derived cells and reduced neuronal tau spread in a mouse model.", "what_it_does_not_show": "Receptor uptake is not identical to recipient conversion; LRP1 has broader trafficking functions and the abstract does not establish neuronal-loss prevention.", "confounders_present": [ "Receptor uptake is not identical to recipient conversion; LRP1 has broader trafficking functions and the abstract does not establish neuronal-loss 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": 6, "pmid": "36056435", "title": "Trem2 deletion enhances tau dispersion and pathology through microglia exosomes.", "citation": "Zhu B, Liu Y, Hwang S et al. Trem2 deletion enhances tau dispersion and pathology through microglia exosomes. Molecular neurodegeneration. 2022.", "doi": "10.1186/s13024-022-00562-8", "pmcid": "PMC9438095", "url": "https://pubmed.ncbi.nlm.nih.gov/36056435/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36056435/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID36056435", "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": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Trem2 deletion enhanced AAV-P301L tau dispersion, EV seeding activity, synaptic dysfunction and memory deficits; exosome inhibition reduced release in culture.", "what_it_does_not_show": "Microglial clearance and broader immune effects confound selective transfer mediation; pathological human tau expression is imposed, and Trem2 can protect in this context.", "confounders_present": [ "Microglial clearance and broader immune effects confound selective transfer mediation; pathological human tau expression is imposed, and Trem2 can protect in this context." ], "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": "27974162", "title": "Tau Prion Strains Dictate Patterns of Cell Pathology, Progression Rate, and Regional Vulnerability In Vivo.", "citation": "Kaufman SK, Sanders DW, Thomas TL et al. Tau Prion Strains Dictate Patterns of Cell Pathology, Progression Rate, and Regional Vulnerability In Vivo. Neuron. 2016.", "doi": "10.1016/j.neuron.2016.09.055", "pmcid": "PMC5392364", "url": "https://pubmed.ncbi.nlm.nih.gov/27974162/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27974162/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID27974162", "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": "Eighteen cell-isolated tau strains induced distinct regional and cellular pathology and different network propagation rates in inoculated PS19 mice.", "what_it_does_not_show": "This demonstrates strain capability in a P301S recipient rather than natural human strain origin or propagation-driven neuronal loss.", "confounders_present": [ "This demonstrates strain capability in a P301S recipient rather than natural human strain origin or propagation-driven neuronal loss." ], "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": "25261551", "title": "Proteopathic tau seeding predicts tauopathy in vivo.", "citation": "Holmes BB, Furman JL, Mahan TE et al. Proteopathic tau seeding predicts tauopathy in vivo. Proceedings of the National Academy of Sciences of the United States of America. 2014.", "doi": "10.1073/pnas.1411649111", "pmcid": "PMC4205609", "url": "https://pubmed.ncbi.nlm.nih.gov/25261551/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25261551/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID25261551", "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": "A FRET biosensor detected tau seeding in P301S mice before histological tau pathology and discriminated AD tissue from comparison samples.", "what_it_does_not_show": "Temporal assay sensitivity and mutant-model correlation do not establish seed necessity, direct transfer or neuronal toxicity.", "confounders_present": [ "Temporal assay sensitivity and mutant-model correlation do not establish seed necessity, direct transfer or neuronal toxicity." ], "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": "33417012", "title": "Exosomes induce endolysosomal permeabilization as a gateway by which exosomal tau seeds escape into the cytosol.", "citation": "Polanco JC, Hand GR, Briner A et al. Exosomes induce endolysosomal permeabilization as a gateway by which exosomal tau seeds escape into the cytosol. Acta neuropathologica. 2021.", "doi": "10.1007/s00401-020-02254-3", "pmcid": "PMC7847444", "url": "https://pubmed.ncbi.nlm.nih.gov/33417012/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33417012/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID33417012", "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": "Weak", "system": "cell culture", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Endolysosomal permeabilization allowed EV-associated tau seeds to reach biosensor-cell cytosol; RAB7 manipulation changed aggregation.", "what_it_does_not_show": "Permeabilization also occurred with tau-free EVs, only a minority of cells aggregated, and RAB7/lysosomal perturbations affect general trafficking.", "confounders_present": [ "Permeabilization also occurred with tau-free EVs, only a minority of cells aggregated, and RAB7/lysosomal perturbations affect general trafficking." ], "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": "33246331", "title": "Alzheimer's disease brain-derived extracellular vesicles spread tau pathology in interneurons.", "citation": "Ruan Z, Pathak D, Venkatesan Kalavai S et al. Alzheimer's disease brain-derived extracellular vesicles spread tau pathology in interneurons. Brain : a journal of neurology. 2021.", "doi": "10.1093/brain/awaa376", "pmcid": "PMC7880668", "url": "https://pubmed.ncbi.nlm.nih.gov/33246331/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33246331/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID33437996" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID33246331", "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", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Human AD EV inoculation in aged wild-type mice induced endogenous tau misfolding with preferential GABAergic pathology and reduced inhibitory synaptic transmission.", "what_it_does_not_show": "Forced brain EV delivery bypasses normal release and dose; dysfunction and marker reductions are not an audited neuron-death mediation assay. A linked correction requires qualification.", "confounders_present": [ "Forced brain EV delivery bypasses normal release and dose; dysfunction and marker reductions are not an audited neuron-death mediation assay. A linked correction requires qualification." ], "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": "27322420", "title": "Neuronal activity enhances tau propagation and tau pathology in vivo.", "citation": "Wu JW, Hussaini SA, Bastille IM et al. Neuronal activity enhances tau propagation and tau pathology in vivo. Nature neuroscience. 2016.", "doi": "10.1038/nn.4328", "pmcid": "PMC4961585", "url": "https://pubmed.ncbi.nlm.nih.gov/27322420/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27322420/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID27322420", "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": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Donor physiological tau transferred through medium; optogenetic and chemogenetic stimulation increased release and in-vivo tau pathology.", "what_it_does_not_show": "Activity also changes intrinsic vulnerability and proteostasis; increased pathology is not proof that transfer-mediated recipient conversion causes degeneration.", "confounders_present": [ "Activity also changes intrinsic vulnerability and proteostasis; increased pathology is not proof that transfer-mediated recipient conversion causes degeneration." ], "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": "24857020", "title": "Distinct tau prion strains propagate in cells and mice and define different tauopathies.", "citation": "Sanders DW, Kaufman SK, DeVos SL et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron. 2014.", "doi": "10.1016/j.neuron.2014.04.047", "pmcid": "PMC4171396", "url": "https://pubmed.ncbi.nlm.nih.gov/24857020/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24857020/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID24857020", "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": "Cell-derived tau conformations retained strain-like characteristics across three inoculated transgenic-mouse generations and patient-derived biosensor isolates differed by tauopathy.", "what_it_does_not_show": "Repeat-domain reporters and imposed serial inoculation establish templating capability, not natural human intercellular disease causation or infectivity equivalence to PrP.", "confounders_present": [ "Repeat-domain reporters and imposed serial inoculation establish templating capability, not natural human intercellular disease causation or infectivity equivalence to PrP." ], "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": "38049923", "title": "Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in an Alzheimer's disease mouse model.", "citation": "Tallon C, Bell BJ, Malvankar MM et al. Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in an Alzheimer's disease mouse model. Translational neurodegeneration. 2023.", "doi": "10.1186/s40035-023-00383-9", "pmcid": "PMC10694940", "url": "https://pubmed.ncbi.nlm.nih.gov/38049923/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38049923/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID37502930" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID38049923", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph5, 2:Results:paragraph7, 2:Results:paragraph9, 2:Results:paragraph14. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Brain-penetrant nSMase2 inhibition normalized ceramides and reduced PS19 tau pathology, neuronal-layer thinning and glial changes; it separately reduced AAV-mutant contralateral tau transfer.", "what_it_does_not_show": "The survival/pathology and transfer experiments use separate systems; ceramide and EV changes have broader effects, so propagation is not the uniquely demonstrated neuroprotective mediator. Original Results show reduced total human tau and loss of the pThr181 difference after total-tau normalization. Layer density/thickness and synaptophysin improve, but no audited total-neuron stereology or behavioral rescue is credited here. The AAV arm normalizes contralateral signal to ipsilateral signal.", "confounders_present": [ "The survival/pathology and transfer experiments use separate systems; ceramide and EV changes have broader effects, so propagation is not the uniquely demonstrated neuroprotective mediator. Original Results show reduced total human tau and loss of the pThr181 difference after total-tau normalization. Layer density/thickness and synaptophysin improve, but no audited total-neuron stereology or behavioral rescue is credited here. The AAV arm normalizes contralateral signal to ipsilateral signal." ], "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": "26538322", "title": "Removing endogenous tau does not prevent tau propagation yet reduces its neurotoxicity.", "citation": "Wegmann S, Maury EA, Kirk MJ et al. Removing endogenous tau does not prevent tau propagation yet reduces its neurotoxicity. The EMBO journal. 2015.", "doi": "10.15252/embj.201592748", "pmcid": "PMC4687785", "url": "https://pubmed.ncbi.nlm.nih.gov/26538322/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26538322/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID26538322", "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", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Removing endogenous mouse tau preserved human-P301L transfer to recipient neurons but reduced neurotoxicity in a separate severe-tauopathy model despite similar tangle numbers.", "what_it_does_not_show": "Donor-protein movement can occur without host templating, and tangle burden can dissociate from toxicity; human transgenes and tau-null physiology limit natural disease generalization.", "confounders_present": [ "Donor-protein movement can occur without host templating, and tangle burden can dissociate from toxicity; human transgenes and tau-null physiology limit natural disease generalization." ], "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": "39500576", "title": "Targeting Endogenous Tau in Seeded Tauopathy Models Inhibits Tau Spread.", "citation": "Jang E, Hoxha K, Mozier D et al. Targeting Endogenous Tau in Seeded Tauopathy Models Inhibits Tau Spread. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2024.", "doi": "10.1523/JNEUROSCI.0877-24.2024", "pmcid": "PMC11604146", "url": "https://pubmed.ncbi.nlm.nih.gov/39500576/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39500576/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID39500576", "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": "A mouse-tau-specific antibody reduced human AD-tau-seeded pathology in female wild-type mice despite not binding the human inoculum.", "what_it_does_not_show": "This narrows recipient-substrate involvement but still begins with imposed seeds; the abstract infers intraneuronal elongation and does not establish selective spread-mediated neuron survival.", "confounders_present": [ "This narrows recipient-substrate involvement but still begins with imposed seeds; the abstract infers intraneuronal elongation and does not establish selective spread-mediated neuron survival." ], "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": "36297501", "title": "Dendrimer-Conjugated nSMase2 Inhibitor Reduces Tau Propagation in Mice.", "citation": "Tallon C, Bell BJ, Sharma A et al. Dendrimer-Conjugated nSMase2 Inhibitor Reduces Tau Propagation in Mice. Pharmaceutics. 2022.", "doi": "10.3390/pharmaceutics14102066", "pmcid": "PMC9609094", "url": "https://pubmed.ncbi.nlm.nih.gov/36297501/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36297501/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID36297501", "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": false, "direction": "supports", "what_it_shows": "Dendrimer-conjugated nSMase2 inhibitor improved exposure and reduced contralateral tau pathology after unilateral mutant-human-tau AAV expression.", "what_it_does_not_show": "EV suppression and trafficking are broader than a tau-only mediator; this is an engineered transfer model without a reported clinical or neuronal-loss endpoint.", "confounders_present": [ "EV suppression and trafficking are broader than a tau-only mediator; this is an engineered transfer model without a reported clinical or neuronal-loss 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": 17, "pmid": "29752551", "title": "Tau seeding activity begins in the transentorhinal/entorhinal regions and anticipates phospho-tau pathology in Alzheimer's disease and PART.", "citation": "Kaufman SK, Del Tredici K, Thomas TL et al. Tau seeding activity begins in the transentorhinal/entorhinal regions and anticipates phospho-tau pathology in Alzheimer's disease and PART. Acta neuropathologica. 2018.", "doi": "10.1007/s00401-018-1855-6", "pmcid": "PMC6015098", "url": "https://pubmed.ncbi.nlm.nih.gov/29752551/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29752551/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID29752551", "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": "Biosensor testing across 247 fixed human brains found early seeding in transentorhinal/entorhinal cortex and activity ahead of phospho-tau staining, including in later cortical regions.", "what_it_does_not_show": "Cross-sectional reconstructed timing and an amplification assay do not trace physical transfer; locus-coeruleus phospho-tau does not imply its seeds initiate the whole sequence.", "confounders_present": [ "Cross-sectional reconstructed timing and an amplification assay do not trace physical transfer; locus-coeruleus phospho-tau does not imply its seeds initiate the whole 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": 18, "pmid": "30526844", "title": "Tau monomer encodes strains.", "citation": "Sharma AM, Thomas TL, Woodard DR et al. Tau monomer encodes strains. eLife. 2018.", "doi": "10.7554/eLife.37813", "pmcid": "PMC6289568", "url": "https://pubmed.ncbi.nlm.nih.gov/30526844/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30526844/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID30526844", "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": "Weak", "system": "cell culture", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Seed-competent monomer ensembles encoded reproducible cell strains and distinct PS19-inoculated pathology, with AD and CBD isolates differing.", "what_it_does_not_show": "Monomer preparation and reporter selection do not establish spontaneous human strain formation or disease progression dependency.", "confounders_present": [ "Monomer preparation and reporter selection do not establish spontaneous human strain formation or disease progression dependency." ], "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": "25862635", "title": "Templated misfolding of Tau by prion-like seeding along neuronal connections impairs neuronal network function and associated behavioral outcomes in Tau transgenic mice.", "citation": "Stancu IC, Vasconcelos B, Ris L et al. Templated misfolding of Tau by prion-like seeding along neuronal connections impairs neuronal network function and associated behavioral outcomes in Tau transgenic mice. Acta neuropathologica. 2015.", "doi": "10.1007/s00401-015-1413-4", "pmcid": "PMC4436846", "url": "https://pubmed.ncbi.nlm.nih.gov/25862635/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25862635/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID25862635", "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", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Injected synthetic tau seeds in P301S mice produced region-dependent spread, impaired synaptic plasticity and corresponding cognitive or motor dysfunction.", "what_it_does_not_show": "Forced seeds plus mutant tau create a bounded sufficiency paradigm; functional deficits are not direct proof that naturally transferred seeds cause progressive human neuron death.", "confounders_present": [ "Forced seeds plus mutant tau create a bounded sufficiency paradigm; functional deficits are not direct proof that naturally transferred seeds cause progressive human neuron death." ], "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": "23946388", "title": "Reversal of neurofibrillary tangles and tau-associated phenotype in the rTgTauEC model of early Alzheimer's disease.", "citation": "Polydoro M, de Calignon A, Suárez-Calvet M et al. Reversal of neurofibrillary tangles and tau-associated phenotype in the rTgTauEC model of early Alzheimer's disease. