{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "Oral Microbiome → Systemic Disease", "entry_form": "phenomenon", "gradeable_restatement": "Oral microbial pathogens, principally Porphyromonas gingivalis, causally drive systemic cardiovascular and neurodegenerative disease in humans.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Baseline periodontal and pathogen status, clinical disease, host genotype, experimental route, diet, age and exposure protocol", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "Oral Microbiome → Systemic Disease", "central_claim": "Oral microbial pathogens, principally Porphyromonas gingivalis, causally drive systemic cardiovascular and neurodegenerative disease in humans.", "proposed_mechanism": "Oral microbial pathogens, principally Porphyromonas gingivalis, causally drive systemic cardiovascular and neurodegenerative disease in humans.", "claimed_scope": "Oral microbial pathogens, principally Porphyromonas gingivalis, causally drive systemic cardiovascular and neurodegenerative disease in humans.", "claimed_level": [ "human vascular and AD causality" ], "is_conjunctive": true, "conjunctive_note": "Use the index central claim and disease-separated subclaims. The human vascular and Alzheimer applications are co-central; the lower of SC3 and SC4 is the scope-matched bundled gate. Animal inoculation and inflammatory-tone changes are scored separately, and cannot replace human disease causality. This co-central interpretation of scope-matched is declared before scoring." }, "rubric_routing": { "primary_rubric": "04-microbiome-systemic.md", "secondary_rubrics": [ "01-neurodegeneration.md", "05-immunology-inflammation.md" ], "index_notes_applied": [ "Use the index central claim and disease-separated subclaims. The human vascular and Alzheimer applications are co-central; the lower of SC3 and SC4 is the scope-matched bundled gate. Animal inoculation and inflammatory-tone changes are scored separately, and cannot replace human disease causality. This co-central interpretation of scope-matched is declared before scoring." ], "rubric_fit_note": "Exact archived v5.3 framework. Any stale index empirical framing is rechecked against primary results." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "Severe periodontal disease co-occurs with cardiovascular events and incident dementia.", "subclaim_type": "existence", "scope": "prospective adult cohorts with baseline periodontal measurement", "claimed_scope": "prospective adult cohorts with baseline periodontal measurement", "governing_rubric": "04-microbiome-systemic.md", "key_evidence_anchor": "Adjusted incident hard outcomes", "hsef_level": "Β", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Prospective cohorts support co-occurrence, with substantial endpoint and population heterogeneity. Swedish dementia, ARIC cognitive decline, adjusted tooth-count and selected cardiovascular comparisons are null or mixed. Association is established as a recurring observation, not a universal risk relation or a microbial causal pathway." }, { "id": "SC2", "statement": "Oral P. gingivalis inoculation accelerates vascular and neural pathology in rodents.", "subclaim_type": "sufficiency", "scope": "prespecified rodent genotypes and oral inoculation protocols", "claimed_scope": "prespecified rodent genotypes and oral inoculation protocols", "governing_rubric": "04-microbiome-systemic.md", "key_evidence_anchor": "Organism and virulence-factor subtraction/rescue", "hsef_level": "Ε", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Defined oral exposures, bacterial virulence subtraction and host-pathway perturbations produce vascular and neural phenotypes in particular rodent systems. Oral versus intracerebral infection and single versus dual inoculation map important failures. Recipient-model causality is credited, but a single conserved organism-specific mediator across both organ systems is not independently isolated." }, { "id": "SC3", "statement": "Oral microbial mechanisms causally drive human atherosclerotic cardiovascular disease.", "subclaim_type": "generalization", "scope": "human atherosclerotic incidence/progression and hard vascular outcomes", "claimed_scope": "human atherosclerotic incidence/progression and hard vascular outcomes", "governing_rubric": "04-microbiome-systemic.md", "key_evidence_anchor": "Selective eradication/periodontal intervention or genetic natural experiment with mediated hard outcomes", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Periodontal treatment causally changes blood pressure or vascular function in some populations, and a two-year randomized trial changes carotid structure. These are positive human effects. However, Pg-specific mediation of clinical atherosclerotic events is not established: PREMIERS did not show superiority on hard events, PAVE was a feasibility pilot with crossover, and genetic liability studies do not provide a specific infection instrument." }, { "id": "SC4", "statement": "Oral microbial mechanisms causally drive human Alzheimer disease.", "subclaim_type": "generalization", "scope": "human AD incidence or clinical progression", "claimed_scope": "human AD incidence or clinical progression", "governing_rubric": "04-microbiome-systemic.md", "key_evidence_anchor": "Pathogen-selective intervention and clinical trajectory, with antecedent oral origin", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Human periodontal associations and low-biomass pathogen detection do not establish an antecedent oral cause of AD. Rodent toxicity/rescue is route- and host-dependent. Genetic analyses are null but imperfect infection instruments. The supplementary GAIN sponsor summary reports no overall efficacy and a positive pathogen-defined subgroup whose effect sizes and multiplicity could not be independently checked; it does not carry a positive threshold." }, { "id": "SC5", "statement": "Oral inflammation contributes to systemic inflammatory tone.", "subclaim_type": "mechanism", "scope": "adults with baseline periodontitis and prespecified inflammatory/endothelial outcomes", "claimed_scope": "adults with baseline periodontitis and prespecified inflammatory/endothelial outcomes", "governing_rubric": "04-microbiome-systemic.md", "key_evidence_anchor": "Randomized periodontal treatment and systemic response", "hsef_level": "Ε", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Randomized periodontal interventions show context-dependent systemic physiological responses, including endothelial function and blood pressure, together with inflammatory changes. Acute treatment can initially increase inflammation; coronary FMD and PAVE hsCRP nulls map limits. This bounded contribution is not organism-specific proof of human ASCVD or AD causation." } ], "aggregation_rule": "scope-matched", "aggregation_preregistered": true, "aggregation_rationale": "Use the index central claim and disease-separated subclaims. The human vascular and Alzheimer applications are co-central; the lower of SC3 and SC4 is the scope-matched bundled gate. Animal inoculation and inflammatory-tone changes are scored separately, and cannot replace human disease causality. This co-central interpretation of scope-matched is declared before scoring.", "primary_subclaim_id": "SC3", "aggregation_derivation": "Γ, Moderate confidence, for the preregistered human vascular-and-neurodegenerative bundle. Scope-matched aggregation takes the highest subclaim whose scope matches the central claim; only the co-central human subclaims SC3 and SC4 match that scope, and both are Γ. Primary-subclaim sensitivity is Γ; weakest-link sensitivity is Β because the presence/co-occurrence subclaim is observational. Model causality and systemic physiological effects are credited at Ε in their stated scopes rather than allowed to replace human disease causality. The convergence was assessed as a set; the missing link is specific human clinical mediation, not an automatic requirement for an impossible experiment.", "aggregation_alternatives": { "weakest_link_would_return": "Β", "primary_subclaim_would_return": "Γ", "scope_matched_would_return": "Γ", "note": "Separate narrow successes do not replace the preregistered gate." }, "index_rule_deviation": "" }, "competing_models": { "models_evaluated": [ { "rank_in_tournament": 1, "model_id": "M3", "is_nominal": false, "name": "Systemic inflammatory burden", "core_claim": "Oral inflammatory burden can affect vascular physiology and interact with existing systemic disease.", "explains_what_nominal_does_not": "Oral inflammatory burden can affect vascular physiology and interact with existing systemic disease.", "strongest_supporting_evidence": [ "Randomized BP, FMD and structural vascular changes and model host perturbations support bounded effects." ], "strongest_contradictory_evidence": [ "Null CAD FMD and PAVE hsCRP contrasts, transient early inflammation and nonspecific periodontal treatment limit universality." ], "hsef_level_for_this_model": "Ε", "rationale": "Randomized BP, FMD and structural vascular changes and model host perturbations support bounded effects. Null CAD FMD and PAVE hsCRP contrasts, transient early inflammation and nonspecific periodontal treatment limit universality." }, { "rank_in_tournament": 2, "model_id": "M2", "is_nominal": false, "name": "Common-cause susceptibility", "core_claim": "Smoking, deprivation, metabolic disease, host genetics and health-care access contribute to both dental and systemic outcomes.", "explains_what_nominal_does_not": "Smoking, deprivation, metabolic disease, host genetics and health-care access contribute to both dental and systemic outcomes.", "strongest_supporting_evidence": [ "Shared genetic architecture, observational heterogeneity and nonspecific exposure proxies favor substantial common causes." ], "strongest_contradictory_evidence": [ "Common causes alone cannot explain all randomized physiological effects or strain-resolved model phenotypes." ], "hsef_level_for_this_model": "Β", "rationale": "Shared genetic architecture, observational heterogeneity and nonspecific exposure proxies favor substantial common causes. Common causes alone cannot explain all randomized physiological effects or strain-resolved model phenotypes." }, { "rank_in_tournament": 3, "model_id": "M1", "is_nominal": true, "name": "Direct oral microbial pathogenesis", "core_claim": "Oral pathogens directly drive human vascular and Alzheimer disease.", "explains_what_nominal_does_not": "Oral pathogens directly drive human vascular and Alzheimer disease.", "strongest_supporting_evidence": [ "Oral exposure, gingipain/FimA subtraction and inhibitor rescue are the strongest recipient-model evidence." ], "strongest_contradictory_evidence": [ "Clinical microbial mediation remains unresolved; oral null/intracerebral positive results and nonspecific human cohorts restrict the claim." ], "hsef_level_for_this_model": "Γ", "rationale": "Oral exposure, gingipain/FimA subtraction and inhibitor rescue are the strongest recipient-model evidence. Clinical microbial mediation remains unresolved; oral null/intracerebral positive results and nonspecific human cohorts restrict the claim." }, { "rank_in_tournament": 4, "model_id": "M4", "is_nominal": false, "name": "Antimicrobial amyloid response", "core_claim": "Amyloid can participate in an innate response to microbial exposure.", "explains_what_nominal_does_not": "Amyloid can participate in an innate response to microbial exposure.", "strongest_supporting_evidence": [ "The Dominy model links infection, Aβ induction and in-vitro antimicrobial activity." ], "strongest_contradictory_evidence": [ "This does not show that human plaques are net protective or that infection is necessary for sporadic AD." ], "hsef_level_for_this_model": "Γ", "rationale": "The Dominy model links infection, Aβ induction and in-vitro antimicrobial activity. This does not show that human plaques are net protective or that infection is necessary for sporadic AD." }, { "rank_in_tournament": 5, "model_id": "M5", "is_nominal": false, "name": "Secondary colonization after barrier failure", "core_claim": "Age or neurodegeneration can permit microbial components or DNA to enter damaged tissues.", "explains_what_nominal_does_not": "Age or neurodegeneration can permit microbial components or DNA to enter damaged tissues.", "strongest_supporting_evidence": [ "Postdiagnostic detection and BBB pathway models are compatible with secondary entry." ], "strongest_contradictory_evidence": [ "Early model pathogen perturbations can cause injury; temporal human barrier-first colonization is not established by compatibility." ], "hsef_level_for_this_model": "Γ", "rationale": "Postdiagnostic detection and BBB pathway models are compatible with secondary entry. Early model pathogen perturbations can cause injury; temporal human barrier-first colonization is not established by compatibility." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. Compare selective pathogen suppression against equally effective nonspecific dental inflammation control, with baseline pathogen/CNS measurements and blinded clinical outcomes. This distinguishes microbial mediation from inflammatory burden and common-cause association.", "study_separating_rank1_from_rank2": "Compare selective pathogen suppression against equally effective nonspecific dental inflammation control, with baseline pathogen/CNS measurements and blinded clinical outcomes. This distinguishes microbial mediation from inflammatory burden and common-cause association.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "36943793", "title": "Periodontitis exacerbates atherosclerosis through Fusobacterium nucleatum-promoted hepatic glycolysis and lipogenesis.", "citation": "Zhou LJ, Lin WZ, Meng XQ et al. Periodontitis exacerbates atherosclerosis through Fusobacterium nucleatum-promoted hepatic glycolysis and lipogenesis. Cardiovascular research. 2023.", "doi": "10.1093/cvr/cvad045", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/36943793/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36943793/", "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": "PMID36943793", "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": "Ligature plus patient plaque and oral F. nucleatum accelerated atheroma in high-cholesterol atheroprone mice; hepatic lipid synthesis was linked to glycolytic signaling.", "what_it_does_not_show": "Forced exposure, ApoE/diet context and in-vitro pathway inhibition do not establish pathogen-specific human ASCVD mediation.", "confounders_present": [ "Forced exposure, ApoE/diet context and in-vitro pathway inhibition do not establish pathogen-specific human ASCVD 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": 2, "pmid": "40859845", "title": "Oral Pathobionts Aggravate Myocardial Infarction Through Mobilization of B2 Cells.", "citation": "Chen BY, Zhu H, Li YL et al. Oral Pathobionts Aggravate Myocardial Infarction Through Mobilization of B2 Cells. Circulation. 2025.", "doi": "10.1161/CIRCULATIONAHA.125.074837", "pmcid": "PMC12594163", "url": "https://pubmed.ncbi.nlm.nih.gov/40859845/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40859845/", "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": "PMID40859845", "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": "Ligature/plaque experiments, gnotobiotic mice, host knockouts and adhesion mutants linked oral pathobionts to B2-cell mobilization and worse experimental infarction; the human arm was associational.", "what_it_does_not_show": "This tests aggravation after induced MI, not spontaneous human coronary initiation or proof that Pg alone is necessary.", "confounders_present": [ "This tests aggravation after induced MI, not spontaneous human coronary initiation or proof that Pg alone is necessary." ], "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": "32432793", "title": "Better oral hygiene is associated with lower risk of stroke.", "citation": "Chang Y, Woo HG, Lee JS et al. Better oral hygiene is associated with lower risk of stroke. Journal of periodontology. 2021.", "doi": "10.1002/JPER.20-0053", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/32432793/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32432793/", "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": "PMID32432793", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "In 206602 Korean participants, frequent brushing was associated with lower incident stroke during median 10.4-year follow-up.", "what_it_does_not_show": "Dental-care behavior, socioeconomic factors and health behaviors confound mediation; stroke subtypes overlap and the result is not a randomized pathogen intervention.", "confounders_present": [ "Dental-care behavior, socioeconomic factors and health behaviors confound mediation; stroke subtypes overlap and the result is not a randomized pathogen 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": 4, "pmid": "31504461", "title": "Causal association between periodontitis and hypertension: evidence from Mendelian randomization and a randomized controlled trial of non-surgical periodontal therapy.", "citation": "Czesnikiewicz-Guzik M, Osmenda G, Siedlinski M et al. Causal association between periodontitis and hypertension: evidence from Mendelian randomization and a randomized controlled trial of non-surgical periodontal therapy. European heart journal. 2019.", "doi": "10.1093/eurheartj/ehz646", "pmcid": "PMC6837161", "url": "https://pubmed.ncbi.nlm.nih.gov/31504461/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31504461/", "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": "PMID31504461", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Methods:paragraph1, 1:Methods:paragraph2, 1:Methods:paragraph4, 1:Methods:paragraph5, 1:Methods:paragraph11. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Periodontitis-linked genetic instruments and a 101-person hypertensive RCT supported a periodontal-treatment effect on two-month ambulatory BP, with cytokine and T-cell changes.", "what_it_does_not_show": "Short-term BP/endothelial effects are narrower than atherosclerotic events; host-instrument pleiotropy and nonspecific treatment do not isolate Pg.", "confounders_present": [ "Short-term BP/endothelial effects are narrower than atherosclerotic events; host-instrument pleiotropy and nonspecific treatment do not isolate Pg." ], "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": "23725030", "title": "Periodontitis in patients with coronary artery disease: an 8-year follow-up.", "citation": "Johansson CS, Ravald N, Pagonis C et al. Periodontitis in patients with coronary artery disease: an 8-year follow-up. Journal of periodontology. 2014.", "doi": "10.1902/jop.2013.120730", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/23725030/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23725030/", "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": "PMID23725030", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "null", "what_it_shows": "An eight-year CAD follow-up found no significant association between baseline periodontal severity and later MI, revascularization or CAD death.", "what_it_does_not_show": "A modest established-CAD cohort can miss effects; the null does not prove no periodontal contribution in other stages.", "confounders_present": [ "A modest established-CAD cohort can miss effects; the null does not prove no periodontal contribution in other stages." ], "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": "33503409", "title": "Periodontal Disease, Atrial Fibrillation and Stroke.", "citation": "Sen S, Redd K, Trivedi T et al. Periodontal Disease, Atrial Fibrillation and Stroke. American heart journal. 2021.", "doi": "10.1016/j.ahj.2021.01.009", "pmcid": "PMC8084947", "url": "https://pubmed.ncbi.nlm.nih.gov/33503409/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33503409/", "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": "ARIC", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "ARIC periodontal severity and dental-care use were associated with incident AF; statistical mediation suggested AF might explain part of the periodontal-stroke association.", "what_it_does_not_show": "Shared ARIC reports are not independent causal lines, and observational mediation does not identify a microbial cause.", "confounders_present": [ "Shared ARIC reports are not independent causal lines, and observational mediation does not identify a microbial cause." ], "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": "34294791", "title": "Periodontitis induces endothelial dysfunction in mice.", "citation": "Parvaneh M, Witting PK, Ku J et al. Periodontitis induces endothelial dysfunction in mice. Scientific reports. 2021.", "doi": "10.1038/s41598-021-94418-8", "pmcid": "PMC8298548", "url": "https://pubmed.ncbi.nlm.nih.gov/34294791/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34294791/", "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": "PMID34294791", "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", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Four-week Pg/S. gordonii oral lavage in ApoE-deficient mice produced bone loss, hepatic inflammatory expression and impaired aortic acetylcholine relaxation without detected caecal-community differences.", "what_it_does_not_show": "Mixed-pathogen exposure and atheroprone genotype do not isolate a human Pg pathway; endothelial function is not a hard clinical event.", "confounders_present": [ "Mixed-pathogen exposure and atheroprone genotype do not isolate a human Pg pathway; endothelial function is not a hard clinical event." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 8, "pmid": "33386631", "title": "Periodontitis is associated with cardiovascular diseases: A 13-year study.", "citation": "Tiensripojamarn N, Lertpimonchai A, Tavedhikul K et al. Periodontitis is associated with cardiovascular diseases: A 13-year study. Journal of clinical periodontology. 2021.", "doi": "10.1111/jcpe.13418", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/33386631/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33386631/", "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": "PMID33386631", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Among 1850 Thai adults followed 13 years, severe periodontitis predicted CHD, but not total cardiovascular events or stroke, after adjustment.", "what_it_does_not_show": "The CHD interval was wide and endpoints differed; association cannot establish pathogen mediation or generalize to every vascular event.", "confounders_present": [ "The CHD interval was wide and endpoints differed; association cannot establish pathogen mediation or generalize to every vascular event." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 9, "pmid": "40796367", "title": "Oral Microbiota Linking Humoral Response, Periodontitis and Atherosclerosis.", "citation": "Akhi R, Lavrinienko A, Hakula M et al. Oral Microbiota Linking Humoral Response, Periodontitis and Atherosclerosis. Journal of clinical periodontology. 2025.", "doi": "10.1111/jcpe.70001", "pmcid": "PMC12531363", "url": "https://pubmed.ncbi.nlm.nih.gov/40796367/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40796367/", "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": "PMID40796367", "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", "SC5" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Northern Finland cohort data associated F. alocis, periodontal pockets, phosphorylcholine antibody responses and carotid thickness.", "what_it_does_not_show": "Cross-sectional microbial/antibody mediation is not causal mediation and is an alternative to a Pg-specific explanation.", "confounders_present": [ "Cross-sectional microbial/antibody mediation is not causal mediation and is an alternative to a Pg-specific explanation." ], "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": "21357860", "title": "The effect of subantimicrobial-dose-doxycycline periodontal therapy on serum biomarkers of systemic inflammation: a randomized, double-masked, placebo-controlled clinical trial.", "citation": "Payne JB, Golub LM, Stoner JA et al. The effect of subantimicrobial-dose-doxycycline periodontal therapy on serum biomarkers of systemic inflammation: a randomized, double-masked, placebo-controlled clinical trial. Journal of the American Dental Association (1939). 2011.", "doi": "10.14219/jada.archive.2011.0165", "pmcid": "PMC3077029", "url": "https://pubmed.ncbi.nlm.nih.gov/21357860/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21357860/", "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": "PMID21357860", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Two-year randomized subantimicrobial doxycycline lowered hs-CRP and MMP-9 in 128 postmenopausal periodontal-maintenance participants, without an overall lipid effect.", "what_it_does_not_show": "Systemic doxycycline is a host-modulating drug, so the effect cannot be assigned to elimination of oral microbes; no CAD event benefit was tested.", "confounders_present": [ "Systemic doxycycline is a host-modulating drug, so the effect cannot be assigned to elimination of oral microbes; no CAD event benefit was tested." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 11, "pmid": "16428788", "title": "Pathogen-accelerated atherosclerosis occurs early after exposure and can be prevented via immunization.", "citation": "Miyamoto T, Yumoto H, Takahashi Y et al. Pathogen-accelerated atherosclerosis occurs early after exposure and can be prevented via immunization. Infection and immunity. 2006.", "doi": "10.1128/IAI.74.2.1376-1380.2006", "pmcid": "PMC1360301", "url": "https://pubmed.ncbi.nlm.nih.gov/16428788/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16428788/", "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": "PMID16428788", "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", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Pg challenge increased early atheroma, macrophages and local innate markers in ApoE-knockout mice; prior immunization prevented this local response without elevated systemic mediators.", "what_it_does_not_show": "Artificial challenge and prophylactic immunization demonstrate model capacity, not spontaneous human disease or an obligatory systemic-CRP pathway.", "confounders_present": [ "Artificial challenge and prophylactic immunization demonstrate model capacity, not spontaneous human disease or an obligatory systemic-CRP pathway." ], "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": "29972709", "title": "Periodontal treatment limits platelet activation in patients with periodontitis-a controlled-randomized intervention trial.", "citation": "Laky M, Anscheringer I, Wolschner L et al. Periodontal treatment limits platelet activation in patients with periodontitis-a controlled-randomized intervention trial. Journal of clinical periodontology. 