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2013.", "doi": "10.1523/JNEUROSCI.0881-13.2013", "pmcid": "PMC3742920", "url": "https://pubmed.ncbi.nlm.nih.gov/23946388/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23946388/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID23946388", "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": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Suppressing entorhinal mutant-tau transgene expression resolved inclusions and abnormal sprouting and prevented progressive neuron loss in rTgTauEC mice.", "what_it_does_not_show": "Doxycycline lowers the source protein and its cell-autonomous toxicity as well as spread; it is not a propagation-selective mediation test.", "confounders_present": [ "Doxycycline lowers the source protein and its cell-autonomous toxicity as well as spread; it is not a propagation-selective mediation test." ], "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": "37902726", "title": "Exploratory Tau Biomarker Results From a Multiple Ascending-Dose Study of BIIB080 in Alzheimer Disease: A Randomized Clinical Trial.", "citation": "Edwards AL, Collins JA, Junge C et al. Exploratory Tau Biomarker Results From a Multiple Ascending-Dose Study of BIIB080 in Alzheimer Disease: A Randomized Clinical Trial. JAMA neurology. 2023.", "doi": "10.1001/jamaneurol.2023.3861", "pmcid": "PMC10616768", "url": "https://pubmed.ncbi.nlm.nih.gov/37902726/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37902726/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "MAPTRx-BIIB080-phase1b", "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", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "The 46-person BIIB080 phase 1b trial and extension showed dose-related fluid tau lowering and reduced PET accumulation in small imaging subsets.", "what_it_does_not_show": "Safety was the original primary endpoint; open-label extension and biomarker outcomes do not establish clinical efficacy or selective propagation blockade. Same trial as MAPTRx primary report.", "confounders_present": [ "Safety was the original primary endpoint; open-label extension and biomarker outcomes do not establish clinical efficacy or selective propagation blockade. Same trial as MAPTRx primary report." ], "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": [ "Same 46-person MAPTRx cohort plus open-label extension and small PET subsets." ] }, { "n": 22, "pmid": "37095250", "title": "Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer's disease: a phase 1b, randomized, placebo-controlled trial.", "citation": "Mummery CJ, Börjesson-Hanson A, Blackburn DJ et al. Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer's disease: a phase 1b, randomized, placebo-controlled trial. Nature medicine. 2023.", "doi": "10.1038/s41591-023-02326-3", "pmcid": "PMC10287562", "url": "https://pubmed.ncbi.nlm.nih.gov/37095250/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37095250/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "ErratumIn: PMID37845513" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "MAPTRx-BIIB080-phase1b", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph13, 1:Results:paragraph18, 1:Results:paragraph20, 1:Results:paragraph22, 1:Results:paragraph23. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "In a randomized 46-person MAPTRx phase 1b study, intrathecal antisense lowered CSF total tau by more than half at higher doses; no treated serious adverse events were reported.", "what_it_does_not_show": "The primary endpoint was safety, not clinical disease modification, and total MAPT synthesis lowering cannot identify spread mediation. A linked author correction remains attached. Original Results show no consistent clinical outcome trend and no dose-responsive injury-biomarker effect; ventricular-volume change was greater in active arms. The examined publisher correction changes an author affiliation, not efficacy results (doi:10.1038/s41591-023-02639-3).", "confounders_present": [ "The primary endpoint was safety, not clinical disease modification, and total MAPT synthesis lowering cannot identify spread mediation. A linked author correction remains attached. Original Results show no consistent clinical outcome trend and no dose-responsive injury-biomarker effect; ventricular-volume change was greater in active arms. The examined publisher correction changes an author affiliation, not efficacy results (doi:10.1038/s41591-023-02639-3)." ], "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": "33609476", "title": "Safety and efficacy of tilavonemab in progressive supranuclear palsy: a phase 2, randomised, placebo-controlled trial.", "citation": "Höglinger GU, Litvan I, Mendonca N et al. Safety and efficacy of tilavonemab in progressive supranuclear palsy: a phase 2, randomised, placebo-controlled trial. The Lancet. Neurology. 2021.", "doi": "10.1016/S1474-4422(20)30489-0", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/33609476/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33609476/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID33609476", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "null", "what_it_shows": "The 378-randomized tilavonemab PSP trial met prespecified futility criteria and showed no beneficial PSPRS trajectory effect versus placebo.", "what_it_does_not_show": "This tests an N-terminal extracellular antibody in symptomatic PSP, not verified removal of every intracellular or transmissible tau species; null efficacy restricts this strategy without disproving all tau mechanisms.", "confounders_present": [ "This tests an N-terminal extracellular antibody in symptomatic PSP, not verified removal of every intracellular or transmissible tau species; null efficacy restricts this strategy without disproving all tau mechanisms." ], "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": "40810361", "title": "Connectivity as a universal predictor of tau progression in atypical Alzheimer's disease.", "citation": "de Bruin H, Groot C, Barthel H et al. Connectivity as a universal predictor of tau progression in atypical Alzheimer's disease. Brain : a journal of neurology. 2025.", "doi": "10.1093/brain/awaf279", "pmcid": "PMC12588720", "url": "https://pubmed.ncbi.nlm.nih.gov/40810361/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40810361/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID40810361", "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": "Across 320 atypical AD PET cases, 78 longitudinal cases and 93 independent autopsies, functional connectivity predicted variant-specific tau patterns and accumulation.", "what_it_does_not_show": "The connectome comes from healthy controls and epicentres are inferred from baseline/accumulation; covariance cannot distinguish tau transfer from network-linked vulnerability or activity.", "confounders_present": [ "The connectome comes from healthy controls and epicentres are inferred from baseline/accumulation; covariance cannot distinguish tau transfer from network-linked vulnerability or activity." ], "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": "39153526", "title": "Increased between-network connectivity: A risk factor for tau elevation and disease progression.", "citation": "Hojjati SH, Butler TA, Luchsinger JA et al. Increased between-network connectivity: A risk factor for tau elevation and disease progression. Neuroscience letters. 2024.", "doi": "10.1016/j.neulet.2024.137943", "pmcid": "PMC11459384", "url": "https://pubmed.ncbi.nlm.nih.gov/39153526/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39153526/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID39153526", "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": "In 46 older participants, increased between-network connectivity predicted later tau PET elevation, cortical thinning and lower delayed recall, particularly with amyloid positivity.", "what_it_does_not_show": "Small observational clustering and correlated vulnerability do not demonstrate molecular movement or recipient templating.", "confounders_present": [ "Small observational clustering and correlated vulnerability do not demonstrate molecular movement or recipient templating." ], "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": "17270732", "title": "Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model.", "citation": "Yoshiyama Y, Higuchi M, Zhang B et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron. 2007.", "doi": "10.1016/j.neuron.2007.01.010", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/17270732/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17270732/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID17270732", "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", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Synaptic loss and microgliosis preceded fibrillar tangles in P301S mice; broad FK506 immunosuppression attenuated pathology and increased lifespan.", "what_it_does_not_show": "Earlier dysfunction weakens a mature-tangle-only model; broad immunosuppression and mutant expression do not identify spread mediation. A linked erratum lacks an identifier and its details remain unexamined.", "confounders_present": [ "Earlier dysfunction weakens a mature-tangle-only model; broad immunosuppression and mutant expression do not identify spread mediation. A linked erratum lacks an identifier and its details remain 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": 27, "pmid": "34314701", "title": "ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids.", "citation": "Bowles KR, Silva MC, Whitney K et al. ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids. Cell. 2021.", "doi": "10.1016/j.cell.2021.07.003", "pmcid": "PMC8635409", "url": "https://pubmed.ncbi.nlm.nih.gov/34314701/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34314701/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID34314701", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "organoid", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Isogenic MAPT-V337M organoids developed splicing/autophagy changes before selective glutamatergic-neuron loss; PIKFYVE inhibition rescued glutamate toxicity.", "what_it_does_not_show": "This establishes a familial cell-intrinsic vulnerability route in organoids, not organismal follow-through or intercellular propagation dependency.", "confounders_present": [ "This establishes a familial cell-intrinsic vulnerability route in organoids, not organismal follow-through or intercellular propagation dependency." ], "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": "33831349", "title": "Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia.", "citation": "Wang C, Xiong M, Gratuze M et al. Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia. Neuron. 2021.", "doi": "10.1016/j.neuron.2021.03.024", "pmcid": "PMC8141024", "url": "https://pubmed.ncbi.nlm.nih.gov/33831349/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33831349/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID33831349", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Conditional astrocytic APOE4 removal after pathology onset protected against neurodegeneration and synaptic loss in P301S mice and reduced microglial phagocytosis.", "what_it_does_not_show": "A real glial causal contribution need not be mediated by tau transfer; mutant-tau and APOE context restrict generalization.", "confounders_present": [ "A real glial causal contribution need not be mediated by tau transfer; mutant-tau and APOE context restrict generalization." ], "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": "33472038", "title": "Lowering Synaptogyrin-3 expression rescues Tau-induced memory defects and synaptic loss in the presence of microglial activation.", "citation": "Largo-Barrientos P, Apóstolo N, Creemers E et al. Lowering Synaptogyrin-3 expression rescues Tau-induced memory defects and synaptic loss in the presence of microglial activation. Neuron. 2021.", "doi": "10.1016/j.neuron.2020.12.016", "pmcid": "PMC7927913", "url": "https://pubmed.ncbi.nlm.nih.gov/33472038/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33472038/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID33472038", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Reducing Synaptogyrin-3 rescued mutant-tau synaptic plasticity, memory and synapse loss while neuroinflammation remained elevated.", "what_it_does_not_show": "The contrast identifies synaptic toxicity independent of persistent glial activation; it does not directly test pathological species transfer.", "confounders_present": [ "The contrast identifies synaptic toxicity independent of persistent glial activation; it does not directly test pathological species transfer." ], "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": "30878534", "title": "Regional vulnerability and spreading of hyperphosphorylated tau in seeded mouse brain.", "citation": "Detrez JR, Maurin H, Van Kolen K et al. Regional vulnerability and spreading of hyperphosphorylated tau in seeded mouse brain. Neurobiology of disease. 2019.", "doi": "10.1016/j.nbd.2019.03.010", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/30878534/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30878534/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID30878534", "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": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Whole-brain mapping showed injected fibrils produced a more AD-like pattern than spontaneous P301L pathology; deposits also appeared beyond direct connections and antibody treatment reduced burden.", "what_it_does_not_show": "Choosing a seed to improve resemblance is not natural disease validation, and static connectivity plus antibody effects does not isolate physical transfer-driven neuronal loss.", "confounders_present": [ "Choosing a seed to improve resemblance is not natural disease validation, and static connectivity plus antibody effects does not isolate physical transfer-driven neuronal loss." ], "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": "37812432", "title": "Tau Oligomer-Containing Synapse Elimination by Microglia and Astrocytes in Alzheimer Disease.", "citation": "Taddei RN, Perbet R, Mate de Gerando A et al. Tau Oligomer-Containing Synapse Elimination by Microglia and Astrocytes in Alzheimer Disease. JAMA neurology. 2023.", "doi": "10.1001/jamaneurol.2023.3530", "pmcid": "PMC10562992", "url": "https://pubmed.ncbi.nlm.nih.gov/37812432/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37812432/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID37812432", "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", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Among 40 autopsies, dementia cases had more tau-oligomer-tagged synapses within glia and lower synaptic density than resilient cases with similar Braak stage.", "what_it_does_not_show": "Cross-sectional engulfment and matching cannot show that transfer or glial activity caused the antecedent cognitive decline; tangle-equivalent resilience challenges burden-only explanations.", "confounders_present": [ "Cross-sectional engulfment and matching cannot show that transfer or glial activity caused the antecedent cognitive decline; tangle-equivalent resilience challenges burden-only explanations." ], "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": "29398363", "title": "Synaptogyrin-3 Mediates Presynaptic Dysfunction Induced by Tau.", "citation": "McInnes J, Wierda K, Snellinx A et al. Synaptogyrin-3 Mediates Presynaptic Dysfunction Induced by Tau. Neuron. 2018.", "doi": "10.1016/j.neuron.2018.01.022", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/29398363/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29398363/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID29398363", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Synaptogyrin-3 reduction in fly and mouse tauopathy restored vesicle mobility and neurotransmission by reducing pathological tau-vesicle association.", "what_it_does_not_show": "This narrows a presynaptic toxicity mechanism, not templated propagation; engineered tau systems and conserved synaptic function require separate generalization.", "confounders_present": [ "This narrows a presynaptic toxicity mechanism, not templated propagation; engineered tau systems and conserved synaptic function require separate generalization." ], "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": "32236736", "title": "PTEN activation contributes to neuronal and synaptic engulfment by microglia in tauopathy.", "citation": "Benetatos J, Bennett RE, Evans HT et al. PTEN activation contributes to neuronal and synaptic engulfment by microglia in tauopathy. Acta neuropathologica. 2020.", "doi": "10.1007/s00401-020-02151-9", "pmcid": "PMC7300099", "url": "https://pubmed.ncbi.nlm.nih.gov/32236736/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32236736/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID32236736", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "PTEN activation and phosphatidylserine exposure preceded neuronal-structure engulfment in rTg4510 mice; PTEN inhibition reduced microglial uptake.", "what_it_does_not_show": "Synaptic tagging and engulfment are rival or downstream toxicity mechanisms, and pharmacology plus mutant overexpression do not isolate templated transfer.", "confounders_present": [ "Synaptic tagging and engulfment are rival or downstream toxicity mechanisms, and pharmacology plus mutant overexpression do not isolate templated transfer." ], "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": "36730056", "title": "Tilavonemab in early Alzheimer's disease: results from a phase 2, randomized, double-blind study.", "citation": "Florian H, Wang D, Arnold SE et al. Tilavonemab in early Alzheimer's disease: results from a phase 2, randomized, double-blind study. Brain : a journal of neurology. 2023.", "doi": "10.1093/brain/awad024", "pmcid": "PMC10232284", "url": "https://pubmed.ncbi.nlm.nih.gov/36730056/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36730056/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID36730056", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph0, 2:Results:paragraph17, 2:Results:paragraph20, 2:Results:paragraph21, 2:Results:paragraph22, 2:Results:paragraph25. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "null", "what_it_shows": "Tilavonemab failed to improve 96-week CDR-SB versus placebo in 453 randomized early-AD participants.", "what_it_does_not_show": "This is a clinical efficacy null for a particular antibody, not a demonstration that every pathogenic tau pool was neutralized or propagation selectively blocked. Original Results confirm lower free CSF tau at higher doses, higher plasma total tau and no tau PET or NfL response. Isolated MRI differences lacked multiplicity adjustment.", "confounders_present": [ "This is a clinical efficacy null for a particular antibody, not a demonstration that every pathogenic tau pool was neutralized or propagation selectively blocked. Original Results confirm lower free CSF tau at higher doses, higher plasma total tau and no tau PET or NfL response. Isolated MRI differences lacked multiplicity adjustment." ], "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": "35696185", "title": "Safety and Efficacy of Semorinemab in Individuals With Prodromal to Mild Alzheimer Disease: A Randomized Clinical Trial.", "citation": "Teng E, Manser PT, Pickthorn K et al. Safety and Efficacy of Semorinemab in Individuals With Prodromal to Mild Alzheimer Disease: A Randomized Clinical Trial. JAMA neurology. 2022.", "doi": "10.1001/jamaneurol.2022.1375", "pmcid": "PMC9194753", "url": "https://pubmed.ncbi.nlm.nih.gov/35696185/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35696185/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "TAURIEL", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "null", "what_it_shows": "TAURIEL semorinemab produced no slowing of 73-week CDR-SB progression in the 422-person modified intention-to-treat cohort.", "what_it_does_not_show": "A symptomatic N-terminal antibody trial does not verify selective interruption of intracellular recipient conversion; failure restricts this clinical strategy.", "confounders_present": [ "A symptomatic N-terminal antibody trial does not verify selective interruption of intracellular recipient conversion; failure restricts this clinical strategy." ], "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": "34385707", "title": "Safety and efficacy of anti-tau monoclonal antibody gosuranemab in progressive supranuclear palsy: a phase 2, randomized, placebo-controlled trial.", "citation": "Dam T, Boxer AL, Golbe LI et al. Safety and efficacy of anti-tau monoclonal antibody gosuranemab in progressive supranuclear palsy: a phase 2, randomized, placebo-controlled trial. Nature medicine. 2021.", "doi": "10.1038/s41591-021-01455-x", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/34385707/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34385707/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "ErratumIn: PMID36253611" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID34385707", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "null", "what_it_shows": "PASSPORT gosuranemab showed no PSPRS or secondary clinical benefit in 486 dosed PSP patients despite a 98 percent fall in unbound N-terminal CSF tau.", "what_it_does_not_show": "Strong fluid target engagement is not complete seed neutralization or proof of all pathogenic-pool blockade; a linked author correction is attached to the parent.", "confounders_present": [ "Strong fluid target engagement is not complete seed neutralization or proof of all pathogenic-pool blockade; a linked author correction is attached to the parent." ], "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": "39513754", "title": "Pharmacodynamic effects of semorinemab on plasma and CSF biomarkers of Alzheimer's disease pathophysiology.", "citation": "Schauer SP, Toth B, Lee J et al. Pharmacodynamic effects of semorinemab on plasma and CSF biomarkers of Alzheimer's disease pathophysiology. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2024.", "doi": "10.1002/alz.14346", "pmcid": "PMC11667501", "url": "https://pubmed.ncbi.nlm.nih.gov/39513754/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39513754/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "TAURIEL-and-LAURIET-biomarker-reanalysis", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Semorinemab biomarker analyses from TAURIEL and LAURIET showed increased CSF YKL-40 and plasma pTau181, with GFAP stabilization in LAURIET but not TAURIEL.", "what_it_does_not_show": "These are reused trial samples and mechanistic biomarker effects, not new independent efficacy trials or direct evidence of beneficial microglial mediation.", "confounders_present": [ "These are reused trial samples and mechanistic biomarker effects, not new independent efficacy trials or direct evidence of beneficial microglial mediation." ], "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": [ "Reuses TAURIEL and LAURIET samples; no new efficacy randomization." ] }, { "n": 38, "pmid": "38012285", "title": "TANGO: a placebo-controlled randomized phase 2 study of efficacy and safety of the anti-tau monoclonal antibody gosuranemab in early Alzheimer's disease.", "citation": "Shulman M, Kong J, O'Gorman J et al. TANGO: a placebo-controlled randomized phase 2 study of efficacy and safety of the anti-tau monoclonal antibody gosuranemab in early Alzheimer's disease. Nature aging. 2023.", "doi": "10.1038/s43587-023-00523-w", "pmcid": "PMC10724064", "url": "https://pubmed.ncbi.nlm.nih.gov/38012285/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38012285/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID38012285", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph19, 1:Results:paragraph23, 1:Results:paragraph28, 1:Results:paragraph33, 1:Results:paragraph38. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "null", "what_it_shows": "TANGO randomized 654 early-AD participants and showed no favorable cognitive/functional CDR-SB change with gosuranemab despite reduced unbound N-terminal CSF tau.", "what_it_does_not_show": "Safety was primary and clinical efficacy secondary; drug engagement of a soluble N-terminal pool does not demonstrate selective blockade of all tau propagation. Original Results confirm 80.1–92.6 percent unbound N-terminal CSF tau reduction, no tau-PET dose response and no favorable atrophy response. An isolated exploratory cognitive result was worse, without a dose response; it is not treated as a definitive toxicity test.", "confounders_present": [ "Safety was primary and clinical efficacy secondary; drug engagement of a soluble N-terminal pool does not demonstrate selective blockade of all tau propagation. Original Results confirm 80.1–92.6 percent unbound N-terminal CSF tau reduction, no tau-PET dose response and no favorable atrophy response. An isolated exploratory cognitive result was worse, without a dose response; it is not treated as a definitive toxicity test." ], "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": "38386949", "title": "Assessment of Efficacy and Safety of Zagotenemab: Results From PERISCOPE-ALZ, a Phase 2 Study in Early Symptomatic Alzheimer Disease.", "citation": "Fleisher AS, Munsie LM, Perahia DGS et al. Assessment of Efficacy and Safety of Zagotenemab: Results From PERISCOPE-ALZ, a Phase 2 Study in Early Symptomatic Alzheimer Disease. Neurology. 2024.", "doi": "10.1212/WNL.0000000000208061", "pmcid": "PMC11067698", "url": "https://pubmed.ncbi.nlm.nih.gov/38386949/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38386949/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "ErratumIn: PMID40184595" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID38386949", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "null", "what_it_shows": "PERISCOPE-ALZ zagotenemab did not slow clinical progression in 360 randomized participants; PET, MRI and NfL showed no disease-modifying response.", "what_it_does_not_show": "Only 218 completed treatment and pathogenic brain engagement was not established; plasma tau increases do not prove seed neutralization. A linked correction remains qualified.", "confounders_present": [ "Only 218 completed treatment and pathogenic brain engagement was not established; plasma tau increases do not prove seed neutralization. A linked correction remains qualified." ], "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": "37643887", "title": "Randomized Phase II Study of the Safety and Efficacy of Semorinemab in Participants With Mild-to-Moderate Alzheimer Disease: Lauriet.", "citation": "Monteiro C, Toth B, Brunstein F et al. Randomized Phase II Study of the Safety and Efficacy of Semorinemab in Participants With Mild-to-Moderate Alzheimer Disease: Lauriet. Neurology. 2023.", "doi": "10.1212/WNL.0000000000207663", "pmcid": "PMC10573141", "url": "https://pubmed.ncbi.nlm.nih.gov/37643887/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37643887/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "LAURIET", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph8, 2:Results:paragraph15, 2:Results:paragraph17, 2:Results:paragraph19, 2:Results:paragraph20. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "LAURIET semorinemab improved ADAS-Cog11 decline at week 49 but not the coprimary activities-of-daily-living endpoint or global secondary measures.", "what_it_does_not_show": "The prespecified coprimary trial result was negative; isolated cognitive benefit is credited without being relabeled overall efficacy or propagation-mediated neuroprotection. Original Results confirm a 2.89-point ADAS-Cog11 difference at week 49, with the largest post hoc item effect in word recognition. CSF tau fell but PET accumulation and atrophy rates did not differ.", "confounders_present": [ "The prespecified coprimary trial result was negative; isolated cognitive benefit is credited without being relabeled overall efficacy or propagation-mediated neuroprotection. Original Results confirm a 2.89-point ADAS-Cog11 difference at week 49, with the largest post hoc item effect in word recognition. CSF tau fell but PET accumulation and atrophy rates did not differ." ], "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": "41789119", "title": "Safety, tolerability and biomarker results of bepranemab in participants with progressive supranuclear palsy: a randomised, multicentre, double-blind, placebo-controlled, phase 1b trial.", "citation": "Höglinger G, Vandenberghe W, Woitalla D et al. Safety, tolerability and biomarker results of bepranemab in participants with progressive supranuclear palsy: a randomised, multicentre, double-blind, placebo-controlled, phase 1b trial. BMJ neurology open. 2026.", "doi": "10.1136/bmjno-2025-001396", "pmcid": "PMC12958890", "url": "https://pubmed.ncbi.nlm.nih.gov/41789119/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41789119/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID41789119", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "A 25-person bepranemab PSP phase 1b trial reported acceptable safety and about 80 percent reduction in mean free CSF tau.", "what_it_does_not_show": "Safety and target occupancy are not clinical disease modification; small phase 1 enrollment cannot settle whether mid-region neutralization blocks propagation-driven degeneration.", "confounders_present": [ "Safety and target occupancy are not clinical disease modification; small phase 1 enrollment cannot settle whether mid-region neutralization blocks propagation-driven degeneration." ], "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": "37988169", "title": "Galectin-3 aggravates microglial activation and tau transmission in tauopathy.", "citation": "Siew JJ, Chen HM, Chiu FL et al. Galectin-3 aggravates microglial activation and tau transmission in tauopathy. The Journal of clinical investigation. 2024.", "doi": "10.1172/JCI165523", "pmcid": "PMC10786694", "url": "https://pubmed.ncbi.nlm.nih.gov/37988169/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37988169/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID37988169", "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": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Galectin-3 deletion in THY-Tau22 mice reduced activation, tau pathology and synaptic loss and rescued memory; cell studies linked Gal3 to EV release and fibrillation.", "what_it_does_not_show": "Genetic removal also changes broad immune responses; the two arms do not isolate propagation as the uniquely causal neuroprotective mediator.", "confounders_present": [ "Genetic removal also changes broad immune responses; the two arms do not isolate propagation as the uniquely causal neuroprotective mediator." ], "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": "39814008", "title": "ApoE3 R136S binds to Tau and blocks its propagation, suppressing neurodegeneration in mice with Alzheimer's disease.", "citation": "Chen G, Wang M, Zhang Z et al. ApoE3 R136S binds to Tau and blocks its propagation, suppressing neurodegeneration in mice with Alzheimer's disease. Neuron. 2025.", "doi": "10.1016/j.neuron.2024.12.015", "pmcid": "PMC12376192", "url": "https://pubmed.ncbi.nlm.nih.gov/39814008/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39814008/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID39814008", "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": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "ApoE3-Christchurch reduced tau uptake and fragmentation, seeded spread, inflammatory signals and cognitive defects relative to wild-type ApoE3 in amyloid and P301S models.", "what_it_does_not_show": "APOE changes several uptake, inflammatory and proteolytic pathways, and PFF initiation remains imposed; a natural human variant does not isolate propagation mediation here.", "confounders_present": [ "APOE changes several uptake, inflammatory and proteolytic pathways, and PFF initiation remains imposed; a natural human variant does not isolate propagation mediation here." ], "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": "19503072", "title": "Transmission and spreading of tauopathy in transgenic mouse brain.", "citation": "Clavaguera F, Bolmont T, Crowther RA et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nature cell biology. 2009.", "doi": "10.1038/ncb1901", "pmcid": "PMC2726961", "url": "https://pubmed.ncbi.nlm.nih.gov/19503072/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19503072/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID19503072", "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": "Mutant-P301S brain extract induced filament assembly of wild-type human tau and regional pathology in inoculated transgenic recipients.", "what_it_does_not_show": "The recipients express human tau and receive artificial intracerebral exposure; capability is not natural cell-to-cell necessity or neurodegeneration mediation.", "confounders_present": [ "The recipients express human tau and receive artificial intracerebral exposure; capability is not natural cell-to-cell necessity or neurodegeneration mediation." ], "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": "22365544", "title": "Propagation of tau pathology in a model of early Alzheimer's disease.", "citation": "de Calignon A, Polydoro M, Suárez-Calvet M et al. Propagation of tau pathology in a model of early Alzheimer's disease. Neuron. 2012.", "doi": "10.1016/j.neuron.2011.11.033", "pmcid": "PMC3292759", "url": "https://pubmed.ncbi.nlm.nih.gov/22365544/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22365544/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID22365544", "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", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Entorhinal-restricted P301L expression was followed by human tau in connected neurons lacking detectable transgene, coaggregation with mouse tau, synapse degeneration and EC loss.", "what_it_does_not_show": "Low-level expression detection and source-cell deafferentation complicate inference; mutant overexpression does not isolate selective endogenous templating. Linked erratum details are unexamined.", "confounders_present": [ "Low-level expression detection and source-cell deafferentation complicate inference; mutant overexpression does not isolate selective endogenous templating. Linked erratum details are 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": 46, "pmid": "40390134", "title": "hiPSC-neurons recapitulate the subtype-specific cell intrinsic nature of susceptibility to neurodegenerative disease-relevant aggregation.", "citation": "Weidling I, Preiss CN, Chancellor SE et al. hiPSC-neurons recapitulate the subtype-specific cell intrinsic nature of susceptibility to neurodegenerative disease-relevant aggregation. Acta neuropathologica communications. 2025.", "doi": "10.1186/s40478-025-02000-4", "pmcid": "PMC12087151", "url": "https://pubmed.ncbi.nlm.nih.gov/40390134/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40390134/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID40390134", "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": "cell culture", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Different human iPSC neuronal subtypes showed distinct susceptibility to identical tau or synuclein seeds; uptake/degradation did not explain the tau differences.", "what_it_does_not_show": "This supports intrinsic vulnerability as a contributor to regional patterns; imposed aggregates and cultured neurons do not establish the full human progression mechanism.", "confounders_present": [ "This supports intrinsic vulnerability as a contributor to regional patterns; imposed aggregates and cultured neurons do not establish the full human progression 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": 47, "pmid": "39841807", "title": "Amyloid-associated hyperconnectivity drives tau spread across connected brain regions in Alzheimer's disease.", "citation": "Roemer-Cassiano SN, Wagner F, Evangelista L et al. Amyloid-associated hyperconnectivity drives tau spread across connected brain regions in Alzheimer's disease. Science translational medicine. 