2018.", "doi": "10.1111/jcpe.12980", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/29972709/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29972709/", "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": "PMID29972709", "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", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "A 52-person randomized study found periodontal treatment prevented worsening of platelet activation over three months, with differences in turnover and collagen responses.", "what_it_does_not_show": "The treated arm was largely unchanged rather than normalized; platelet assays do not demonstrate prevention of MI or stroke.", "confounders_present": [ "The treated arm was largely unchanged rather than normalized; platelet assays do not demonstrate prevention of MI or stroke." ], "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": "21831372", "title": "Prospective association of periodontal disease with cardiovascular and all-cause mortality: NHANES III follow-up study.", "citation": "Xu F, Lu B et al. Prospective association of periodontal disease with cardiovascular and all-cause mortality: NHANES III follow-up study. Atherosclerosis. 2011.", "doi": "10.1016/j.atherosclerosis.2011.07.091", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/21831372/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21831372/", "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": "NHANES-III", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "NHANES III mortality follow-up associated severe periodontitis with cardiovascular/all-cause death in men aged 30–64, but not older men or women.", "what_it_does_not_show": "Subgroup heterogeneity, residual health-behavior confounding and shared NHANES material limit causal and independence claims.", "confounders_present": [ "Subgroup heterogeneity, residual health-behavior confounding and shared NHANES material limit causal and independence claims." ], "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": "26309048", "title": "The association between subgingival periodontal pathogens and systemic inflammation.", "citation": "Winning L, Patterson CC, Cullen KM et al. The association between subgingival periodontal pathogens and systemic inflammation. Journal of clinical periodontology. 2015.", "doi": "10.1111/jcpe.12450", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/26309048/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26309048/", "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": "PMID26309048", "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", "SC5" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "In 518 older dentate Northern Irish men, detectable subgingival Pg was associated with higher CRP after selected adjustments.", "what_it_does_not_show": "The cross-sectional finding cannot establish direction or exclude all obesity, smoking and host-susceptibility pathways.", "confounders_present": [ "The cross-sectional finding cannot establish direction or exclude all obesity, smoking and host-susceptibility pathways." ], "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": "36621868", "title": "Periodontitis and stroke: A Mendelian randomization study.", "citation": "Ma C, Wu M, Gao J et al. Periodontitis and stroke: A Mendelian randomization study. Brain and behavior. 2023.", "doi": "10.1002/brb3.2888", "pmcid": "PMC9927832", "url": "https://pubmed.ncbi.nlm.nih.gov/36621868/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36621868/", "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": "PMID36621868", "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": "natural experiment", "decisive_perturbation": false, "endogenous": true, "direction": "null", "what_it_shows": "Genetic proxies for chronic/aggressive periodontitis were null for overall ischemic stroke; a nominal chronic-periodontitis cardioembolic association contrasted with null large-artery and small-vessel results.", "what_it_does_not_show": "Limited periodontal instruments, multiple subtype tests and host pleiotropy prevent interpreting the isolated nominal result as microbial mediation.", "confounders_present": [ "Limited periodontal instruments, multiple subtype tests and host pleiotropy prevent interpreting the isolated nominal result as microbial 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": 16, "pmid": "37029659", "title": "Cyclic di-AMP Rescues Porphyromonas gingivalis-Aggravated Atherosclerosis.", "citation": "Wu Q, Li Z, Zhang Y et al. Cyclic di-AMP Rescues Porphyromonas gingivalis-Aggravated Atherosclerosis. Journal of dental research. 2023.", "doi": "10.1177/00220345231162344", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/37029659/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37029659/", "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": "PMID37029659", "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", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Cyclic di-AMP prophylaxis reduced periodontal bone loss, lipids and atheroma in Pg-challenged, ligature-treated high-fat ApoE-knockout mice.", "what_it_does_not_show": "A broad STING/trained-immunity adjuvant is not pathogen-specific rescue or proof of necessary human Pg infection.", "confounders_present": [ "A broad STING/trained-immunity adjuvant is not pathogen-specific rescue or proof of necessary human Pg infection." ], "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": "30746447", "title": "Porphyromonas gingivalis in Alzheimer's disease brains: Evidence for disease causation and treatment with small-molecule inhibitors.", "citation": "Dominy SS, Lynch C, Ermini F et al. Porphyromonas gingivalis in Alzheimer's disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Science advances. 2019.", "doi": "10.1126/sciadv.aau3333", "pmcid": "PMC6357742", "url": "https://pubmed.ncbi.nlm.nih.gov/30746447/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30746447/", "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": "PMID30746447", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:INTRODUCTION:paragraph13, 0:INTRODUCTION:paragraph14, 0:INTRODUCTION:paragraph26, 0:INTRODUCTION:paragraph27, 0:INTRODUCTION:paragraph30, 0:INTRODUCTION:paragraph31. 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": "Human gingipain/tau associations accompanied mouse oral-infection brain bacterial/amyloid findings and inhibitor protection in neurotoxicity paradigms.", "what_it_does_not_show": "Postmortem detection cannot establish antecedent oral-to-brain transit in humans; the routes, outcomes and controls of distinct mouse experiments must remain separate. Original sections show PCR positivity also in five of six nondemented controls, no healthy CSF comparison in the ten-AD-person pilot, direct hippocampal gingipain injection in one toxicity experiment, and oral inhibitor effects coupled to reduced pathogen burden. Gad67-positive interneuron counts are not a complete unbiased neuron-survival audit.", "confounders_present": [ "Postmortem detection cannot establish antecedent oral-to-brain transit in humans; the routes, outcomes and controls of distinct mouse experiments must remain separate. Original sections show PCR positivity also in five of six nondemented controls, no healthy CSF comparison in the ten-AD-person pilot, direct hippocampal gingipain injection in one toxicity experiment, and oral inhibitor effects coupled to reduced pathogen burden. Gad67-positive interneuron counts are not a complete unbiased neuron-survival audit." ], "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": "26963387", "title": "Periodontitis and Cognitive Decline in Alzheimer's Disease.", "citation": "Ide M, Harris M, Stevens A et al. Periodontitis and Cognitive Decline in Alzheimer's Disease. PloS one. 2016.", "doi": "10.1371/journal.pone.0151081", "pmcid": "PMC4786266", "url": "https://pubmed.ncbi.nlm.nih.gov/26963387/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26963387/", "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": "PMID26963387", "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", "SC5" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "A six-month observational cohort of 60 mild/moderate AD participants linked baseline periodontitis to faster ADAS-cog decline and increased inflammatory tone.", "what_it_does_not_show": "This is established-AD progression, not initiation, and frailty/caregiving or disease severity can affect oral health despite baseline adjustment.", "confounders_present": [ "This is established-AD progression, not initiation, and frailty/caregiving or disease severity can affect oral health despite baseline 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": 19, "pmid": "38278517", "title": "Periodontitis and brain magnetic resonance imaging markers of Alzheimer's disease and cognitive aging.", "citation": "Rubinstein T, Brickman AM, Cheng B et al. Periodontitis and brain magnetic resonance imaging markers of Alzheimer's disease and cognitive aging. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2024.", "doi": "10.1002/alz.13683", "pmcid": "PMC10984451", "url": "https://pubmed.ncbi.nlm.nih.gov/38278517/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38278517/", "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": "WHICAP", "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": "WHICAP oral-health data in 468 people associated periodontal/tooth and microbial-response features with brain MRI atrophy and vascular markers.", "what_it_does_not_show": "The analysis does not show AD causality; bacterial-specific associations differed and MRI endpoints are not a randomized clinical trajectory.", "confounders_present": [ "The analysis does not show AD causality; bacterial-specific associations differed and MRI endpoints are not a randomized clinical trajectory." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 20, "pmid": "36175166", "title": "Periodontitis-related salivary microbiota aggravates Alzheimer's disease via gut-brain axis crosstalk.", "citation": "Lu J, Zhang S, Huang Y et al. Periodontitis-related salivary microbiota aggravates Alzheimer's disease via gut-brain axis crosstalk. Gut microbes. 2022.", "doi": "10.1080/19490976.2022.2126272", "pmcid": "PMC9542625", "url": "https://pubmed.ncbi.nlm.nih.gov/36175166/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36175166/", "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": "PMID36175166", "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": "Two-month gavage of periodontal-patient salivary communities worsened cognition, amyloid and inflammation in APP/PS1 transgenic mice compared with healthy saliva.", "what_it_does_not_show": "Crude transfer does not identify a necessary Pg strain, separate gut/community/inflammation mediation, or establish endogenous human AD.", "confounders_present": [ "Crude transfer does not identify a necessary Pg strain, separate gut/community/inflammation mediation, or establish endogenous human AD." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 21, "pmid": "36796586", "title": "Extracellular vesicles derived from Porphyromonas gingivalis induce trigeminal nerve-mediated cognitive impairment.", "citation": "Ma X, Shin YJ, Yoo JW et al. Extracellular vesicles derived from Porphyromonas gingivalis induce trigeminal nerve-mediated cognitive impairment. Journal of advanced research. 2023.", "doi": "10.1016/j.jare.2023.02.006", "pmcid": "PMC10703712", "url": "https://pubmed.ncbi.nlm.nih.gov/36796586/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36796586/", "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": "PMID36796586", "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": "Gingival exposure to Pg or its EVs impaired mouse memory, unlike oral gavage; labeled-vesicle transport to the ipsilateral trigeminal ganglion was reduced by neurectomy.", "what_it_does_not_show": "Label movement is not intact replicating-organism transit; neuronal markers are not stereological loss, and route-specific inoculation bounds generalization.", "confounders_present": [ "Label movement is not intact replicating-organism transit; neuronal markers are not stereological loss, and route-specific inoculation bounds 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": 22, "pmid": "36631446", "title": "Porphyromonas gingivalis bacteremia increases the permeability of the blood-brain barrier via the Mfsd2a/Caveolin-1 mediated transcytosis pathway.", "citation": "Lei S, Li J, Yu J et al. Porphyromonas gingivalis bacteremia increases the permeability of the blood-brain barrier via the Mfsd2a/Caveolin-1 mediated transcytosis pathway. International journal of oral science. 2023.", "doi": "10.1038/s41368-022-00215-y", "pmcid": "PMC9834243", "url": "https://pubmed.ncbi.nlm.nih.gov/36631446/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36631446/", "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": "PMID36631446", "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": "Repeated tail-vein bacteremia increased rat BBB leakage; cellular Cav-1 reduction and Mfsd2a overexpression reversed permeability responses.", "what_it_does_not_show": "Forced bloodstream delivery and cell-level rescue do not establish an oral initiating route or rescue of human dementia.", "confounders_present": [ "Forced bloodstream delivery and cell-level rescue do not establish an oral initiating route or rescue of human dementia." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 23, "pmid": "40684176", "title": "Periodontitis-induced neuroinflammation triggers IFITM3-Aβ axis to cause alzheimer's disease-like pathology and cognitive decline.", "citation": "Kong L, Li J, Gao L et al. Periodontitis-induced neuroinflammation triggers IFITM3-Aβ axis to cause alzheimer's disease-like pathology and cognitive decline. Alzheimer's research & therapy. 