2025.", "doi": "10.1126/scitranslmed.adp2564", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/39841807/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39841807/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID39841807", "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": "Two human imaging samples associated amyloid-related hyperconnectivity with later regional tau accumulation, with statistical mediation of the amyloid association.", "what_it_does_not_show": "Observational mediation requires unverified no-confounding assumptions and does not trace molecular transfer; the paper's causal wording exceeds selective perturbation evidence.", "confounders_present": [ "Observational mediation requires unverified no-confounding assumptions and does not trace molecular transfer; the paper's causal wording exceeds selective perturbation evidence." ], "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": "38072056", "title": "Tau seeding without tauopathy.", "citation": "LaCroix MS, Artikis E, Hitt BD et al. Tau seeding without tauopathy. The Journal of biological chemistry. 2024.", "doi": "10.1016/j.jbc.2023.105545", "pmcid": "PMC10797195", "url": "https://pubmed.ncbi.nlm.nih.gov/38072056/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38072056/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID38072056", "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": "mixed", "what_it_shows": "Seed-enriched material from 19 neurologically normal human brains showed parietal-cortex seeding by two amplification assays without conventional tau pathology.", "what_it_does_not_show": "Control seeds differed conformationally from AD seeds; seeding positivity alone is not pathological progression, and assay amplification is not natural neuronal conversion.", "confounders_present": [ "Control seeds differed conformationally from AD seeds; seeding positivity alone is not pathological progression, and assay amplification is not natural neuronal conversion." ], "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": "41610849", "title": "CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis.", "citation": "Samelson AJ, Ariqat N, McKetney J et al. CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis. Cell. 2026.", "doi": "10.1016/j.cell.2025.12.038", "pmcid": "PMC12978015", "url": "https://pubmed.ncbi.nlm.nih.gov/41610849/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41610849/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID37398204" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID41610849", "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", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell culture", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Human-neuron CRISPR screens identified tau proteostasis dependencies including UFMylation, GPI biosynthesis and CRL5-SOCS4, with mitochondrial disruption generating altered tau fragments.", "what_it_does_not_show": "Cellular aggregation control and disease correlation do not demonstrate intercellular spread or clinical neuroprotection; the linked preprint is not a second study.", "confounders_present": [ "Cellular aggregation control and disease correlation do not demonstrate intercellular spread or clinical neuroprotection; the linked preprint is not a second study." ], "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": "34635189", "title": "Anatomic survey of seeding in Alzheimer's disease brains reveals unexpected patterns.", "citation": "Stopschinski BE, Del Tredici K, Estill-Terpack SJ et al. Anatomic survey of seeding in Alzheimer's disease brains reveals unexpected patterns. Acta neuropathologica communications. 2021.", "doi": "10.1186/s40478-021-01255-x", "pmcid": "PMC8507321", "url": "https://pubmed.ncbi.nlm.nih.gov/34635189/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34635189/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID38835097" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID34635189", "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": "mixed", "what_it_shows": "Twenty AD brains sampled across 25 regions showed seeding before some AT8 pathology and in unexpected sites including axons and Bergmann glia.", "what_it_does_not_show": "Cross-sectional seed maps are not lineage tracing and complicate a single canonical regional sequence; the linked correction requires qualification.", "confounders_present": [ "Cross-sectional seed maps are not lineage tracing and complicate a single canonical regional sequence; the linked correction requires qualification." ], "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": "33246962", "title": "Patient-centered connectivity-based prediction of tau pathology spread in Alzheimer's disease.", "citation": "Franzmeier N, Dewenter A, Frontzkowski L et al. Patient-centered connectivity-based prediction of tau pathology spread in Alzheimer's disease. Science advances. 2020.", "doi": "10.1126/sciadv.abd1327", "pmcid": "PMC7695466", "url": "https://pubmed.ncbi.nlm.nih.gov/33246962/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33246962/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID33246962", "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": "Patient-specific connectivity predicted longitudinal tau accumulation in two imaging samples better than fixed Braak readouts; simulated trials required smaller samples.", "what_it_does_not_show": "Simulated intervention efficiency is not a conducted therapeutic test, and model fit cannot establish physical transfer or necessity.", "confounders_present": [ "Simulated intervention efficiency is not a conducted therapeutic test, and model fit cannot establish physical transfer or necessity." ], "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": [ "Human PET/connectivity datasets may overlap HABS/ADNI diffusion analyses." ] }, { "n": 52, "pmid": "33957234", "title": "Longitudinal predictive modeling of tau progression along the structural connectome.", "citation": "Yang F, Chowdhury SR, Jacobs HIL et al. Longitudinal predictive modeling of tau progression along the structural connectome. NeuroImage. 2021.", "doi": "10.1016/j.neuroimage.2021.118126", "pmcid": "PMC8260445", "url": "https://pubmed.ncbi.nlm.nih.gov/33957234/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33957234/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID33957234", "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": "A structural-connectome diffusion model fit two-timepoint HABS/ADNI PET and predicted a third measurement in available participants.", "what_it_does_not_show": "Source/clearance terms and graph diffusion are mathematical assumptions, not measured intracellular conversion; cohort and imaging overlap restrict independence.", "confounders_present": [ "Source/clearance terms and graph diffusion are mathematical assumptions, not measured intracellular conversion; cohort and imaging overlap restrict independence." ], "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": [ "HABS/ADNI cohorts overlap other PET literature; not wholly independent participants." ] }, { "n": 53, "pmid": "33752701", "title": "Plaque associated microglia hyper-secrete extracellular vesicles and accelerate tau propagation in a humanized APP mouse model.", "citation": "Clayton K, Delpech JC, Herron S et al. Plaque associated microglia hyper-secrete extracellular vesicles and accelerate tau propagation in a humanized APP mouse model. Molecular neurodegeneration. 2021.", "doi": "10.1186/s13024-021-00440-9", "pmcid": "PMC7986521", "url": "https://pubmed.ncbi.nlm.nih.gov/33752701/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33752701/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID33853665" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID33752701", "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": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Microglial depletion reduced AAV-tau spread in wild-type and APP-knock-in mice but increased plaques and plaque-associated dystrophic-neurite tau; tagged microglial EVs carried tau.", "what_it_does_not_show": "Depletion changes clearance and injury as well as transfer, so reduced distal signal cannot be relabeled uniform protection. A linked correction remains attached.", "confounders_present": [ "Depletion changes clearance and injury as well as transfer, so reduced distal signal cannot be relabeled uniform protection. A linked correction remains attached." ], "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": "36344699", "title": "Bassoon contributes to tau-seed propagation and neurotoxicity.", "citation": "Martinez P, Patel H, You Y et al. Bassoon contributes to tau-seed propagation and neurotoxicity. Nature neuroscience. 2022.", "doi": "10.1038/s41593-022-01191-6", "pmcid": "PMC9708566", "url": "https://pubmed.ncbi.nlm.nih.gov/36344699/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36344699/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID36344699", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph21, 1:Results:paragraph26, 1:Results:paragraph33, 1:Results:paragraph36, 1:Results:paragraph44. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Bassoon downregulation reduced tau seed-associated pathology and spread and rescued synaptic/behavioral defects and atrophy in experimental tauopathy systems.", "what_it_does_not_show": "Bassoon regulates presynaptic function and seed stability as well as transport; matching source toxicity and selective recipient conversion remains essential to propagation mediation. Original Results show unchanged total human tau after preventive P0 Bassoon shRNA, and source GFP controls in the separate AAV transfer arm. These controls strengthen seed-mediated contribution but do not make presynaptic Bassoon a transfer-only intervention.", "confounders_present": [ "Bassoon regulates presynaptic function and seed stability as well as transport; matching source toxicity and selective recipient conversion remains essential to propagation mediation. Original Results show unchanged total human tau after preventive P0 Bassoon shRNA, and source GFP controls in the separate AAV transfer arm. These controls strengthen seed-mediated contribution but do not make presynaptic Bassoon a transfer-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": 55, "pmid": "34100905", "title": "Activated microglia mitigate Aβ-associated tau seeding and spreading.", "citation": "Gratuze M, Chen Y, Parhizkar S et al. Activated microglia mitigate Aβ-associated tau seeding and spreading. The Journal of experimental medicine. 2021.", "doi": "10.1084/jem.20210542", "pmcid": "PMC8190588", "url": "https://pubmed.ncbi.nlm.nih.gov/34100905/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34100905/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID34100905", "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": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "TREM2 deficiency or microglial ablation increased amyloid-associated tau seeding/spread, and repopulated microglia did not recover the protective activation state.", "what_it_does_not_show": "This shows protective microglial function in an amyloid-seeded context and contradicts universal beneficial depletion; seed burden is not equivalent to neuron-loss causality.", "confounders_present": [ "This shows protective microglial function in an amyloid-seeded context and contradicts universal beneficial depletion; seed burden is not equivalent to neuron-loss causality." ], "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": "29686391", "title": "Tau Internalization is Regulated by 6-O Sulfation on Heparan Sulfate Proteoglycans (HSPGs).", "citation": "Rauch JN, Chen JJ, Sorum AW et al. Tau Internalization is Regulated by 6-O Sulfation on Heparan Sulfate Proteoglycans (HSPGs). Scientific reports. 2018.", "doi": "10.1038/s41598-018-24904-z", "pmcid": "PMC5913225", "url": "https://pubmed.ncbi.nlm.nih.gov/29686391/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29686391/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID29686391", "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": "cell culture", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "CRISPRi and sulfation manipulation identified HSPG 6-O-sulfation dependence of tau uptake across cells, human-derived neurons and mouse slices.", "what_it_does_not_show": "Uptake is one step; these experiments do not establish intact-animal endogenous transfer, conversion or degeneration dependency.", "confounders_present": [ "Uptake is one step; these experiments do not establish intact-animal endogenous transfer, conversion or degeneration dependency." ], "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": "25887395", "title": "Tau Trimers Are the Minimal Propagation Unit Spontaneously Internalized to Seed Intracellular Aggregation.", "citation": "Mirbaha H, Holmes BB, Sanders DW et al. Tau Trimers Are the Minimal Propagation Unit Spontaneously Internalized to Seed Intracellular Aggregation. The Journal of biological chemistry. 2015.", "doi": "10.1074/jbc.M115.652693", "pmcid": "PMC4463437", "url": "https://pubmed.ncbi.nlm.nih.gov/25887395/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25887395/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID25887395", "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": "cell culture", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Fractionated recombinant and AD-derived tau assemblies of at least three units underwent uptake and seeded biosensor aggregation, with HSPG-sensitive entry.", "what_it_does_not_show": "The minimum size depends on preparation and assay; extracellular exposure and reporter amplification do not prove a universal naturally propagating toxic species.", "confounders_present": [ "The minimum size depends on preparation and assay; extracellular exposure and reporter amplification do not prove a universal naturally propagating toxic species." ], "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": "26126828", "title": "Distinct Therapeutic Mechanisms of Tau Antibodies: Promoting Microglial Clearance Versus Blocking Neuronal Uptake.", "citation": "Funk KE, Mirbaha H, Jiang H et al. Distinct Therapeutic Mechanisms of Tau Antibodies: Promoting Microglial Clearance Versus Blocking Neuronal Uptake. The Journal of biological chemistry. 2015.", "doi": "10.1074/jbc.M115.657924", "pmcid": "PMC4571888", "url": "https://pubmed.ncbi.nlm.nih.gov/26126828/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26126828/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID26126828", "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": "cell culture", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Tau antibodies differed in promoting Fc-mediated microglial uptake versus blocking neuronal uptake according to epitope and aggregate preparation/size.", "what_it_does_not_show": "An antibody's pathology benefit cannot be assigned automatically to transfer blockade; this is cultured-cell mechanism analysis, not new in-vivo disease causality.", "confounders_present": [ "An antibody's pathology benefit cannot be assigned automatically to transfer blockade; this is cultured-cell mechanism analysis, not new in-vivo disease causality." ], "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": "40886860", "title": "Spontaneous pathology in PS19 tauopathy mice progresses via brain networks.", "citation": "Ramirez DMO, Whitesell JD, Bhagwat N et al. Spontaneous pathology in PS19 tauopathy mice progresses via brain networks. Neurobiology of disease. 2025.", "doi": "10.1016/j.nbd.2025.107072", "pmcid": "PMC13411113", "url": "https://pubmed.ncbi.nlm.nih.gov/40886860/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40886860/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID37293074" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID40886860", "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": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Whole-brain age-series maps of pan-neuronal P301S PS19 mice fitted retrograde-biased connectivity models without injected seeds.", "what_it_does_not_show": "Spontaneous pathology is valuable but still occurs with widespread mutant human tau expression; modeled phospho-tau progression is not directly traced protein transfer or selective spread blockade.", "confounders_present": [ "Spontaneous pathology is valuable but still occurs with widespread mutant human tau expression; modeled phospho-tau progression is not directly traced protein transfer or selective spread blockade." ], "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": "34714685", "title": "In vivo rate-determining steps of tau seed accumulation in Alzheimer's disease.", "citation": "Meisl G, Hidari E, Allinson K et al. In vivo rate-determining steps of tau seed accumulation in Alzheimer's disease. Science advances. 2021.", "doi": "10.1126/sciadv.abh1448", "pmcid": "PMC8555892", "url": "https://pubmed.ncbi.nlm.nih.gov/34714685/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34714685/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID34714685", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph3, 1:RESULTS:paragraph4, 1:RESULTS:paragraph5, 1:RESULTS:paragraph13, 1:RESULTS:paragraph14, 1:RESULTS:paragraph15, 1:RESULTS:paragraph16, 1:RESULTS:paragraph17. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Kinetic fits across multiple human seed/tau measures suggested local replication, rather than interregional spread, limits neocortical accumulation from Braak III onward.", "what_it_does_not_show": "The inferred approximately five-year seed doubling is model-dependent and stage-specific; it does not show early seeding is irrelevant or experimentally identify a clinical rate-limiting mediator. Original Results explicitly subsume local cell-to-cell transfer into the replication term. The contrast concerns interregional spread, not all transfer; extrapolation before Braak III is untested.", "confounders_present": [ "The inferred approximately five-year seed doubling is model-dependent and stage-specific; it does not show early seeding is irrelevant or experimentally identify a clinical rate-limiting mediator. Original Results explicitly subsume local cell-to-cell transfer into the replication term. The contrast concerns interregional spread, not all transfer; extrapolation before Braak III is untested." ], "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": "39284839", "title": "The cellular prion protein does not affect tau seeding and spreading of sarkosyl-insoluble fractions from Alzheimer's disease.", "citation": "Sala-Jarque J, Gil V, Andrés-Benito P et al. The cellular prion protein does not affect tau seeding and spreading of sarkosyl-insoluble fractions from Alzheimer's disease. Scientific reports. 2024.", "doi": "10.1038/s41598-024-72232-2", "pmcid": "PMC11405773", "url": "https://pubmed.ncbi.nlm.nih.gov/39284839/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39284839/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID39284839", "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": "mixed", "what_it_shows": "Human AD insoluble tau induced host-tau pathology in mice across Prnp genotypes; tau-null and species-specific antibody comparisons supported recipient tau origin, while PrP genotype did not change seeding/spread.", "what_it_does_not_show": "Forced inoculation establishes host conversion capability and excludes an obligatory PrP receptor in this setting, not natural human tau propagation necessity.", "confounders_present": [ "Forced inoculation establishes host conversion capability and excludes an obligatory PrP receptor in this setting, not natural human tau propagation necessity." ], "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": "41691301", "title": "Timing matters: early administration of a high-affinity antibody targeting the tau repeat domain prevents aggregation in a mouse tauopathy model.", "citation": "Penny LK, Arastoo M, Lofthouse R et al. Timing matters: early administration of a high-affinity antibody targeting the tau repeat domain prevents aggregation in a mouse tauopathy model. Alzheimer's research & therapy. 2026.", "doi": "10.1186/s13195-026-01985-x", "pmcid": "PMC13020213", "url": "https://pubmed.ncbi.nlm.nih.gov/41691301/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41691301/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID41691301", "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", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "A repeat-domain antibody reduced seed-competent/aggregated tau and injury biomarkers when started early in Line66 mice, but later treatment did not remove established aggregates below baseline.", "what_it_does_not_show": "The endpoints were aggregation and fluid injury markers, without a reported functional trajectory test; epitope and timing matter but do not establish spread-mediated neuroprotection.", "confounders_present": [ "The endpoints were aggregation and fluid injury markers, without a reported functional trajectory test; epitope and timing matter but do not establish spread-mediated neuroprotection." ], "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": "22312444", "title": "Trans-synaptic spread of tau pathology in vivo.", "citation": "Liu L, Drouet V, Wu JW et al. Trans-synaptic spread of tau pathology in vivo. PloS one. 2012.", "doi": "10.1371/journal.pone.0031302", "pmcid": "PMC3270029", "url": "https://pubmed.ncbi.nlm.nih.gov/22312444/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22312444/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID22312444", "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": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Entorhinal-biased human-tau transgenic mice developed human tau staining and mature pathology in connected hippocampal and cortical regions with age.", "what_it_does_not_show": "Distribution and expression restriction support transfer but do not directly visualize a precursor-product lineage or separate low-level transgene expression from recipient conversion.", "confounders_present": [ "Distribution and expression restriction support transfer but do not directly visualize a precursor-product lineage or separate low-level transgene expression from recipient conversion." ], "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": "31038156", "title": "Prevention of tau seeding and propagation by immunotherapy with a central tau epitope antibody.", "citation": "Albert M, Mairet-Coello G, Danis C et al. Prevention of tau seeding and propagation by immunotherapy with a central tau epitope antibody. Brain : a journal of neurology. 2019.", "doi": "10.1093/brain/awz100", "pmcid": "PMC6536853", "url": "https://pubmed.ncbi.nlm.nih.gov/31038156/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31038156/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID31038156", "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": "A central-epitope antibody neutralized human AD-extract seeding and reduced distal pathology after K18-P301L fibrils, outperforming one N-terminal comparator.", "what_it_does_not_show": "Imposed seeds and transgenic substrate limit inference; reducing secondary pathology is more specific than inoculum neutralization but not proof of clinical neuronal-loss mediation.", "confounders_present": [ "Imposed seeds and transgenic substrate limit inference; reducing secondary pathology is more specific than inoculum neutralization but not proof of clinical neuronal-loss mediation." ], "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": "33179866", "title": "Fate and propagation of endogenously formed Tau aggregates in neuronal cells.", "citation": "Chastagner P, Loria F, Vargas JY et al. Fate and propagation of endogenously formed Tau aggregates in neuronal cells. EMBO molecular medicine. 2020.", "doi": "10.15252/emmm.202012025", "pmcid": "PMC7721367", "url": "https://pubmed.ncbi.nlm.nih.gov/33179866/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33179866/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID33179866", "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": "cell culture", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "A neuronal reporter model visualized K18/AD-seeded aggregate formation and contact-dependent transfer with new deposits in neighboring cells, including nanotube-associated material.", "what_it_does_not_show": "Endogenously formed refers to aggregates formed inside reporter cells after seeding, not native unseeded human disease; tau-fragment reporters and cultures restrict generalization.", "confounders_present": [ "Endogenously formed refers to aggregates formed inside reporter cells after seeding, not native unseeded human disease; tau-fragment reporters and cultures restrict generalization." ], "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": "33005889", "title": "Dextran sulphate-induced tau assemblies cause endogenous tau aggregation and propagation in wild-type mice.", "citation": "Masuda-Suzukake M, Suzuki G, Hosokawa M et al. Dextran sulphate-induced tau assemblies cause endogenous tau aggregation and propagation in wild-type mice. Brain communications. 2020.", "doi": "10.1093/braincomms/fcaa091", "pmcid": "PMC7519727", "url": "https://pubmed.ncbi.nlm.nih.gov/33005889/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33005889/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID33005889", "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": "Dextran-sulfate-assembled full-length tau induced host mouse-tau aggregation and connected-region pathology in nontransgenic mice after intracerebral injection.", "what_it_does_not_show": "This removes a recipient overexpression requirement but retains artificial seed creation and forced entry; it is not observation of spontaneous human transmission.", "confounders_present": [ "This removes a recipient overexpression requirement but retains artificial seed creation and forced entry; it is not observation of spontaneous human transmission." ], "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": 71, "verified": 71, "unverified": 0, "contradicted": 0, "note": "Verified attribution is distinct from mechanism truth or complete body access." }, "factual_issues_found": [], "cap_rules_applied": [ { "subclaim_id": "SC3", "cap": "Γ", "cap_source": "rubric", "triggered": true, "trigger_text_quoted": "Exogenous seeding models alone", "specific_trigger": "Wild-type recipients, mouse-specific antibody and tau-null/species-specific comparisons strengthen physiological host-tau conversion after imposed seeds. These establish important bounded capabilities. The registered transferred endogenous pathway remains reliant on forced initiation; host recruitment alone does not prove natural disease necessity.", "resulting_ceiling": "Γ" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Pathological tau spreads between anatomically connected neurons by templated seeding, and this cell-to-cell propagation drives the progression of neurodegeneration in tauopathies.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "The neurodegeneration rubric credits endogenous mediator perturbation only within the actual tested system. Recipient physiological tau conversion after injected seeds is real capability but remains subject to the exogenous-seeding ceiling for the natural propagation subclaim. Longitudinal human temporal data exceed a static-association-only Β rule, yet do not establish physical transfer. Bassoon and Arc are endogenous manipulations in engineered tau backgrounds; their controls strengthen specific model claims without proving the full propagation mediator. The assembled evidence is assessed together without re-capping independent convergence.", "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": "PMID37902726, PMID17270732, PMID30878534, PMID40390134", "gamma_hard_rules_triggered": [ "Forced seeds alone do not establish endogenous propagation necessity.", "Overexpressed source tau does not by itself identify natural human precursor-product transfer.", "Fluid or PET movement is not clinical neuroprotection.", "Convergent lines were assessed together; the unresolved mediator remains selective propagation, not the absence of an all-purpose RCT." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Longitudinal PET predicts later accumulation along connected systems, supported by anatomical and perturbational models. This is temporal proof beyond static association, but physical propagation is inferred and disease-pattern exceptions remain. The causal explanation of human network progression is Γ.", "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": "no", "qualifying_evidence_citation": "PMID26436904, PMID39736627, PMID42372723, PMID32296178, PMID36056435, PMID33246331, PMID27322420, PMID38049923, PMID26538322, PMID36297501, PMID25862635, PMID23946388, PMID30878534, PMID37988169, PMID39814008, PMID22365544, PMID33752701, PMID36344699, PMID34100905, PMID29686391, PMID25887395, PMID26126828, PMID31038156, PMID33179866, PMID33005889", "gamma_hard_rules_triggered": [ "Forced seeds alone do not establish endogenous propagation necessity.", "Overexpressed source tau does not by itself identify natural human precursor-product transfer.", "Fluid or PET movement is not clinical neuroprotection.", "Convergent lines were assessed together; the unresolved mediator remains selective propagation, not the absence of an all-purpose RCT." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Donor-restricted models, receptor perturbations and activity experiments establish transport capability. Spontaneous PS19 patterns lack injected seeds but retain widespread mutant tau expression. Direct endogenous lineage transfer under natural disease conditions has not been separated from recipient expression and selective vulnerability.", "ceiling_from_boundary_check": "Γ" }, { "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": "PMID27974162, PMID33417012, PMID33246331, PMID24857020, PMID26538322, PMID39500576, PMID30526844, PMID25862635, PMID19503072, PMID22365544, PMID40390134, PMID41610849, PMID36344699, PMID25887395, PMID39284839, PMID41691301, PMID31038156, PMID33179866, PMID33005889", "gamma_hard_rules_triggered": [ "Forced seeds alone do not establish endogenous propagation necessity.", "Overexpressed source tau does not by itself identify natural human precursor-product transfer.", "Fluid or PET movement is not clinical neuroprotection.", "Convergent lines were assessed together; the unresolved mediator remains selective propagation, not the absence of an all-purpose RCT." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Wild-type recipients, mouse-specific antibody and tau-null/species-specific comparisons strengthen physiological host-tau conversion after imposed seeds. These establish important bounded capabilities. The registered transferred endogenous pathway remains reliant on forced initiation; host recruitment alone does not prove natural disease necessity.", "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": "PMID26436904, PMID42372723, PMID36056435, PMID33246331, PMID27322420, PMID38049923, PMID26538322, PMID25862635, PMID23946388, PMID37902726, PMID37095250, PMID17270732, PMID34314701, PMID33831349, PMID33472038, PMID29398363, PMID32236736, PMID39513754, PMID37643887, PMID41789119, PMID37988169, PMID39814008, PMID22365544, PMID41610849, PMID33752701, PMID36344699, PMID34100905, PMID41691301", "gamma_hard_rules_triggered": [ "Forced seeds alone do not establish endogenous propagation necessity.", "Overexpressed source tau does not by itself identify natural human precursor-product transfer.", "Fluid or PET movement is not clinical neuroprotection.", "Convergent lines were assessed together; the unresolved mediator remains selective propagation, not the absence of an all-purpose RCT." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Bassoon, exosome-pathway, antibody and source-suppression contrasts affect pathology or function, but also source tau, synaptic physiology, ceramides, clearance or inflammation. Arc loss reduces transmission with early toxicity increased; clinical antibody failures and a mixed LAURIET result constrain progression mediation without proving all tau biology irrelevant.", "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": [ "[21] The 46-person BIIB080 phase 1b trial and extension showed dose-related fluid tau lowering and reduced PET accumulation in small imaging subsets.", "[26] Synaptic loss and microgliosis preceded fibrillar tangles in P301S mice; broad FK506 immunosuppression attenuated pathology and increased lifespan.", "[30] Whole-brain mapping showed injected fibrils produced a more AD-like pattern than spontaneous P301L pathology; deposits also appeared beyond direct connections and antibody treatment reduced burden.", "[46] Different human iPSC neuronal subtypes showed distinct susceptibility to identical tau or synuclein seeds; uptake/degradation did not explain the tau differences." ], "what_would_cross_it": "Donor-specific native tau tracking combined with prespecified longitudinal prediction and a selective intervention would identify the explanation of the spatial trajectory." }, { "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": "no", "supporting_evidence": [ "[1] Microglial depletion and exosome-synthesis inhibition reduced tau propagation in an AAV entorhinal-to-dentate model and changed dentate excitability.", "[2] Human neuron assays distinguished aggregate uptake through HSPG-related mechanisms from largely LRP1-dependent monomer accumulation.", "[3] Arc knockout nearly abolished intercellular transmission in mutant-tau mice while reducing EV tau and increasing intracellular accumulation with modest early toxicity.", "[5] LRP1 knockdown reduced tau uptake in human-derived cells and reduced neuronal tau spread in a mouse model.", "[6] Trem2 deletion enhanced AAV-P301L tau dispersion, EV seeding activity, synaptic dysfunction and memory deficits; exosome inhibition reduced release in culture.", "[10] Human AD EV inoculation in aged wild-type mice induced endogenous tau misfolding with preferential GABAergic pathology and reduced inhibitory synaptic transmission.", "[11] Donor physiological tau transferred through medium; optogenetic and chemogenetic stimulation increased release and in-vivo tau pathology.", "[13] Brain-penetrant nSMase2 inhibition normalized ceramides and reduced PS19 tau pathology, neuronal-layer thinning and glial changes; it separately reduced AAV-mutant contralateral tau transfer.", "[14] Removing endogenous mouse tau preserved human-P301L transfer to recipient neurons but reduced neurotoxicity in a separate severe-tauopathy model despite similar tangle numbers.", "[16] Dendrimer-conjugated nSMase2 inhibitor improved exposure and reduced contralateral tau pathology after unilateral mutant-human-tau AAV expression.", "[19] Injected synthetic tau seeds in P301S mice produced region-dependent spread, impaired synaptic plasticity and corresponding cognitive or motor dysfunction.", "[20] Suppressing entorhinal mutant-tau transgene expression resolved inclusions and abnormal sprouting and prevented progressive neuron loss in rTgTauEC mice.", "[30] Whole-brain mapping showed injected fibrils produced a more AD-like pattern than spontaneous P301L pathology; deposits also appeared beyond direct connections and antibody treatment reduced burden.", "[42] Galectin-3 deletion in THY-Tau22 mice reduced activation, tau pathology and synaptic loss and rescued memory; cell studies linked Gal3 to EV release and fibrillation.", "[43] ApoE3-Christchurch reduced tau uptake and fragmentation, seeded spread, inflammatory signals and cognitive defects relative to wild-type ApoE3 in amyloid and P301S models.", "[45] Entorhinal-restricted P301L expression was followed by human tau in connected neurons lacking detectable transgene, coaggregation with mouse tau, synapse degeneration and EC loss.", "[53] Microglial depletion reduced AAV-tau spread in wild-type and APP-knock-in mice but increased plaques and plaque-associated dystrophic-neurite tau; tagged microglial EVs carried tau.", "[54] Bassoon downregulation reduced tau seed-associated pathology and spread and rescued synaptic/behavioral defects and atrophy in experimental tauopathy systems.", "[55] TREM2 deficiency or microglial ablation increased amyloid-associated tau seeding/spread, and repopulated microglia did not recover the protective activation state.", "[56] CRISPRi and sulfation manipulation identified HSPG 6-O-sulfation dependence of tau uptake across cells, human-derived neurons and mouse slices.", "[57] Fractionated recombinant and AD-derived tau assemblies of at least three units underwent uptake and seeded biosensor aggregation, with HSPG-sensitive entry.", "[58] Tau