2025.", "doi": "10.1186/s13195-025-01818-3", "pmcid": "PMC12275411", "url": "https://pubmed.ncbi.nlm.nih.gov/40684176/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40684176/", "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": "PMID40684176", "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": "Pg-induced periodontitis impaired cognition in wild-type mice and worsened APP/PS1 decline, with IFN-beta, glial IFITM3 and amyloid changes.", "what_it_does_not_show": "The abstract does not report IFITM3-specific loss/rescue; correlated pathway activation does not isolate the mediator or establish human initiation.", "confounders_present": [ "The abstract does not report IFITM3-specific loss/rescue; correlated pathway activation does not isolate the mediator or establish human initiation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 24, "pmid": "33122702", "title": "Microglial response to experimental periodontitis in a murine model of Alzheimer's disease.", "citation": "Kantarci A, Tognoni CM, Yaghmoor W et al. Microglial response to experimental periodontitis in a murine model of Alzheimer's disease. Scientific reports. 2020.", "doi": "10.1038/s41598-020-75517-4", "pmcid": "PMC7596239", "url": "https://pubmed.ncbi.nlm.nih.gov/33122702/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33122702/", "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": "PMID33122702", "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", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Ligature periodontitis increased insoluble amyloid in 5xFAD mice, but glial and cytokine effects differed from wild type, including reduced plaque-associated microglia.", "what_it_does_not_show": "State-specific responses oppose a simple uniform activation account; amyloid/glial changes do not demonstrate cognitive rescue or a Pg-specific cause.", "confounders_present": [ "State-specific responses oppose a simple uniform activation account; amyloid/glial changes do not demonstrate cognitive rescue or a Pg-specific cause." ], "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": "32280099", "title": "Clinical and Bacterial Markers of Periodontitis and Their Association with Incident All-Cause and Alzheimer's Disease Dementia in a Large National Survey.", "citation": "Beydoun MA, Beydoun HA, Hossain S et al. Clinical and Bacterial Markers of Periodontitis and Their Association with Incident All-Cause and Alzheimer's Disease Dementia in a Large National Survey. Journal of Alzheimer's disease : JAD. 2020.", "doi": "10.3233/JAD-200064", "pmcid": "PMC11008556", "url": "https://pubmed.ncbi.nlm.nih.gov/32280099/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32280099/", "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": "NHANES-III", "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": "NHANES III linked periodontal pockets and multi-pathogen IgG composites to incident dementia/AD mortality over long follow-up, particularly in older adults.", "what_it_does_not_show": "Composite antibodies and administrative outcomes do not identify active CNS infection; multiple analyses of the same NHANES cohort are one study family.", "confounders_present": [ "Composite antibodies and administrative outcomes do not identify active CNS infection; multiple analyses of the same NHANES cohort are one study family." ], "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": "36017373", "title": "Outer membrane vesicles of Porphyromonas gingivalis trigger NLRP3 inflammasome and induce neuroinflammation, tau phosphorylation, and memory dysfunction in mice.", "citation": "Gong T, Chen Q, Mao H et al. Outer membrane vesicles of Porphyromonas gingivalis trigger NLRP3 inflammasome and induce neuroinflammation, tau phosphorylation, and memory dysfunction in mice. Frontiers in cellular and infection microbiology. 2022.", "doi": "10.3389/fcimb.2022.925435", "pmcid": "PMC9397999", "url": "https://pubmed.ncbi.nlm.nih.gov/36017373/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36017373/", "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": "PMID36017373", "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": "Eight-week oral OMV dosing impaired aged-mouse memory and increased barrier, inflammatory and phospho-tau abnormalities; MCC950 attenuated cellular inflammasome/conditioned-medium effects.", "what_it_does_not_show": "The NLRP3 inhibition was in vitro, not a demonstrated in-vivo cognitive rescue; forced vesicle dose and substrate assays do not establish human AD.", "confounders_present": [ "The NLRP3 inhibition was in vitro, not a demonstrated in-vivo cognitive rescue; forced vesicle dose and substrate assays do not establish human AD." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 27, "pmid": "34391814", "title": "GSK3β is involved in promoting Alzheimer's disease pathologies following chronic systemic exposure to Porphyromonas gingivalis lipopolysaccharide in amyloid precursor proteinNL-F/NL-F knock-in mice.", "citation": "Jiang M, Zhang X, Yan X et al. GSK3β is involved in promoting Alzheimer's disease pathologies following chronic systemic exposure to Porphyromonas gingivalis lipopolysaccharide in amyloid precursor proteinNL-F/NL-F knock-in mice. Brain, behavior, and immunity. 2021.", "doi": "10.1016/j.bbi.2021.08.213", "pmcid": "PMC8849844", "url": "https://pubmed.ncbi.nlm.nih.gov/34391814/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34391814/", "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": "PMID34391814", "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": "Daily intraperitoneal Pg LPS worsened memory, synaptic proteins and tau phosphorylation in APP knock-in mice without changing amyloid; cellular GSK3/TNF interventions supported a pathway.", "what_it_does_not_show": "A systemic endotoxin regimen is not oral infection, and cell-level inhibition is not organismal mediator-specific rescue.", "confounders_present": [ "A systemic endotoxin regimen is not oral infection, and cell-level inhibition is not organismal mediator-specific rescue." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 28, "pmid": "35275538", "title": "The Oral and Fecal Microbiota in a Canadian Cohort of Alzheimer's Disease.", "citation": "Cirstea MS, Kliger D, MacLellan AD et al. The Oral and Fecal Microbiota in a Canadian Cohort of Alzheimer's Disease. Journal of Alzheimer's disease : JAD. 2022.", "doi": "10.3233/JAD-215520", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/35275538/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35275538/", "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": "PMID35275538", "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": "A Canadian case-control cohort found altered oral microbiota and greater Pg prevalence in AD, but no significant oral or gut microbial association with cognition.", "what_it_does_not_show": "A 45-case/54-control cross-section cannot establish direction; the lack of a cognition signature limits a simple abundance-to-progression inference.", "confounders_present": [ "A 45-case/54-control cross-section cannot establish direction; the lack of a cognition signature limits a simple abundance-to-progression inference." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 29, "pmid": "25517641", "title": "Evaluation of patients with Alzheimer's disease before and after dental treatment.", "citation": "Rolim Tde S, Fabri GM, Nitrini R et al. Evaluation of patients with Alzheimer's disease before and after dental treatment. Arquivos de neuro-psiquiatria. 2014.", "doi": "10.1590/0004-282X20140140", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/25517641/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25517641/", "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": "PMID25517641", "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", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Before/after dental care in 29 mild-AD patients improved pain, periodontal indices, quality of life and reported functional impairment.", "what_it_does_not_show": "An uncontrolled multicomponent intervention with symptomatic dental benefits cannot establish disease modification or microbial mediation.", "confounders_present": [ "An uncontrolled multicomponent intervention with symptomatic dental benefits cannot establish disease modification or microbial 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": 30, "pmid": "25491073", "title": "Periodontal disease associates with higher brain amyloid load in normal elderly.", "citation": "Kamer AR, Pirraglia E, Tsui W et al. Periodontal disease associates with higher brain amyloid load in normal elderly. Neurobiology of aging. 2015.", "doi": "10.1016/j.neurobiolaging.2014.10.038", "pmcid": "PMC4399973", "url": "https://pubmed.ncbi.nlm.nih.gov/25491073/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25491073/", "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": "PMID25491073", "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": "Clinical attachment loss was associated with greater amyloid PET uptake in 38 cognitively normal older people after selected adjustment.", "what_it_does_not_show": "Small observational amyloid imaging does not establish a causal infectious origin or clinical trajectory change.", "confounders_present": [ "Small observational amyloid imaging does not establish a causal infectious origin or clinical trajectory change." ], "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": "34151813", "title": "Porphyromonas gingivalis (W83) Infection Induces Alzheimer's Disease-Like Pathophysiology in Obese and Diabetic Mice.", "citation": "Bahar B, Kanagasingam S, Tambuwala MM et al. Porphyromonas gingivalis (W83) Infection Induces Alzheimer's Disease-Like Pathophysiology in Obese and Diabetic Mice. Journal of Alzheimer's disease : JAD. 2021.", "doi": "10.3233/JAD-210465", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/34151813/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34151813/", "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": "PMID34151813", "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": false, "endogenous": false, "direction": "null", "what_it_shows": "Oral Pg exposure in obese diabetic db/db mice produced glial/tau immunoreactivity and signaling changes, but silver staining detected neither amyloid plaques nor neurofibrillary tangles.", "what_it_does_not_show": "This is a constrained comorbidity model; transcriptional pathway activation and immunoreactivity cannot be equated with full AD or proven neuronal loss.", "confounders_present": [ "This is a constrained comorbidity model; transcriptional pathway activation and immunoreactivity cannot be equated with full AD or proven 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": 32, "pmid": "25061055", "title": "Active invasion of Porphyromonas gingivalis and infection-induced complement activation in ApoE-/- mice brains.", "citation": "Poole S, Singhrao SK, Chukkapalli S et al. Active invasion of Porphyromonas gingivalis and infection-induced complement activation in ApoE-/- mice brains. Journal of Alzheimer's disease : JAD. 2015.", "doi": "10.3233/JAD-140315", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/25061055/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25061055/", "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": "PMID25061055", "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": "Oral infection in ApoE-deficient mice yielded Pg brain DNA at 12/24 weeks and neuronal complement-fragment deposition in a subset.", "what_it_does_not_show": "Bacterial DNA and complement staining do not prove viable CNS replication, generalized neuronal death or spontaneous human initiation.", "confounders_present": [ "Bacterial DNA and complement staining do not prove viable CNS replication, generalized neuronal death or spontaneous human initiation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 33, "pmid": "40960941", "title": "Cerebrospinal fluid microbiome revisited: no evidence of resident bacteria in archived samples.", "citation": "Ward A, Park H, Cheng B et al. Cerebrospinal fluid microbiome revisited: no evidence of resident bacteria in archived samples. Microbiology spectrum. 2025.", "doi": "10.1128/spectrum.01308-25", "pmcid": "PMC12502689", "url": "https://pubmed.ncbi.nlm.nih.gov/40960941/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40960941/", "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": "PMID40960941", "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 observational", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Spike-in and meningitis-positive controls worked in 176 archived CSF specimens, while ordinary samples yielded negligible bacterial reads consistent with contamination/error.", "what_it_does_not_show": "This limits a resident-CSF microbiome claim; it does not exclude transient infection, focal brain organisms or every oral inflammatory pathway.", "confounders_present": [ "This limits a resident-CSF microbiome claim; it does not exclude transient infection, focal brain organisms or every oral inflammatory pathway." ], "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": "34926316", "title": "Porphyromonas gingivalis-Induced Cognitive Impairment Is Associated With Gut Dysbiosis, Neuroinflammation, and Glymphatic Dysfunction.", "citation": "Chi L, Cheng X, Lin L et al. Porphyromonas gingivalis-Induced Cognitive Impairment Is Associated With Gut Dysbiosis, Neuroinflammation, and Glymphatic Dysfunction. Frontiers in cellular and infection microbiology. 2021.", "doi": "10.3389/fcimb.2021.755925", "pmcid": "PMC8672439", "url": "https://pubmed.ncbi.nlm.nih.gov/34926316/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34926316/", "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": "PMID34926316", "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": "A month of oral Pg administration impaired mouse cognition with gut-composition, glymphatic, inflammatory and neuronal changes.", "what_it_does_not_show": "Co-occurring routes and pathways were not separately rescued in the abstract; alpha diversity was unchanged and an induced model is not human mediation.", "confounders_present": [ "Co-occurring routes and pathways were not separately rescued in the abstract; alpha diversity was unchanged and an induced model is not human 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": 35, "pmid": "34050719", "title": "Effect of periodontal treatment on preclinical Alzheimer's disease-Results of a trial emulation approach.", "citation": "Schwahn C, Frenzel S, Holtfreter B et al. Effect of periodontal treatment on preclinical Alzheimer's disease-Results of a trial emulation approach. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2022.", "doi": "10.1002/alz.12378", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/34050719/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34050719/", "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": "PMID34050719", "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 observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "A trial-emulation comparison of 177 treated and 409 untreated cohort members associated periodontal care with less AD-pattern brain atrophy after median 7.3 years.", "what_it_does_not_show": "Treatment was not randomized, the groups came from different cohorts, and MRI atrophy is neither AD diagnosis nor a clinical dementia endpoint.", "confounders_present": [ "Treatment was not randomized, the groups came from different cohorts, and MRI atrophy is neither AD diagnosis nor a clinical dementia 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": 36, "pmid": "22546352", "title": "Serum antibodies to periodontal pathogens are a risk factor for Alzheimer's disease.", "citation": "Sparks Stein P, Steffen MJ, Smith C et al. Serum antibodies to periodontal pathogens are a risk factor for Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2012.", "doi": "10.1016/j.jalz.2011.04.006", "pmcid": "PMC3712346", "url": "https://pubmed.ncbi.nlm.nih.gov/22546352/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22546352/", "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": "PMID22546352", "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": "Kentucky longitudinal samples showed elevated antibodies to F. nucleatum and P. intermedia before AD conversion, after selected adjustment.", "what_it_does_not_show": "The principal positive species were not Pg; antibody antecedence to symptoms does not establish antecedence to preclinical brain disease or causality.", "confounders_present": [ "The principal positive species were not Pg; antibody antecedence to symptoms does not establish antecedence to preclinical brain disease or 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": 37, "pmid": "29603738", "title": "Increased systemic levels of inflammatory mediators following one-stage full-mouth scaling and root planing.", "citation": "Morozumi T, Yashima A, Gomi K et al. Increased systemic levels of inflammatory mediators following one-stage full-mouth scaling and root planing. Journal of periodontal research. 2018.", "doi": "10.1111/jre.12543", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/29603738/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29603738/", "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": "PMID29603738", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Full-mouth scaling in 31 patients improved periodontal/bacterial measures by six weeks but produced an acute next-day systemic inflammatory response.", "what_it_does_not_show": "The uncontrolled before/after design and procedure-induced acute inflammation do not establish chronic pathogenic mediation or vascular-event prevention.", "confounders_present": [ "The uncontrolled before/after design and procedure-induced acute inflammation do not establish chronic pathogenic mediation or vascular-event 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": 38, "pmid": "22437687", "title": "Increased levels of Porphyromonas gingivalis are associated with ischemic and hemorrhagic cerebrovascular disease in humans: an in vivo study.", "citation": "Ghizoni JS, Taveira LA, Garlet GP et al. Increased levels of Porphyromonas gingivalis are associated with ischemic and hemorrhagic cerebrovascular disease in humans: an in vivo study. Journal of applied oral science : revista FOB. 2012.", "doi": "10.1590/s1678-77572012000100019", "pmcid": "PMC3928781", "url": "https://pubmed.ncbi.nlm.nih.gov/22437687/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22437687/", "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": "PMID22437687", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "A small stroke case-control study found worse periodontal health and more Pg-contaminated sites in stroke patients.", "what_it_does_not_show": "The title's in-vivo wording does not make this an intervention; post-stroke sampling and a very wide association interval permit reverse causation/confounding.", "confounders_present": [ "The title's in-vivo wording does not make this an intervention; post-stroke sampling and a very wide association interval permit reverse causation/confounding." ], "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": "21586133", "title": "Oral P. gingivalis infection alters the vascular reactivity in healthy and spontaneously atherosclerotic mice.", "citation": "Pereira RB, Vasquez EC, Stefanon I et al. Oral P. gingivalis infection alters the vascular reactivity in healthy and spontaneously atherosclerotic mice. Lipids in health and disease. 2011.", "doi": "10.1186/1476-511X-10-80", "pmcid": "PMC3118371", "url": "https://pubmed.ncbi.nlm.nih.gov/21586133/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21586133/", "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": "PMID21586133", "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": "Oral Pg increased phenylephrine vasoconstriction in healthy and ApoE-deficient mice, while acetylcholine and nitroprusside relaxation remained similar.", "what_it_does_not_show": "The receptor-specific response is not uniform endothelial failure and does not demonstrate human clinical-event causality.", "confounders_present": [ "The receptor-specific response is not uniform endothelial failure and does not demonstrate human clinical-event 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": 40, "pmid": "24002697", "title": "Porphyromonas gingivalis promotes neointimal formation after arterial injury through toll-like receptor 2 signaling.", "citation": "Kobayashi N, Suzuki J, Ogawa M et al. Porphyromonas gingivalis promotes neointimal formation after arterial injury through toll-like receptor 2 signaling. Heart and vessels. 2014.", "doi": "10.1007/s00380-013-0405-3", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/24002697/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24002697/", "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": "PMID24002697", "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": "Subcutaneous Pg after femoral injury increased neointima and MCP1 in wild-type mice; TLR2 deficiency prevented this response despite antibody induction.", "what_it_does_not_show": "Arterial injury and forced systemic exposure establish a recipient-model dependency, not spontaneous oral-pathogen-mediated human ASCVD.", "confounders_present": [ "Arterial injury and forced systemic exposure establish a recipient-model dependency, not spontaneous oral-pathogen-mediated human ASCVD." ], "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": "25663345", "title": "Activation of the NLRP3 inflammasome in Porphyromonas gingivalis-accelerated atherosclerosis.", "citation": "Yamaguchi Y, Kurita-Ochiai T, Kobayashi R et al. Activation of the NLRP3 inflammasome in Porphyromonas gingivalis-accelerated atherosclerosis. Pathogens and disease. 2015.", "doi": "10.1093/femspd/ftv011", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/25663345/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25663345/", "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": "PMID25663345", "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": "Oral wild-type Pg increased plaque, bone loss and inflammatory signals in hyperlipidemic Apoe-shl mice relative to gingipain-null and FimA-deficient strains.", "what_it_does_not_show": "Virulence mutations also change dissemination and burden; NLRP3 expression was measured without a reported NLRP3 necessity manipulation in the abstract.", "confounders_present": [ "Virulence mutations also change dissemination and burden; NLRP3 expression was measured without a reported NLRP3 necessity manipulation in the abstract." ], "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": "15123526", "title": "Innate immune recognition of invasive bacteria accelerates atherosclerosis in apolipoprotein E-deficient mice.", "citation": "Gibson FC, Hong C, Chou HH et al. Innate immune recognition of invasive bacteria accelerates atherosclerosis in apolipoprotein E-deficient mice. Circulation. 2004.", "doi": "10.1161/01.CIR.0000129769.17895.F0", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/15123526/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15123526/", "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": "PMID15123526", "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": "Oral wild-type Pg but not FimA-mutant Pg accelerated periodontal and atherosclerotic pathology in ApoE-null mice; immunization prevented the phenotype.", "what_it_does_not_show": "Both strains were detected by PCR in blood and aorta; coupled changes in periodontal disease and virulence do not isolate invasion as the sole mediator.", "confounders_present": [ "Both strains were detected by PCR in blood and aorta; coupled changes in periodontal disease and virulence do not isolate invasion as the sole 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": "40344434", "title": "Porphyromonas gingivalis Induces Endothelial Dysfunction Through Sirt3-Dependent CypD Acetylation.", "citation": "Xu S, Zheng C, Huang J et al. Porphyromonas gingivalis Induces Endothelial Dysfunction Through Sirt3-Dependent CypD Acetylation. Journal of periodontal research. 2025.", "doi": "10.1111/jre.13416", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/40344434/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40344434/", "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": "PMID40344434", "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": "Pg impaired endothelial integrity and vasorelaxation; Sirt3 activation reversed mitochondrial and vascular defects in cells and orally exposed mice.", "what_it_does_not_show": "Honokiol activation is not equivalent to a selective genetic rescue, and vascular physiology does not establish human clinical event prevention.", "confounders_present": [ "Honokiol activation is not equivalent to a selective genetic rescue, and vascular physiology does not establish human clinical event 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": 44, "pmid": "32681704", "title": "Mechanisms of vascular damage by systemic dissemination of the oral pathogen Porphyromonas gingivalis.", "citation": "Farrugia C, Stafford GP, Potempa J et al. Mechanisms of vascular damage by systemic dissemination of the oral pathogen Porphyromonas gingivalis. The FEBS journal. 2021.", "doi": "10.1111/febs.15486", "pmcid": "PMC9994420", "url": "https://pubmed.ncbi.nlm.nih.gov/32681704/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32681704/", "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": "PMID32681704", "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": "Wild-type Pg caused endothelial junction loss and leakage in human cells and systemically exposed zebrafish, unlike gingipain-deficient bacteria.", "what_it_does_not_show": "Cell culture and forced systemic zebrafish infection do not reproduce endogenous human oral-to-vascular mediation.", "confounders_present": [ "Cell culture and forced systemic zebrafish infection do not reproduce endogenous human oral-to-vascular 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": "24324141", "title": "Pivotal role of NOD2 in inflammatory processes affecting atherosclerosis and periodontal bone loss.", "citation": "Yuan H, Zelkha S, Burkatovskaya M et al. Pivotal role of NOD2 in inflammatory processes affecting atherosclerosis and periodontal bone loss. Proceedings of the National Academy of Sciences of the United States of America. 2013.", "doi": "10.1073/pnas.1320862110", "pmcid": "PMC3876260", "url": "https://pubmed.ncbi.nlm.nih.gov/24324141/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24324141/", "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": "PMID24324141", "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", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "NOD2 deficiency worsened oral-Pg inflammation, cholesterol and atheroma in ApoE mice; MDP stimulation reduced these phenotypes.", "what_it_does_not_show": "NOD2 signaling was protective here; systemic MDP also affected weight and metabolic inflammation. The linked correction concerns an author name, not a new study.", "confounders_present": [ "NOD2 signaling was protective here; systemic MDP also affected weight and metabolic inflammation. The linked correction concerns an author name, not a new 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": 46, "pmid": "40827724", "title": "Periodontitis treatment and progression of carotid intima-media thickness: a randomized trial.", "citation": "Orlandi M, Masi S, Lucenteforte E et al. Periodontitis treatment and progression of carotid intima-media thickness: a randomized trial. European heart journal. 