antibodies differed in promoting Fc-mediated microglial uptake versus blocking neuronal uptake according to epitope and aggregate preparation/size.", "[64] A central-epitope antibody neutralized human AD-extract seeding and reduced distal pathology after K18-P301L fibrils, outperforming one N-terminal comparator.", "[65] A neuronal reporter model visualized K18/AD-seeded aggregate formation and contact-dependent transfer with new deposits in neighboring cells, including nanotube-associated material.", "[66] Dextran-sulfate-assembled full-length tau induced host mouse-tau aggregation and connected-region pathology in nontransgenic mice after intracerebral injection." ], "what_would_cross_it": "Trace a pathogenic donor species at physiological expression in spontaneous disease, showing transfer to genetically distinguished recipients without forced seeds and with matched transfer-loss/rescue controls." }, { "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": [ "[7] Eighteen cell-isolated tau strains induced distinct regional and cellular pathology and different network propagation rates in inoculated PS19 mice.", "[9] Endolysosomal permeabilization allowed EV-associated tau seeds to reach biosensor-cell cytosol; RAB7 manipulation changed aggregation.", "[10] Human AD EV inoculation in aged wild-type mice induced endogenous tau misfolding with preferential GABAergic pathology and reduced inhibitory synaptic transmission.", "[12] Cell-derived tau conformations retained strain-like characteristics across three inoculated transgenic-mouse generations and patient-derived biosensor isolates differed by tauopathy.", "[14] Removing endogenous mouse tau preserved human-P301L transfer to recipient neurons but reduced neurotoxicity in a separate severe-tauopathy model despite similar tangle numbers.", "[15] A mouse-tau-specific antibody reduced human AD-tau-seeded pathology in female wild-type mice despite not binding the human inoculum.", "[18] Seed-competent monomer ensembles encoded reproducible cell strains and distinct PS19-inoculated pathology, with AD and CBD isolates differing.", "[19] Injected synthetic tau seeds in P301S mice produced region-dependent spread, impaired synaptic plasticity and corresponding cognitive or motor dysfunction.", "[44] Mutant-P301S brain extract induced filament assembly of wild-type human tau and regional pathology in inoculated transgenic recipients.", "[45] Entorhinal-restricted P301L expression was followed by human tau in connected neurons lacking detectable transgene, coaggregation with mouse tau, synapse degeneration and EC loss.", "[46] Different human iPSC neuronal subtypes showed distinct susceptibility to identical tau or synuclein seeds; uptake/degradation did not explain the tau differences.", "[49] Human-neuron CRISPR screens identified tau proteostasis dependencies including UFMylation, GPI biosynthesis and CRL5-SOCS4, with mitochondrial disruption generating altered tau fragments.", "[54] Bassoon downregulation reduced tau seed-associated pathology and spread and rescued synaptic/behavioral defects and atrophy in experimental tauopathy systems.", "[57] Fractionated recombinant and AD-derived tau assemblies of at least three units underwent uptake and seeded biosensor aggregation, with HSPG-sensitive entry.", "[61] Human AD insoluble tau induced host-tau pathology in mice across Prnp genotypes; tau-null and species-specific antibody comparisons supported recipient tau origin, while PrP genotype did not change seeding/spread.", "[62] A repeat-domain antibody reduced seed-competent/aggregated tau and injury biomarkers when started early in Line66 mice, but later treatment did not remove established aggregates below baseline.", "[64] A central-epitope antibody neutralized human AD-extract seeding and reduced distal pathology after K18-P301L fibrils, outperforming one N-terminal comparator.", "[65] A neuronal reporter model visualized K18/AD-seeded aggregate formation and contact-dependent transfer with new deposits in neighboring cells, including nanotube-associated material.", "[66] Dextran-sulfate-assembled full-length tau induced host mouse-tau aggregation and connected-region pathology in nontransgenic mice after intracerebral injection." ], "what_would_cross_it": "Demonstrate physiological recipient precursor-product conversion after native donor release, suppress recipient conversion without disrupting tau transport/viability, then restore it with matched rescue." }, { "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": [ "[1] Microglial depletion and exosome-synthesis inhibition reduced tau propagation in an AAV entorhinal-to-dentate model and changed dentate excitability.", "[3] Arc knockout nearly abolished intercellular transmission in mutant-tau mice while reducing EV tau and increasing intracellular accumulation with modest early toxicity.", "[6] Trem2 deletion enhanced AAV-P301L tau dispersion, EV seeding activity, synaptic dysfunction and memory deficits; exosome inhibition reduced release in culture.", "[10] Human AD EV inoculation in aged wild-type mice induced endogenous tau misfolding with preferential GABAergic pathology and reduced inhibitory synaptic transmission.", "[11] Donor physiological tau transferred through medium; optogenetic and chemogenetic stimulation increased release and in-vivo tau pathology.", "[13] Brain-penetrant nSMase2 inhibition normalized ceramides and reduced PS19 tau pathology, neuronal-layer thinning and glial changes; it separately reduced AAV-mutant contralateral tau transfer.", "[14] Removing endogenous mouse tau preserved human-P301L transfer to recipient neurons but reduced neurotoxicity in a separate severe-tauopathy model despite similar tangle numbers.", "[19] Injected synthetic tau seeds in P301S mice produced region-dependent spread, impaired synaptic plasticity and corresponding cognitive or motor dysfunction.", "[20] Suppressing entorhinal mutant-tau transgene expression resolved inclusions and abnormal sprouting and prevented progressive neuron loss in rTgTauEC mice.", "[21] The 46-person BIIB080 phase 1b trial and extension showed dose-related fluid tau lowering and reduced PET accumulation in small imaging subsets.", "[22] In a randomized 46-person MAPTRx phase 1b study, intrathecal antisense lowered CSF total tau by more than half at higher doses; no treated serious adverse events were reported.", "[26] Synaptic loss and microgliosis preceded fibrillar tangles in P301S mice; broad FK506 immunosuppression attenuated pathology and increased lifespan.", "[27] Isogenic MAPT-V337M organoids developed splicing/autophagy changes before selective glutamatergic-neuron loss; PIKFYVE inhibition rescued glutamate toxicity.", "[28] Conditional astrocytic APOE4 removal after pathology onset protected against neurodegeneration and synaptic loss in P301S mice and reduced microglial phagocytosis.", "[29] Reducing Synaptogyrin-3 rescued mutant-tau synaptic plasticity, memory and synapse loss while neuroinflammation remained elevated.", "[32] Synaptogyrin-3 reduction in fly and mouse tauopathy restored vesicle mobility and neurotransmission by reducing pathological tau-vesicle association.", "[33] PTEN activation and phosphatidylserine exposure preceded neuronal-structure engulfment in rTg4510 mice; PTEN inhibition reduced microglial uptake.", "[37] Semorinemab biomarker analyses from TAURIEL and LAURIET showed increased CSF YKL-40 and plasma pTau181, with GFAP stabilization in LAURIET but not TAURIEL.", "[40] LAURIET semorinemab improved ADAS-Cog11 decline at week 49 but not the coprimary activities-of-daily-living endpoint or global secondary measures.", "[41] A 25-person bepranemab PSP phase 1b trial reported acceptable safety and about 80 percent reduction in mean free CSF tau.", "[42] Galectin-3 deletion in THY-Tau22 mice reduced activation, tau pathology and synaptic loss and rescued memory; cell studies linked Gal3 to EV release and fibrillation.", "[43] ApoE3-Christchurch reduced tau uptake and fragmentation, seeded spread, inflammatory signals and cognitive defects relative to wild-type ApoE3 in amyloid and P301S models.", "[45] Entorhinal-restricted P301L expression was followed by human tau in connected neurons lacking detectable transgene, coaggregation with mouse tau, synapse degeneration and EC loss.", "[49] Human-neuron CRISPR screens identified tau proteostasis dependencies including UFMylation, GPI biosynthesis and CRL5-SOCS4, with mitochondrial disruption generating altered tau fragments.", "[53] Microglial depletion reduced AAV-tau spread in wild-type and APP-knock-in mice but increased plaques and plaque-associated dystrophic-neurite tau; tagged microglial EVs carried tau.", "[54] Bassoon downregulation reduced tau seed-associated pathology and spread and rescued synaptic/behavioral defects and atrophy in experimental tauopathy systems.", "[55] TREM2 deficiency or microglial ablation increased amyloid-associated tau seeding/spread, and repopulated microglia did not recover the protective activation state.", "[62] A repeat-domain antibody reduced seed-competent/aggregated tau and injury biomarkers when started early in Line66 mice, but later treatment did not remove established aggregates below baseline." ], "what_would_cross_it": "Selectively block the implicated transfer/conversion step after onset, preserve source tau and recipient baseline physiology, and alter blinded function and neuron-survival trajectories; mechanistically matched rescue must reinstate both propagation and injury." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "Mouse-tau-null recipients versus intact host substrate.", "Mouse-specific antibody that does not bind human inoculum.", "Central antibody that does not bind K18 inoculum but reduces secondary pathology.", "Arc loss lowers transmission while intracellular accumulation and early toxicity increase.", "TREM2/microglial protective versus injurious contexts.", "Neurologically normal brain seeds differ from pathological seeds.", "Null functional clinical endpoints despite fluid tau engagement." ], "note": "Generalization is tested across tau strains, stages, recipient genotypes, amyloid backgrounds, neuronal types and human PSP/AD interventions. These comparisons reveal genuine context boundaries. Positive engineered conversion is not negated by late clinical nulls, but neither is converted into universal human progression necessity. Local replication in Meisl includes possible local cell-to-cell transfer; its late-stage interregional result does not refute all propagation." }, "falsification_patterns_met": [ { "pattern": "Reduced transmission does not uniformly improve toxicity", "evidence": "PMID42372723 Arc loss nearly removes transfer yet increases intracellular tau and modest early toxicity in its mutant model.", "downgrade_applied": false }, { "pattern": "Simple transfer equals templating equals injury conflation fails", "evidence": "PMID26538322 reports host-null transfer and a separate host-null neuroprotection experiment; these are distinct models.", "downgrade_applied": false }, { "pattern": "Fluid engagement does not ensure clinical trajectory change", "evidence": "PASSPORT, TANGO and tilavonemab have clinical nulls; LAURIET has isolated cognitive benefit but no coprimary functional/PET/atrophy benefit.", "downgrade_applied": false } ], "pitfalls_flagged": [ { "pitfall": "Network covariance mistaken for directly observed transfer", "where": "Human PET and reconstructed staging." }, { "pitfall": "Spontaneous pathology mistaken for physiological tau expression", "where": "PS19 age-series models retain pan-neuronal mutant human tau." }, { "pitfall": "Local replication misread as excluding all cell transfer", "where": "Meisl Results explicitly include local transfer in replication." }, { "pitfall": "All antibody trials described as uniformly null", "where": "LAURIET cognitive success retained with negative overall trial interpretation." }, { "pitfall": "Endogenously formed reporter aggregates mistaken for native unseeded disease", "where": "K18 seeded reporter assays." }, { "pitfall": "Retrospective score target or blinded claim", "where": "Historical Γ tau/neuro scores were visible in a memory quick pass; explicitly unblinded fresh appraisal." } ], "causal_tally_audit": { "tally_claimed_by_document": 46, "tally_after_audit": 46, "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 Δ case combines native Bassoon/Arc perturbations, source-restricted donor tracing, wild-type host conversion and clinical fluid engagement. This is a serious mechanistic case. Yet the selective natural spread-to-neuron-loss mediator is still unisolated: Bassoon affects intrinsic seeds/synapses, Arc toxicity moves in the opposite direction and clinical occupancy does not prove seed blockade.", "case_one_rung_lower": "The strongest Β case treats everything as anatomical association and artificial seed capability. It misses actual donor transfer, recipient substrate controls, temporal human progression and function-changing perturbations. Γ is justified even though the conjunctive disease-driving necessity has not crossed Δ.", "which_rejected": "Reject Δ for the broad conjunction on missing selective endogenous mediation; reject Β for the assembled temporal and mechanistic case. Defined conversion capabilities remain meaningful rather than being dismissed as artifacts.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: In spontaneous tauopathy with physiological donor and recipient tau, induce a selective transfer/conversion block after pathology onset and provide mechanistically matched rescue, with source tau burden and neuronal physiology held comparable." }, "final_score": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "66 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": "The preregistered weakest-link conjunction returns Γ. Longitudinal human network progression, recipient-host conversion experiments and causal modifiers make the claim more than association alone. None of the assembled lines selectively establishes that spontaneous templated neuronal propagation is necessary for the neuronal-loss trajectory across tauopathies. Defined laboratory capability is credited, while selective propagation mediation is the remaining gate." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": 5, "derivation": "The mechanism exceeds co-occurrence in laboratory transfer/conversion systems. Human initiation plus prevention and rate limitation is not established; necessity across progression is unresolved. Conditional amplification of established pathology is the best-supported role. Reactive release and local transfer may participate causally without being the initiating event, and the conditional role does not assert universal human mediation.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "Recent Arc loss, physiological recipient-origin controls, neuronal proteostasis screens and bepranemab safety/occupancy interrogate relevant boundaries. No verified pending clinical efficacy result is asserted.", "justification": "Recent Arc loss, physiological recipient-origin controls, neuronal proteostasis screens and bepranemab safety/occupancy interrogate relevant boundaries. No verified pending clinical efficacy result is asserted." }, "stability": { "value": "Stable", "trigger": "The packet verifies completed reports, not a presently pending result expected to move the registered level.", "justification": "The packet verifies completed reports, not a presently pending result expected to move the registered level." }, "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 category and historical Γ tau/neuro levels were visible in memory before adjudication; fresh packet is unblinded, and those levels were not adopted as score targets.", "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": "In spontaneous tauopathy with physiological donor and recipient tau, induce a selective transfer/conversion block after pathology onset and provide mechanistically matched rescue, with source tau burden and neuronal physiology held comparable.", "readout": "Direct recipient lineage conversion, regional spread, blinded neuron counts and cognitive/functional trajectory", "critical_control": "Donor and recipient allele tags, source load, synaptic/lysosomal viability, transfer-independent intracellular toxicity and sham rescue", "supporting_result": "Selective interruption reduces new recipient conversion and subsequent neuronal loss, and matched rescue restores both", "falsifying_result": "Verified selective interruption leaves neuronal-loss progression unchanged or worsens it while matched intrinsic-toxicity control explains the trajectory" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Identify the transmitted species, route and physiological recipient conversion separately; seed-positive assays need not report a pathogenic species.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Distinguish local cell transfer, intracellular replication and interregional migration across preclinical and late stages.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Test whether blocking transfer shifts toxic material back into donor cells, as the Arc contrast suggests, rather than assuming that all spread suppression protects.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Resolve clinical epitope/compartment occupancy and whether a trial truly neutralized relevant seeds; CSF free tau is incomplete engagement evidence.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Replicate subtype-specific causal mediation across AD, PSP and other tauopathies without treating forced inoculation as natural origin.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 6", "statement": "Separate glial protective clearance from glial EV-mediated amplification in amyloid and nonamyloid settings.