2025.", "doi": "10.1093/eurheartj/ehaf555", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/40827724/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40827724/", "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": "PMID40827724", "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", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "In 135 otherwise healthy periodontal patients, randomized intensive treatment improved FMD and reduced carotid intima-media thickness at 24 months; blood pressure and PWV did not substantially differ.", "what_it_does_not_show": "The primary outcome was vascular structure, not MI, stroke or death; the PubMed abstract confidence interval is malformed and is not reproduced.", "confounders_present": [ "The primary outcome was vascular structure, not MI, stroke or death; the PubMed abstract confidence interval is malformed and is not reproduced." ], "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": "40273963", "title": "Determinants of post-stroke cognitive impairment in patients with periodontal disease.", "citation": "Pikel K, Logue L, Verkuilen H et al. Determinants of post-stroke cognitive impairment in patients with periodontal disease. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 2025.", "doi": "10.1016/j.jstrokecerebrovasdis.2025.108327", "pmcid": "PMC12163726", "url": "https://pubmed.ncbi.nlm.nih.gov/40273963/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40273963/", "tier": "A", "source_tier": "A", "kind": "observational", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PREMIERS", "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", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Cross-sectional baseline analysis of 280 PREMIERS participants associated severe periodontitis with post-stroke cognitive impairment.", "what_it_does_not_show": "This report is not a randomized cognitive-treatment result; stroke severity, education and race-related factors remain relevant, and it shares the PREMIERS trial population. Publication-type labeling was overridden to observational baseline analysis.", "confounders_present": [ "This report is not a randomized cognitive-treatment result; stroke severity, education and race-related factors remain relevant, and it shares the PREMIERS trial population. Publication-type labeling was overridden to observational baseline analysis." ], "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": "17329698", "title": "Treatment of periodontitis and endothelial function.", "citation": "Tonetti MS, D'Aiuto F, Nibali L et al. Treatment of periodontitis and endothelial function. The New England journal of medicine. 2007.", "doi": "10.1056/NEJMoa063186", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/17329698/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17329698/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "ErratumIn: PMID29898373" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID17329698", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: Original web Methods: enrollment and vascular assessment; linked correction NEJMx180022. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Randomized intensive treatment in 120 periodontal patients transiently worsened FMD and inflammation at 24 hours but improved FMD at 60 and 180 days; no cardiovascular events occurred.", "what_it_does_not_show": "Healthy participants and a surrogate endpoint limit clinical ASCVD inference; the parent paper has a correction to tPA variability reporting and a figure day label.", "confounders_present": [ "Healthy participants and a surrogate endpoint limit clinical ASCVD inference; the parent paper has a correction to tPA variability reporting and a figure day label." ], "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": "35052354", "title": "Causal Association between Periodontal Diseases and Cardiovascular Diseases.", "citation": "Zhou M, Dong J, Zha L et al. Causal Association between Periodontal Diseases and Cardiovascular Diseases. Genes. 2021.", "doi": "10.3390/genes13010013", "pmcid": "PMC8775300", "url": "https://pubmed.ncbi.nlm.nih.gov/35052354/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35052354/", "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": "PMID35052354", "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": "natural experiment", "decisive_perturbation": false, "endogenous": true, "direction": "null", "what_it_shows": "Two-sample Mendelian randomization found no supported periodontitis effect on major cardiovascular outcomes across several estimators.", "what_it_does_not_show": "Genetic liability instruments are not pathogen-specific eradication experiments and may not capture acquired infection severity or timing.", "confounders_present": [ "Genetic liability instruments are not pathogen-specific eradication experiments and may not capture acquired infection severity or timing." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 50, "pmid": "38817545", "title": "Alzheimer's disease and oral manifestations: a bi-directional Mendelian randomization study.", "citation": "Huang J, Deng A, Bai Y et al. Alzheimer's disease and oral manifestations: a bi-directional Mendelian randomization study. Frontiers in neurology. 2024.", "doi": "10.3389/fneur.2024.1391625", "pmcid": "PMC11138153", "url": "https://pubmed.ncbi.nlm.nih.gov/38817545/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38817545/", "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": "PMID38817545", "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": "natural experiment", "decisive_perturbation": false, "endogenous": true, "direction": "null", "what_it_shows": "Bidirectional genetic analyses did not support oral disease liability causing AD; a reverse AD-risk association was reported for oral cancer.", "what_it_does_not_show": "This does not isolate Pg infection, and instrument validity and phenotype specificity restrict a universal absence conclusion.", "confounders_present": [ "This does not isolate Pg infection, and instrument validity and phenotype specificity restrict a universal absence conclusion." ], "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": [ "Summary GWAS reused in other oral-disease MR reports." ] }, { "n": 51, "pmid": "25466412", "title": "Genetic evidence for PLASMINOGEN as a shared genetic risk factor of coronary artery disease and periodontitis.", "citation": "Schaefer AS, Bochenek G, Jochens A et al. Genetic evidence for PLASMINOGEN as a shared genetic risk factor of coronary artery disease and periodontitis. Circulation. Cardiovascular genetics. 2015.", "doi": "10.1161/CIRCGENETICS.114.000554", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/25466412/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25466412/", "tier": "A", "source_tier": "A", "kind": "genetic association", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID25466412", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Candidate-gene analysis linked aggressive periodontitis and CAD susceptibility through shared ANRIL and PLG-related loci.", "what_it_does_not_show": "Shared genetic susceptibility can support common causes; it is not Mendelian randomization or a randomized clinical intervention despite its database trial tag. Publication-type labeling was overridden to genetic association.", "confounders_present": [ "Shared genetic susceptibility can support common causes; it is not Mendelian randomization or a randomized clinical intervention despite its database trial tag. Publication-type labeling was overridden to genetic association." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 52, "pmid": "38648391", "title": "Periodontal disease and risk of Alzheimer's disease: A two-sample Mendelian randomization.", "citation": "Hu C, Li H, Huang L et al. Periodontal disease and risk of Alzheimer's disease: A two-sample Mendelian randomization. Brain and behavior. 2024.", "doi": "10.1002/brb3.3486", "pmcid": "PMC11034860", "url": "https://pubmed.ncbi.nlm.nih.gov/38648391/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38648391/", "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": "PMID38648391", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:METHOD, 2:RESULTS. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "natural experiment", "decisive_perturbation": false, "endogenous": true, "direction": "null", "what_it_shows": "Periodontitis-to-AD Mendelian randomization using FinnGen and two AD datasets produced null estimates with reported sensitivity analyses.", "what_it_does_not_show": "Host liability instruments and relaxed selection thresholds do not exclude all microbial causal effects, and summary datasets are reused across MR reports. Original Methods use p<1e-5 instruments and a small clinically ascertained AD case count in one outcome; nonsignificant Egger tests do not prove absence of pleiotropy.", "confounders_present": [ "Host liability instruments and relaxed selection thresholds do not exclude all microbial causal effects, and summary datasets are reused across MR reports. Original Methods use p<1e-5 instruments and a small clinically ascertained AD case count in one outcome; nonsignificant Egger tests do not prove absence of pleiotropy." ], "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": [ "Two AD outcomes share the same FinnGen periodontal exposure; validations are not independent exposure instruments." ] }, { "n": 53, "pmid": "39115027", "title": "Infection burden, periodontal pathogens, and their interactive association with incident all-cause and Alzheimer's disease dementia in a large national survey.", "citation": "Beydoun MA, Beydoun HA, Hedges DW et al. Infection burden, periodontal pathogens, and their interactive association with incident all-cause and Alzheimer's disease dementia in a large national survey. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2024.", "doi": "10.1002/alz.14141", "pmcid": "PMC11497652", "url": "https://pubmed.ncbi.nlm.nih.gov/39115027/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39115027/", "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": "NHANES-III", "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": "NHANES III antibody and infection-burden models associated Pg-related interactions with incident AD over linked follow-up.", "what_it_does_not_show": "Antibody exposure, multiple interactions and CMS outcome ascertainment do not prove CNS infection; other NHANES III reports are not independent cohorts.", "confounders_present": [ "Antibody exposure, multiple interactions and CMS outcome ascertainment do not prove CNS infection; other NHANES III reports are not independent cohorts." ], "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": "39905278", "title": "Porphyromonas gingivalis Induces Disturbance of Kynurenine Metabolism Through the Gut-Brain Axis: Implications for Alzheimer's Disease.", "citation": "Zhu H, Huang C, Luo Z et al. Porphyromonas gingivalis Induces Disturbance of Kynurenine Metabolism Through the Gut-Brain Axis: Implications for Alzheimer's Disease. Journal of dental research. 2025.", "doi": "10.1177/00220345241303141", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/39905278/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39905278/", "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": "PMID39905278", "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": "Oral Pg altered oral and gut communities, barrier measures and AD-like pathology; 3-hydroxykynurenine exposure promoted neuronal apoptosis in model systems.", "what_it_does_not_show": "The abstract does not report necessity blockade of the entire oral-to-brain pathway; indirect metabolic mediation remains distinct from direct CNS infection.", "confounders_present": [ "The abstract does not report necessity blockade of the entire oral-to-brain pathway; indirect metabolic mediation remains distinct from direct CNS infection." ], "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": "32727837", "title": "Periodontal disease and incident dementia: The Atherosclerosis Risk in Communities Study (ARIC).", "citation": "Demmer RT, Norby FL, Lakshminarayan K et al. Periodontal disease and incident dementia: The Atherosclerosis Risk in Communities Study (ARIC). Neurology. 2020.", "doi": "10.1212/WNL.0000000000010312", "pmcid": "PMC7713724", "url": "https://pubmed.ncbi.nlm.nih.gov/32727837/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32727837/", "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": "ARIC", "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 8275 ARIC participants followed for an average 18.4 years, severe periodontitis showed a modest association with incident dementia.", "what_it_does_not_show": "Some tooth-loss and cognitive endpoints had intervals spanning no association; confounding and shared ARIC participants preclude an independent causal line.", "confounders_present": [ "Some tooth-loss and cognitive endpoints had intervals spanning no association; confounding and shared ARIC participants preclude an independent causal line." ], "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": "35099831", "title": "Periodontal conditions and incident dementia: A nationwide Swedish cohort study.", "citation": "Holmer J, Eriksdotter M, Häbel H et al. Periodontal conditions and incident dementia: A nationwide Swedish cohort study. Journal of periodontology. 2022.", "doi": "10.1002/JPER.21-0518", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/35099831/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35099831/", "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": "PMID35099831", "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 observational", "decisive_perturbation": false, "endogenous": false, "direction": "null", "what_it_shows": "A Swedish matched cohort of 7992 deep-pocket patients and 29182 controls found similar dementia incidence over mean 7.6 years and no adjusted association.", "what_it_does_not_show": "The exposure is a periodontitis proxy; the wide adjusted interval does not demonstrate equivalence or rule out all pathogen-defined effects.", "confounders_present": [ "The exposure is a periodontitis proxy; the wide adjusted interval does not demonstrate equivalence or rule out all pathogen-defined effects." ], "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": "25363061", "title": "Tooth loss, periodontal disease, and cognitive decline in the Atherosclerosis Risk in Communities (ARIC) study.", "citation": "Naorungroj S, Schoenbach VJ, Wruck L et al. Tooth loss, periodontal disease, and cognitive decline in the Atherosclerosis Risk in Communities (ARIC) study. Community dentistry and oral epidemiology. 2015.", "doi": "10.1111/cdoe.12128", "pmcid": "PMC4303516", "url": "https://pubmed.ncbi.nlm.nih.gov/25363061/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25363061/", "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": "ARIC", "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 observational", "decisive_perturbation": false, "endogenous": false, "direction": "null", "what_it_shows": "An ARIC subset showed lower cognitive performance with complete tooth loss but no greater eight-year cognitive decline predicted by periodontal disease, tooth count or edentulism.", "what_it_does_not_show": "This shares the ARIC source population and evaluates limited cognitive tests rather than biomarker-defined AD or Pg exposure.", "confounders_present": [ "This shares the ARIC source population and evaluates limited cognitive tests rather than biomarker-defined AD or Pg exposure." ], "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": "25597561", "title": "Associations between oral health and risk of dementia in a 37-year follow-up study: the prospective population study of women in Gothenburg.", "citation": "Stewart R, Stenman U, Hakeberg M et al. Associations between oral health and risk of dementia in a 37-year follow-up study: the prospective population study of women in Gothenburg. Journal of the American Geriatrics Society. 2015.", "doi": "10.1111/jgs.13194", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/25597561/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25597561/", "tier": "A", "source_tier": "A", "kind": "observational", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID25597561", "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 observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "In the Gothenburg women's cohort, most adjusted tooth-count comparisons over 37 years were not associated with dementia; one examination remained positive.", "what_it_does_not_show": "Tooth count is an indirect exposure and selective positive time points do not establish periodontal microbial mediation.", "confounders_present": [ "Tooth count is an indirect exposure and selective positive time points do not establish periodontal microbial 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": 59, "pmid": "25522313", "title": "Serum IgG antibody levels to periodontal microbiota are associated with incident Alzheimer disease.", "citation": "Noble JM, Scarmeas N, Celenti RS et al. Serum IgG antibody levels to periodontal microbiota are associated with incident Alzheimer disease. PloS one. 2014.", "doi": "10.1371/journal.pone.0114959", "pmcid": "PMC4270775", "url": "https://pubmed.ncbi.nlm.nih.gov/25522313/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25522313/", "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": "WHICAP", "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": "In a 219-person WHICAP case-cohort, high A. naeslundii IgG predicted higher AD risk and E. nodatum IgG lower risk after adjustment.", "what_it_does_not_show": "The reported positive pathogen was not Pg; baseline age differed markedly, antibody response is indirect, and other WHICAP reports reuse the cohort.", "confounders_present": [ "The reported positive pathogen was not Pg; baseline age differed markedly, antibody response is indirect, and other WHICAP reports reuse the cohort." ], "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": "37548008", "title": "Periodontal Disease Treatment After Stroke or Transient Ischemic Attack: The PREMIERS Study, a Randomized Clinical Trial.", "citation": "Sen S, Curtis J, Hicklin D et al. Periodontal Disease Treatment After Stroke or Transient Ischemic Attack: The PREMIERS Study, a Randomized Clinical Trial. Stroke. 2023.", "doi": "10.1161/STROKEAHA.122.042047", "pmcid": "PMC10668075", "url": "https://pubmed.ncbi.nlm.nih.gov/37548008/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37548008/", "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": "PREMIERS", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: Original web Methods: Design, Treatment, Statistical considerations; Results: Trial population and events. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "null", "what_it_shows": "PREMIERS randomized 280 recent stroke or TIA patients to intensive or standard periodontal care; 12-month death, MI or stroke occurred in 11 versus 17, without significant superiority.", "what_it_does_not_show": "Both arms received active care, the phase II trial had few events and broad uncertainty; nonsuperiority is not proof of no clinical effect or pathogen irrelevance. Original Methods show an open-label masked-endpoint trial, standard-arm rescue treatment for periodontal worsening, a low observed event rate relative to planning, baseline diabetes/BMI imbalance, and no missing primary time-to-event data.", "confounders_present": [ "Both arms received active care, the phase II trial had few events and broad uncertainty; nonsuperiority is not proof of no clinical effect or pathogen irrelevance. Original Methods show an open-label masked-endpoint trial, standard-arm rescue treatment for periodontal worsening, a low observed event rate relative to planning, baseline diabetes/BMI imbalance, and no missing primary time-to-event data." ], "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": "41916952", "title": "Exploring the shared genetic architecture between periodontitis and cardiovascular disease.", "citation": "Jin T, Lin J, Zhang P et al. Exploring the shared genetic architecture between periodontitis and cardiovascular disease. BDJ open. 2026.", "doi": "10.1038/s41405-026-00421-4", "pmcid": "PMC13039211", "url": "https://pubmed.ncbi.nlm.nih.gov/41916952/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41916952/", "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": "PMID41916952", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Materials and methods:paragraph2, 1:Materials and methods:paragraph4, 1:Materials and methods:paragraph5, 1:Materials and methods:paragraph8. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "natural experiment", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "Bidirectional and multivariable MR did not support direct periodontitis-CVD causality, while colocalization and cross-trait analyses identified shared loci and immune-metabolic pathways.", "what_it_does_not_show": "Shared variants and pathway annotation do not establish oral infection mediation; phenotype instruments and reused summary data constrain independence.", "confounders_present": [ "Shared variants and pathway annotation do not establish oral infection mediation; phenotype instruments and reused summary data constrain 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": [ "GLIDE/FinnGen summary sources and clinical phenotypes may overlap other genetic analyses." ] }, { "n": 62, "pmid": "19214202", "title": "Identification of a shared genetic susceptibility locus for coronary heart disease and periodontitis.", "citation": "Schaefer AS, Richter GM, Groessner-Schreiber B et al. Identification of a shared genetic susceptibility locus for coronary heart disease and periodontitis. PLoS genetics. 2009.", "doi": "10.1371/journal.pgen.1000378", "pmcid": "PMC2632758", "url": "https://pubmed.ncbi.nlm.nih.gov/19214202/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19214202/", "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": "PMID19214202", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Candidate-gene analysis identified shared 9p21 susceptibility for aggressive periodontitis and coronary disease, distinct from a nearby diabetes variant.", "what_it_does_not_show": "Shared ANRIL-region association does not resolve disease direction or prove pathogen-mediated coronary disease.", "confounders_present": [ "Shared ANRIL-region association does not resolve disease direction or prove pathogen-mediated coronary disease." ], "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": "39290820", "title": "The Association Between Periodontal Disease and Cardiovascular Disease: Insights From Imaging, Observational, and Genetic Data.", "citation": "Sanghvi MM, Ramírez J, Chadalavada S et al. The Association Between Periodontal Disease and Cardiovascular Disease: Insights From Imaging, Observational, and Genetic Data. JACC. Advances. 2024.", "doi": "10.1016/j.jacadv.2024.101241", "pmcid": "PMC11406040", "url": "https://pubmed.ncbi.nlm.nih.gov/39290820/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39290820/", "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": "PMID39290820", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Discussion:paragraph7, 2:Discussion:paragraph8, 2:Discussion:paragraph10. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "In UK Biobank, self-reported periodontal disease was associated with cardiac remodeling and incident CAD; its polygenic score also associated with CAD.", "what_it_does_not_show": "The polygenic-score analysis is not a valid pathogen-specific causal instrument; weak liability and pleiotropy prevent treating it as decisive Mendelian randomization. Original Discussion expressly says MR was avoided because of instrument weakness and acknowledges horizontal or indirect pleiotropy.", "confounders_present": [ "The polygenic-score analysis is not a valid pathogen-specific causal instrument; weak liability and pleiotropy prevent treating it as decisive Mendelian randomization. Original Discussion expressly says MR was avoided because of instrument weakness and acknowledges horizontal or indirect pleiotropy." ], "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": [ "UK Biobank imaging, longitudinal and polygenic analyses share one population; the related conference abstract is not an extra causal line." ] }, { "n": 64, "pmid": "19186958", "title": "Results from the Periodontitis and Vascular Events (PAVE) Study: a pilot multicentered, randomized, controlled trial to study effects of periodontal therapy in a secondary prevention model of cardiovascular disease.", "citation": "Offenbacher S, Beck JD, Moss K et al. Results from the Periodontitis and Vascular Events (PAVE) Study: a pilot multicentered, randomized, controlled trial to study effects of periodontal therapy in a secondary prevention model of cardiovascular disease. Journal of periodontology. 2009.", "doi": "10.1902/jop.2009.080007", "pmcid": "PMC2778200", "url": "https://pubmed.ncbi.nlm.nih.gov/19186958/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19186958/", "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": "PMID19186958", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: Original web Introduction/Methods: pilot aims and randomization. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "null", "what_it_shows": "The 303-person PAVE pilot improved periodontal measures but showed no intention-to-treat reduction in hsCRP at six months; nearly half of community controls obtained dental care.", "what_it_does_not_show": "Post-randomization any-care and obesity subgroup comparisons do not retain the randomized contrast; this feasibility pilot was not powered for clinical cardiovascular efficacy.", "confounders_present": [ "Post-randomization any-care and obesity subgroup comparisons do not retain the randomized contrast; this feasibility pilot was not powered for clinical cardiovascular efficacy." ], "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": "42271186", "title": "Porphyromonas gingivalis disrupts hippocampal circadian clock via PI3K/AKT pathway, exacerbating Alzheimer-like pathology.", "citation": "Huang C, Cai Q, Feng Z et al. Porphyromonas gingivalis disrupts hippocampal circadian clock via PI3K/AKT pathway, exacerbating Alzheimer-like pathology. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2026.", "doi": "10.1002/alz.71543", "pmcid": "PMC13253356", "url": "https://pubmed.ncbi.nlm.nih.gov/42271186/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42271186/", "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": "PMID42271186", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:METHODS:paragraph6, 1:METHODS:paragraph7, 1:METHODS:paragraph12, 1:METHODS:paragraph17, 2:RESULTS:paragraph0, 2:RESULTS:paragraph6, 2:RESULTS:paragraph8. 