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-06", "reviewer": "Codex", "evidence_base_note": "66 primary reports; literature cutoff 2026-10-06; source examination UTC date 2026-10-06; 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.", "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": "Human anti-tau clinical trials, MAPT-linked biology and natural variant-related protection were considered. MAPT disease causality and APOE protection do not identify propagation as their mediator. Biomarker-only ASO effects and negative/mixed extracellular-antibody outcomes cannot cross the clinical propagation gate. Orthogonal endogenous selective inhibition with clinical or neuronal-survival benefit could support higher levels without requiring one impossible experiment." }, { "kind": "natural_experiment", "available": true, "why_not_sufficient": "Human anti-tau clinical trials, MAPT-linked biology and natural variant-related protection were considered. MAPT disease causality and APOE protection do not identify propagation as their mediator. Biomarker-only ASO effects and negative/mixed extracellular-antibody outcomes cannot cross the clinical propagation gate. Orthogonal endogenous selective inhibition with clinical or neuronal-survival benefit could support higher levels without requiring one impossible experiment." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "Human anti-tau clinical trials, MAPT-linked biology and natural variant-related protection were considered. MAPT disease causality and APOE protection do not identify propagation as their mediator. Biomarker-only ASO effects and negative/mixed extracellular-antibody outcomes cannot cross the clinical propagation gate. Orthogonal endogenous selective inhibition with clinical or neuronal-survival benefit could support higher levels without requiring one impossible experiment." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Human anti-tau clinical trials, MAPT-linked biology and natural variant-related protection were considered. MAPT disease causality and APOE protection do not identify propagation as their mediator. Biomarker-only ASO effects and negative/mixed extracellular-antibody outcomes cannot cross the clinical propagation gate. Orthogonal endogenous selective inhibition with clinical or neuronal-survival benefit could support higher levels without requiring one impossible experiment." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": true, "why_not_sufficient": "Human anti-tau clinical trials, MAPT-linked biology and natural variant-related protection were considered. MAPT disease causality and APOE protection do not identify propagation as their mediator. Biomarker-only ASO effects and negative/mixed extracellular-antibody outcomes cannot cross the clinical propagation gate. Orthogonal endogenous selective inhibition with clinical or neuronal-survival benefit could support higher levels without requiring one impossible experiment." } ], "convergence_present": true, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 66, "claims_total": 71, "claims_verified": 71, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 66, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "Microglial depletion and exosome-synthesis inhibition reduced tau propagation in an AAV entorhinal-to-dentate model and changed dentate excitability. AAV expression and broad microglial/exosome effects do not isolate spontaneous tau templating as the mediator of neuron death.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C2", "text": "Human neuron assays distinguished aggregate uptake through HSPG-related mechanisms from largely LRP1-dependent monomer accumulation. Recombinant protein exposure and uptake assays do not demonstrate recipient conversion or endogenous human disease progression; the abstract's leading-cause framing exceeds its experiment.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C3", "text": "Arc knockout nearly abolished intercellular transmission in mutant-tau mice while reducing EV tau and increasing intracellular accumulation with modest early toxicity. Transmission reduction did not yield uniform neuroprotection; developmental Arc functions and mutant transgenic expression complicate selective spread mediation. UpdateOf links the preceding version, not a separate replication.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C4", "text": "Postmortem subdiffraction microscopy detected oligomeric tau in human pre- and postsynaptic terminals, including regions with little fibrillar deposition. Static terminal colocalization does not trace transfer direction, recipient templating or an early causal sequence in living people.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C5", "text": "LRP1 knockdown reduced tau uptake in human-derived cells and reduced neuronal tau spread in a mouse model. Receptor uptake is not identical to recipient conversion; LRP1 has broader trafficking functions and the abstract does not establish neuronal-loss prevention.", "carries_number": true, "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": "2026-10-06", "note": "" }, { "id": "C6", "text": "Trem2 deletion enhanced AAV-P301L tau dispersion, EV seeding activity, synaptic dysfunction and memory deficits; exosome inhibition reduced release in culture. Microglial clearance and broader immune effects confound selective transfer mediation; pathological human tau expression is imposed, and Trem2 can protect in this context.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C7", "text": "Eighteen cell-isolated tau strains induced distinct regional and cellular pathology and different network propagation rates in inoculated PS19 mice. This demonstrates strain capability in a P301S recipient rather than natural human strain origin or propagation-driven neuronal loss.", "carries_number": true, "load_bearing_for": [ "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": "2026-10-06", "note": "" }, { "id": "C8", "text": "A FRET biosensor detected tau seeding in P301S mice before histological tau pathology and discriminated AD tissue from comparison samples. Temporal assay sensitivity and mutant-model correlation do not establish seed necessity, direct transfer or neuronal toxicity.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C9", "text": "Endolysosomal permeabilization allowed EV-associated tau seeds to reach biosensor-cell cytosol; RAB7 manipulation changed aggregation. Permeabilization also occurred with tau-free EVs, only a minority of cells aggregated, and RAB7/lysosomal perturbations affect general trafficking.", "carries_number": true, "load_bearing_for": [ "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": "2026-10-06", "note": "" }, { "id": "C10", "text": "Human AD EV inoculation in aged wild-type mice induced endogenous tau misfolding with preferential GABAergic pathology and reduced inhibitory synaptic transmission. Forced brain EV delivery bypasses normal release and dose; dysfunction and marker reductions are not an audited neuron-death mediation assay. A linked correction requires qualification.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C11", "text": "Donor physiological tau transferred through medium; optogenetic and chemogenetic stimulation increased release and in-vivo tau pathology. Activity also changes intrinsic vulnerability and proteostasis; increased pathology is not proof that transfer-mediated recipient conversion causes degeneration.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C12", "text": "Cell-derived tau conformations retained strain-like characteristics across three inoculated transgenic-mouse generations and patient-derived biosensor isolates differed by tauopathy. Repeat-domain reporters and imposed serial inoculation establish templating capability, not natural human intercellular disease causation or infectivity equivalence to PrP.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C13", "text": "Brain-penetrant nSMase2 inhibition normalized ceramides and reduced PS19 tau pathology, neuronal-layer thinning and glial changes; it separately reduced AAV-mutant contralateral tau transfer. The survival/pathology and transfer experiments use separate systems; ceramide and EV changes have broader effects, so propagation is not the uniquely demonstrated neuroprotective mediator. Original Results show reduced total human tau and loss of the pThr181 difference after total-tau normalization. Layer density/thickness and synaptophysin improve, but no audited total-neuron stereology or behavioral rescue is credited here. The AAV arm normalizes contralateral signal to ipsilateral signal.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph5, 2:Results:paragraph7, 2:Results:paragraph9, 2:Results:paragraph14. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C14", "text": "Removing endogenous mouse tau preserved human-P301L transfer to recipient neurons but reduced neurotoxicity in a separate severe-tauopathy model despite similar tangle numbers. Donor-protein movement can occur without host templating, and tangle burden can dissociate from toxicity; human transgenes and tau-null physiology limit natural disease generalization.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C15", "text": "A mouse-tau-specific antibody reduced human AD-tau-seeded pathology in female wild-type mice despite not binding the human inoculum. This narrows recipient-substrate involvement but still begins with imposed seeds; the abstract infers intraneuronal elongation and does not establish selective spread-mediated neuron survival.", "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": "2026-10-06", "note": "" }, { "id": "C16", "text": "Dendrimer-conjugated nSMase2 inhibitor improved exposure and reduced contralateral tau pathology after unilateral mutant-human-tau AAV expression. EV suppression and trafficking are broader than a tau-only mediator; this is an engineered transfer model without a reported clinical or neuronal-loss endpoint.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C17", "text": "Biosensor testing across 247 fixed human brains found early seeding in transentorhinal/entorhinal cortex and activity ahead of phospho-tau staining, including in later cortical regions. Cross-sectional reconstructed timing and an amplification assay do not trace physical transfer; locus-coeruleus phospho-tau does not imply its seeds initiate the whole sequence.", "carries_number": true, "load_bearing_for": [ "SC1", "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": "2026-10-06", "note": "" }, { "id": "C18", "text": "Seed-competent monomer ensembles encoded reproducible cell strains and distinct PS19-inoculated pathology, with AD and CBD isolates differing. Monomer preparation and reporter selection do not establish spontaneous human strain formation or disease progression dependency.", "carries_number": true, "load_bearing_for": [ "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": "2026-10-06", "note": "" }, { "id": "C19", "text": "Injected synthetic tau seeds in P301S mice produced region-dependent spread, impaired synaptic plasticity and corresponding cognitive or motor dysfunction. Forced seeds plus mutant tau create a bounded sufficiency paradigm; functional deficits are not direct proof that naturally transferred seeds cause progressive human neuron death.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C20", "text": "Suppressing entorhinal mutant-tau transgene expression resolved inclusions and abnormal sprouting and prevented progressive neuron loss in rTgTauEC mice. Doxycycline lowers the source protein and its cell-autonomous toxicity as well as spread; it is not a propagation-selective mediation test.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C21", "text": "The 46-person BIIB080 phase 1b trial and extension showed dose-related fluid tau lowering and reduced PET accumulation in small imaging subsets. Safety was the original primary endpoint; open-label extension and biomarker outcomes do not establish clinical efficacy or selective propagation blockade. Same trial as MAPTRx primary report.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C22", "text": "In a randomized 46-person MAPTRx phase 1b study, intrathecal antisense lowered CSF total tau by more than half at higher doses; no treated serious adverse events were reported. The primary endpoint was safety, not clinical disease modification, and total MAPT synthesis lowering cannot identify spread mediation. A linked author correction remains attached. Original Results show no consistent clinical outcome trend and no dose-responsive injury-biomarker effect; ventricular-volume change was greater in active arms. The examined publisher correction changes an author affiliation, not efficacy results (doi:10.1038/s41591-023-02639-3).", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph13, 1:Results:paragraph18, 1:Results:paragraph20, 1:Results:paragraph22, 1:Results:paragraph23. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C23", "text": "The 378-randomized tilavonemab PSP trial met prespecified futility criteria and showed no beneficial PSPRS trajectory effect versus placebo. This tests an N-terminal extracellular antibody in symptomatic PSP, not verified removal of every intracellular or transmissible tau species; null efficacy restricts this strategy without disproving all tau mechanisms.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C24", "text": "Across 320 atypical AD PET cases, 78 longitudinal cases and 93 independent autopsies, functional connectivity predicted variant-specific tau patterns and accumulation. The connectome comes from healthy controls and epicentres are inferred from baseline/accumulation; covariance cannot distinguish tau transfer from network-linked vulnerability or activity.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C25", "text": "In 46 older participants, increased between-network connectivity predicted later tau PET elevation, cortical thinning and lower delayed recall, particularly with amyloid positivity. Small observational clustering and correlated vulnerability do not demonstrate molecular movement or recipient templating.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C26", "text": "Synaptic loss and microgliosis preceded fibrillar tangles in P301S mice; broad FK506 immunosuppression attenuated pathology and increased lifespan. Earlier dysfunction weakens a mature-tangle-only model; broad immunosuppression and mutant expression do not identify spread mediation. A linked erratum lacks an identifier and its details remain unexamined.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C27", "text": "Isogenic MAPT-V337M organoids developed splicing/autophagy changes before selective glutamatergic-neuron loss; PIKFYVE inhibition rescued glutamate toxicity. This establishes a familial cell-intrinsic vulnerability route in organoids, not organismal follow-through or intercellular propagation dependency.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C28", "text": "Conditional astrocytic APOE4 removal after pathology onset protected against neurodegeneration and synaptic loss in P301S mice and reduced microglial phagocytosis. A real glial causal contribution need not be mediated by tau transfer; mutant-tau and APOE context restrict generalization.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C29", "text": "Reducing Synaptogyrin-3 rescued mutant-tau synaptic plasticity, memory and synapse loss while neuroinflammation remained elevated. The contrast identifies synaptic toxicity independent of persistent glial activation; it does not directly test pathological species transfer.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C30", "text": "Whole-brain mapping showed injected fibrils produced a more AD-like pattern than spontaneous P301L pathology; deposits also appeared beyond direct connections and antibody treatment reduced burden. Choosing a seed to improve resemblance is not natural disease validation, and static connectivity plus antibody effects does not isolate physical transfer-driven neuronal loss.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C31", "text": "Among 40 autopsies, dementia cases had more tau-oligomer-tagged synapses within glia and lower synaptic density than resilient cases with similar Braak stage. Cross-sectional engulfment and matching cannot show that transfer or glial activity caused the antecedent cognitive decline; tangle-equivalent resilience challenges burden-only explanations.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C32", "text": "Synaptogyrin-3 reduction in fly and mouse tauopathy restored vesicle mobility and neurotransmission by reducing pathological tau-vesicle association. This narrows a presynaptic toxicity mechanism, not templated propagation; engineered tau systems and conserved synaptic function require separate generalization.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C33", "text": "PTEN activation and phosphatidylserine exposure preceded neuronal-structure engulfment in rTg4510 mice; PTEN inhibition reduced microglial uptake. Synaptic tagging and engulfment are rival or downstream toxicity mechanisms, and pharmacology plus mutant overexpression do not isolate templated transfer.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C34", "text": "Tilavonemab failed to improve 96-week CDR-SB versus placebo in 453 randomized early-AD participants. This is a clinical efficacy null for a particular antibody, not a demonstration that every pathogenic tau pool was neutralized or propagation selectively blocked. Original Results confirm lower free CSF tau at higher doses, higher plasma total tau and no tau PET or NfL response. Isolated MRI differences lacked multiplicity adjustment.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph0, 2:Results:paragraph17, 2:Results:paragraph20, 2:Results:paragraph21, 2:Results:paragraph22, 2:Results:paragraph25. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C35", "text": "TAURIEL semorinemab produced no slowing of 73-week CDR-SB progression in the 422-person modified intention-to-treat cohort. A symptomatic N-terminal antibody trial does not verify selective interruption of intracellular recipient conversion; failure restricts this clinical strategy.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C36", "text": "PASSPORT gosuranemab showed no PSPRS or secondary clinical benefit in 486 dosed PSP patients despite a 98 percent fall in unbound N-terminal CSF tau. Strong fluid target engagement is not complete seed neutralization or proof of all pathogenic-pool blockade; a linked author correction is attached to the parent.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C37", "text": "Semorinemab biomarker analyses from TAURIEL and LAURIET showed increased CSF YKL-40 and plasma pTau181, with GFAP stabilization in LAURIET but not TAURIEL. These are reused trial samples and mechanistic biomarker effects, not new independent efficacy trials or direct evidence of beneficial microglial mediation.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C38", "text": "TANGO randomized 654 early-AD participants and showed no favorable cognitive/functional CDR-SB change with gosuranemab despite reduced unbound N-terminal CSF tau. Safety was primary and clinical efficacy secondary; drug engagement of a soluble N-terminal pool does not demonstrate selective blockade of all tau propagation. Original Results confirm 80.1–92.6 percent unbound N-terminal CSF tau reduction, no tau-PET dose response and no favorable atrophy response. An isolated exploratory cognitive result was worse, without a dose response; it is not treated as a definitive toxicity test.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph19, 1:Results:paragraph23, 1:Results:paragraph28, 1:Results:paragraph33, 1:Results:paragraph38. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C39", "text": "PERISCOPE-ALZ zagotenemab did not slow clinical progression in 360 randomized participants; PET, MRI and NfL showed no disease-modifying response. Only 218 completed treatment and pathogenic brain engagement was not established; plasma tau increases do not prove seed neutralization. A linked correction remains qualified.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C40", "text": "LAURIET semorinemab improved ADAS-Cog11 decline at week 49 but not the coprimary activities-of-daily-living endpoint or global secondary measures. The prespecified coprimary trial result was negative; isolated cognitive benefit is credited without being relabeled overall efficacy or propagation-mediated neuroprotection. Original Results confirm a 2.89-point ADAS-Cog11 difference at week 49, with the largest post hoc item effect in word recognition. CSF tau fell but PET accumulation and atrophy rates did not differ.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph8, 2:Results:paragraph15, 2:Results:paragraph17, 2:Results:paragraph19, 2:Results:paragraph20. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C41", "text": "A 25-person bepranemab PSP phase 1b trial reported acceptable safety and about 80 percent reduction in mean free CSF tau. Safety and target occupancy are not clinical disease modification; small phase 1 enrollment cannot settle whether mid-region neutralization blocks propagation-driven degeneration.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C42", "text": "Galectin-3 deletion in THY-Tau22 mice reduced activation, tau pathology and synaptic loss and rescued memory; cell studies linked Gal3 to EV release and fibrillation. Genetic removal also changes broad immune responses; the two arms do not isolate propagation as the uniquely causal neuroprotective mediator.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C43", "text": "ApoE3-Christchurch reduced tau uptake and fragmentation, seeded spread, inflammatory signals and cognitive defects relative to wild-type ApoE3 in amyloid and P301S models. APOE changes several uptake, inflammatory and proteolytic pathways, and PFF initiation remains imposed; a natural human variant does not isolate propagation mediation here.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C44", "text": "Mutant-P301S brain extract induced filament assembly of wild-type human tau and regional pathology in inoculated transgenic recipients. The recipients express human tau and receive artificial intracerebral exposure; capability is not natural cell-to-cell necessity or neurodegeneration mediation.", "carries_number": true, "load_bearing_for": [ "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": "2026-10-06", "note": "" }, { "id": "C45", "text": "Entorhinal-restricted P301L expression was followed by human tau in connected neurons lacking detectable transgene, coaggregation with mouse tau, synapse degeneration and EC loss. Low-level expression detection and source-cell deafferentation complicate inference; mutant overexpression does not isolate selective endogenous templating. Linked erratum details are unexamined.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C46", "text": "Different human iPSC neuronal subtypes showed distinct susceptibility to identical tau or synuclein seeds; uptake/degradation did not explain the tau differences. This supports intrinsic vulnerability as a contributor to regional patterns; imposed aggregates and cultured neurons do not establish the full human progression mechanism.", "carries_number": false, "load_bearing_for": [ "SC1", "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": "2026-10-06", "note": "" }, { "id": "C47", "text": "Two human imaging samples associated amyloid-related hyperconnectivity with later regional tau accumulation, with statistical mediation of the amyloid association. Observational mediation requires unverified no-confounding assumptions and does not trace molecular transfer; the paper's causal wording exceeds selective perturbation evidence.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C48", "text": "Seed-enriched material from 19 neurologically normal human brains showed parietal-cortex seeding by two amplification assays without conventional tau pathology. Control seeds differed conformationally from AD seeds; seeding positivity alone is not pathological progression, and assay amplification is not natural neuronal conversion.", "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": "2026-10-06", "note": "" }, { "id": "C49", "text": "Human-neuron CRISPR screens identified tau proteostasis dependencies including UFMylation, GPI biosynthesis and CRL5-SOCS4, with mitochondrial disruption generating altered tau fragments. Cellular aggregation control and disease correlation do not demonstrate intercellular spread or clinical neuroprotection; the linked preprint is not a second study.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C50", "text": "Twenty AD brains sampled across 25 regions showed seeding before some AT8 pathology and in unexpected sites including axons and Bergmann glia. Cross-sectional seed maps are not lineage tracing and complicate a single canonical regional sequence; the linked correction requires qualification.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C51", "text": "Patient-specific connectivity predicted longitudinal tau accumulation in two imaging samples better than fixed Braak readouts; simulated trials required smaller samples. Simulated intervention efficiency is not a conducted therapeutic test, and model fit cannot establish physical transfer or necessity.", "carries_number": false, "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": "2026-10-06", "note": "" }, { "id": "C52", "text": "A structural-connectome diffusion model fit two-timepoint HABS/ADNI PET and predicted a third measurement in available participants. Source/clearance terms and graph diffusion are mathematical assumptions, not measured intracellular conversion; cohort and imaging overlap restrict independence.", "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": "2026-10-06", "note": "" }, { "id": "C53", "text": "Microglial depletion reduced AAV-tau spread in wild-type and APP-knock-in mice but increased plaques and plaque-associated dystrophic-neurite tau; tagged microglial EVs carried tau. Depletion changes clearance and injury as well as transfer, so reduced distal signal cannot be relabeled uniform protection. A linked correction remains attached.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C54", "text": "Bassoon downregulation reduced tau seed-associated pathology and spread and rescued synaptic/behavioral defects and atrophy in experimental tauopathy systems. Bassoon regulates presynaptic function and seed stability as well as transport; matching source toxicity and selective recipient conversion remains essential to propagation mediation. Original Results show unchanged total human tau after preventive P0 Bassoon shRNA, and source GFP controls in the separate AAV transfer arm. These controls strengthen seed-mediated contribution but do not make presynaptic Bassoon a transfer-only intervention.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph21, 1:Results:paragraph26, 1:Results:paragraph33, 1:Results:paragraph36, 1:Results:paragraph44. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C55", "text": "TREM2 deficiency or microglial ablation increased amyloid-associated tau seeding/spread, and repopulated microglia did not recover the protective activation state. This shows protective microglial function in an amyloid-seeded context and contradicts universal beneficial depletion; seed burden is not equivalent to neuron-loss causality.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C56", "text": "CRISPRi and sulfation manipulation identified HSPG 6-O-sulfation dependence of tau uptake across cells, human-derived neurons and mouse slices. Uptake is one step; these experiments do not establish intact-animal endogenous transfer, conversion or degeneration dependency.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C57", "text": "Fractionated recombinant and AD-derived tau assemblies of at least three units underwent uptake and seeded biosensor aggregation, with HSPG-sensitive entry. The minimum size depends on preparation and assay; extracellular exposure and reporter amplification do not prove a universal naturally propagating toxic species.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C58", "text": "Tau antibodies differed in promoting Fc-mediated microglial uptake versus blocking neuronal uptake according to epitope and aggregate preparation/size. An antibody's pathology benefit cannot be assigned automatically to transfer blockade; this is cultured-cell mechanism analysis, not new in-vivo disease causality.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C59", "text": "Whole-brain age-series maps of pan-neuronal P301S PS19 mice fitted retrograde-biased connectivity models without injected seeds. Spontaneous pathology is valuable but still occurs with widespread mutant human tau expression; modeled phospho-tau progression is not directly traced protein transfer or selective spread blockade.", "carries_number": true, "load_bearing_for": [ "SC1", "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": "2026-10-06", "note": "" }, { "id": "C60", "text": "Kinetic fits across multiple human seed/tau measures suggested local replication, rather than interregional spread, limits neocortical accumulation from Braak III onward. The inferred approximately five-year seed doubling is model-dependent and stage-specific; it does not show early seeding is irrelevant or experimentally identify a clinical rate-limiting mediator. Original Results explicitly subsume local cell-to-cell transfer into the replication term. The contrast concerns interregional spread, not all transfer; extrapolation before Braak III is untested.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph3, 1:RESULTS:paragraph4, 1:RESULTS:paragraph5, 1:RESULTS:paragraph13, 1:RESULTS:paragraph14, 1:RESULTS:paragraph15, 1:RESULTS:paragraph16, 1:RESULTS:paragraph17. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C61", "text": "Human AD insoluble tau induced host-tau pathology in mice across Prnp genotypes; tau-null and species-specific antibody comparisons supported recipient tau origin, while PrP genotype did not change seeding/spread. Forced inoculation establishes host conversion capability and excludes an obligatory PrP receptor in this setting, not natural human tau propagation necessity.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 61 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C62", "text": "A repeat-domain antibody reduced seed-competent/aggregated tau and injury biomarkers when started early in Line66 mice, but later treatment did not remove established aggregates below baseline. The endpoints were aggregation and fluid injury markers, without a reported functional trajectory test; epitope and timing matter but do not establish spread-mediated neuroprotection.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 62 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C63", "text": "Entorhinal-biased human-tau transgenic mice developed human tau staining and mature pathology in connected hippocampal and cortical regions with age. Distribution and expression restriction support transfer but do not directly visualize a precursor-product lineage or separate low-level transgene expression from recipient conversion.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 63 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C64", "text": "A central-epitope antibody neutralized human AD-extract seeding and reduced distal pathology after K18-P301L fibrils, outperforming one N-terminal comparator. Imposed seeds and transgenic substrate limit inference; reducing secondary pathology is more specific than inoculum neutralization but not proof of clinical neuronal-loss mediation.", "carries_number": true, "load_bearing_for": [ "SC2", "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": "2026-10-06", "note": "" }, { "id": "C65", "text": "A neuronal reporter model visualized K18/AD-seeded aggregate formation and contact-dependent transfer with new deposits in neighboring cells, including nanotube-associated material. Endogenously formed refers to aggregates formed inside reporter cells after seeding, not native unseeded human disease; tau-fragment reporters and cultures restrict generalization.", "carries_number": true, "load_bearing_for": [ "SC2", "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": "2026-10-06", "note": "" }, { "id": "C66", "text": "Dextran-sulfate-assembled full-length tau induced host mouse-tau aggregation and connected-region pathology in nontransgenic mice after intracerebral injection. This removes a recipient overexpression requirement but retains artificial seed creation and forced entry; it is not observation of spontaneous human transmission.", "carries_number": false, "load_bearing_for": [ "SC2", "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": "2026-10-06", "note": "" }, { "id": "CSC1", "text": "Longitudinal PET predicts later accumulation along connected systems, supported by anatomical and perturbational models. This is temporal proof beyond static association, but physical propagation is inferred and disease-pattern exceptions remain. The causal explanation of human network progression is Γ.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 4, 8, 17, 21, 24, 25, 26, 30, 31, 46, 47, 48, 50, 51, 52, 59, 60, 63 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-06", "note": "" }, { "id": "CSC2", "text": "Donor-restricted models, receptor perturbations and activity experiments establish transport capability. Spontaneous PS19 patterns lack injected seeds but retain widespread mutant tau expression. Direct endogenous lineage transfer under natural disease conditions has not been separated from recipient expression and selective vulnerability.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 1, 2, 3, 4, 5, 6, 10, 11, 13, 14, 16, 19, 20, 30, 42, 43, 45, 53, 54, 55, 56, 57, 58, 59, 63, 64, 65, 66 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-06", "note": "" }, { "id": "CSC3", "text": "Wild-type recipients, mouse-specific antibody and tau-null/species-specific comparisons strengthen physiological host-tau conversion after imposed seeds. These establish important bounded capabilities. The registered transferred endogenous pathway remains reliant on forced initiation; host recruitment alone does not prove natural disease necessity.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 7, 8, 9, 10, 12, 14, 15, 17, 18, 19, 44, 45, 46, 48, 49, 50, 54, 57, 61, 62, 64, 65, 66 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-06", "note": "" }, { "id": "CSC4", "text": "Bassoon, exosome-pathway, antibody and source-suppression contrasts affect pathology or function, but also source tau, synaptic physiology, ceramides, clearance or inflammation. Arc loss reduces transmission with early toxicity increased; clinical antibody failures and a mixed LAURIET result constrain progression mediation without proving all tau biology irrelevant.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 1, 3, 6, 10, 11, 13, 14, 19, 20, 21, 22, 23, 26, 27, 28, 29, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 45, 49, 53, 54, 55, 60, 62 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-06", "note": "" }, { "id": "CH", "text": "Tau transfer and templating are experimentally demonstrable; their necessity as the driver of natural tauopathy neurodegeneration remains unresolved.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 45, 66, 54, 3, 38, 40 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-06", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Asai H, Ikezu S, Tsunoda S et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nature neuroscience. 2015.", "tier": "A", "kind": "primary", "pmid": "26436904", "doi": "10.1038/nn.4132", "url": "https://pubmed.ncbi.nlm.nih.gov/26436904/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID26436904", "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", "CSC4" ] }, { "n": 2, "citation": "Marvian AT, Strauss T, Tang Q et al. Distinct regulation of Tau Monomer and aggregate uptake and intracellular accumulation in human neurons. Molecular neurodegeneration. 2024.", "tier": "A", "kind": "primary", "pmid": "39736627", "doi": "10.1186/s13024-024-00786-w", "url": "https://pubmed.ncbi.nlm.nih.gov/39736627/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID39736627", "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" ] }, { "n": 3, "citation": "Tyagi M, de Hoog E, Grega M et al. Arc mediates intercellular tau transmission via extracellular vesicles. 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MAPTRx/PET reports and semorinemab biomarker reanalyses are grouped by original trial. Human imaging datasets overlap. These are not 66 independent demonstrations of propagation-mediated neuron loss." }, "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": "66 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": "The preregistered weakest-link conjunction returns Γ. 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