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": "Six months of oral Pg after antibiotic conditioning caused poorer water-maze performance, neuronal pathology and altered hippocampal rhythms; cultured-glial AKT activation and Bmal1 knockdown interrogated the clock pathway.", "what_it_does_not_show": "Original Methods/Results specify twice-weekly exposure for 24 weeks after kanamycin, matched oral handling, and cell-line rather than in-vivo pathway rescue. Cognitive pathology is present; in-vivo clock-mediated necessity remains untested in the examined sections.", "confounders_present": [ "Original Methods/Results specify twice-weekly exposure for 24 weeks after kanamycin, matched oral handling, and cell-line rather than in-vivo pathway rescue. Cognitive pathology is present; in-vivo clock-mediated necessity remains untested in the examined sections." ], "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": "39255392", "title": "Chronic Oral Inoculation of Porphyromonas gingivalis and Treponema denticola Induce Different Brain Pathologies in a Mouse Model of Alzheimer Disease.", "citation": "Ciccotosto GD, Mohammed AI, Paolini R et al. Chronic Oral Inoculation of Porphyromonas gingivalis and Treponema denticola Induce Different Brain Pathologies in a Mouse Model of Alzheimer Disease. The Journal of infectious diseases. 2024.", "doi": "10.1093/infdis/jiae286", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/39255392/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39255392/", "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": "PMID39255392", "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": "Twelve-week oral Pg and T. denticola exposures produced differing brain pathology in female mice; coinoculation was less pathogenic than each alone.", "what_it_does_not_show": "Pathogen combination and host context alter outcomes; AD-like histology is not human AD, and a stronger universal synergistic prediction failed in this context.", "confounders_present": [ "Pathogen combination and host context alter outcomes; AD-like histology is not human AD, and a stronger universal synergistic prediction failed 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": 67, "pmid": "35328748", "title": "Intracerebral but Not Peripheral Infection of Live Porphyromonas gingivalis Exacerbates Alzheimer's Disease Like Amyloid Pathology in APP-TgCRND8 Mice.", "citation": "Aravindraja C, Sakthivel R, Liu X et al. Intracerebral but Not Peripheral Infection of Live Porphyromonas gingivalis Exacerbates Alzheimer's Disease Like Amyloid Pathology in APP-TgCRND8 Mice. International journal of molecular sciences. 2022.", "doi": "10.3390/ijms23063328", "pmcid": "PMC8954230", "url": "https://pubmed.ncbi.nlm.nih.gov/35328748/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35328748/", "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": "PMID35328748", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:2. Results:paragraph0, 1:2. Results:paragraph5, 1:2. Results:paragraph9, 1:2. Results:paragraph10. 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": "In APP-TgCRND8 mice, chronic oral infection caused bone loss and gliosis without accelerating Aβ; live intracerebral Pg increased Aβ after eight weeks, unlike heat-killed bacteria.", "what_it_does_not_show": "Direct brain injection bypasses the proposed oral route; peripheral and central results provide a route boundary rather than a general oral-infection proof.", "confounders_present": [ "Direct brain injection bypasses the proposed oral route; peripheral and central results provide a route boundary rather than a general oral-infection proof." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 68, "pmid": "31810741", "title": "Treating periodontal disease in patients with myocardial infarction: A randomized clinical trial.", "citation": "Lobo MG, Schmidt MM, Lopes RD et al. Treating periodontal disease in patients with myocardial infarction: A randomized clinical trial. European journal of internal medicine. 2020.", "doi": "10.1016/j.ejim.2019.08.012", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/31810741/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31810741/", "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": "PMID31810741", "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", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "A randomized 48-person recent-STEMI trial improved six-month FMD after periodontal treatment; inflammatory markers and cardiovascular events did not significantly differ.", "what_it_does_not_show": "The small trial's primary endpoint was endothelial physiology; it cannot establish prevention of recurrent clinical events or Pg-specific mediation.", "confounders_present": [ "The small trial's primary endpoint was endothelial physiology; it cannot establish prevention of recurrent clinical events or Pg-specific 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": 69, "pmid": "29873864", "title": "Periodontal therapy and endothelial function in coronary artery disease: A randomized controlled trial.", "citation": "Saffi MAL, Rabelo-Silva ER, Polanczyk CA et al. Periodontal therapy and endothelial function in coronary artery disease: A randomized controlled trial. Oral diseases. 2018.", "doi": "10.1111/odi.12909", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/29873864/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29873864/", "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": "PMID29873864", "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", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "null", "what_it_shows": "In 69 stable coronary patients, periodontal treatment improved dental status but did not improve three-month FMD relative to control; some vascular inflammatory markers were maintained.", "what_it_does_not_show": "Short follow-up and limited size constrain inference; positive adhesion-marker comparisons do not replace the null vasodilation contrast.", "confounders_present": [ "Short follow-up and limited size constrain inference; positive adhesion-marker comparisons do not replace the null vasodilation contrast." ], "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": 75, "verified": 75, "unverified": 0, "contradicted": 0, "note": "Verified attribution is distinct from mechanism truth or complete body access." }, "factual_issues_found": [], "cap_rules_applied": [ { "subclaim_id": "SC1", "cap": "Β", "cap_source": "universal", "triggered": true, "trigger_text_quoted": "Association-only microbiome work caps at Β.", "specific_trigger": "Prospective cohorts support co-occurrence, with substantial endpoint and population heterogeneity. Swedish dementia, ARIC cognitive decline, adjusted tooth-count and selected cardiovascular comparisons are null or mixed. Association is established as a recurring observation, not a universal risk relation or a microbial causal pathway.", "resulting_ceiling": "Β" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Oral microbial pathogens, principally Porphyromonas gingivalis, causally drive systemic cardiovascular and neurodegenerative disease in humans.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "The microbiome rubric explicitly credits transfer for recipient-model subclaims while universal cap 5 restricts inference to endogenous human biology. SC2 is therefore Ε, not demoted for being experimentally inoculated, while SC3/SC4 require their own human evidence. Clinical physiology is a real treatment effect; cap 4 still blocks converting a marker or structural change into disease-outcome proof. Eradication trials, natural experiments and human genetic convergence remain valid upper-ladder routes. The assembled human case is not literally recapped as cell culture: it stops at unresolved microbial mediation.", "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- Gnotobiotic or transfer experiment showing phenotype movement, at minimum\n- Even without defined-consortium precision or robust rescue, a transfer paradigm in vivo is the minimum that crosses this threshold\n\nPer **Cap precedence** above, a gnotobiotic or forced-transfer experiment crosses Δ for the recipient-animal subclaim it was actually run in, while universal cap 5 (seeding or forced-transfer paradigms cap at Γ) still blocks the inference from that result to endogenous human biology — score the two scopes separately rather than choosing between the rules.", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "Association alone." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Prospective cohorts support co-occurrence, with substantial endpoint and population heterogeneity. Swedish dementia, ARIC cognitive decline, adjusted tooth-count and selected cardiovascular comparisons are null or mixed. Association is established as a recurring observation, not a universal risk relation or a microbial causal pathway.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC2", "field_valid_perturbation_quote": "\n- Gnotobiotic or transfer experiment showing phenotype movement, at minimum\n- Even without defined-consortium precision or robust rescue, a transfer paradigm in vivo is the minimum that crosses this threshold\n\nPer **Cap precedence** above, a gnotobiotic or forced-transfer experiment crosses Δ for the recipient-animal subclaim it was actually run in, while universal cap 5 (seeding or forced-transfer paradigms cap at Γ) still blocks the inference from that result to endogenous human biology — score the two scopes separately rather than choosing between the rules.", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID36943793, PMID40859845, PMID34294791, PMID16428788, PMID37029659, PMID30746447, PMID36175166, PMID36796586, PMID36631446, PMID40684176, PMID33122702, PMID36017373, PMID34391814, PMID25061055, PMID34926316, PMID21586133, PMID24002697, PMID25663345, PMID15123526, PMID40344434, PMID32681704, PMID24324141, PMID39905278, PMID42271186, PMID39255392, PMID35328748", "gamma_hard_rules_triggered": [ "Recipient-animal scope: transfer is credited; human inference remains capped." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Defined oral exposures, bacterial virulence subtraction and host-pathway perturbations produce vascular and neural phenotypes in particular rodent systems. Oral versus intracerebral infection and single versus dual inoculation map important failures. Recipient-model causality is credited, but a single conserved organism-specific mediator across both organ systems is not independently isolated.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC3", "field_valid_perturbation_quote": "\n- Gnotobiotic or transfer experiment showing phenotype movement, at minimum\n- Even without defined-consortium precision or robust rescue, a transfer paradigm in vivo is the minimum that crosses this threshold\n\nPer **Cap precedence** above, a gnotobiotic or forced-transfer experiment crosses Δ for the recipient-animal subclaim it was actually run in, while universal cap 5 (seeding or forced-transfer paradigms cap at Γ) still blocks the inference from that result to endogenous human biology — score the two scopes separately rather than choosing between the rules.", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "PMID40859845, PMID31504461, PMID29972709, PMID21586133, PMID24002697, PMID40344434, PMID40827724, PMID17329698, PMID31810741", "gamma_hard_rules_triggered": [ "Positive physiology/structure, unresolved microbial clinical-event mediation." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Periodontal treatment causally changes blood pressure or vascular function in some populations, and a two-year randomized trial changes carotid structure. These are positive human effects. However, Pg-specific mediation of clinical atherosclerotic events is not established: PREMIERS did not show superiority on hard events, PAVE was a feasibility pilot with crossover, and genetic liability studies do not provide a specific infection instrument.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC4", "field_valid_perturbation_quote": "\n- Gnotobiotic or transfer experiment showing phenotype movement, at minimum\n- Even without defined-consortium precision or robust rescue, a transfer paradigm in vivo is the minimum that crosses this threshold\n\nPer **Cap precedence** above, a gnotobiotic or forced-transfer experiment crosses Δ for the recipient-animal subclaim it was actually run in, while universal cap 5 (seeding or forced-transfer paradigms cap at Γ) still blocks the inference from that result to endogenous human biology — score the two scopes separately rather than choosing between the rules.", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "PMID30746447, PMID36175166, PMID36796586, PMID36631446, PMID40684176, PMID33122702, PMID36017373, PMID34391814, PMID25061055, PMID34926316, PMID39905278, PMID42271186, PMID39255392, PMID35328748", "gamma_hard_rules_triggered": [ "Unresolved human oral origin and pathogen-specific clinical dependency." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Human periodontal associations and low-biomass pathogen detection do not establish an antecedent oral cause of AD. Rodent toxicity/rescue is route- and host-dependent. Genetic analyses are null but imperfect infection instruments. The supplementary GAIN sponsor summary reports no overall efficacy and a positive pathogen-defined subgroup whose effect sizes and multiplicity could not be independently checked; it does not carry a positive threshold.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC5", "field_valid_perturbation_quote": "\n- Gnotobiotic or transfer experiment showing phenotype movement, at minimum\n- Even without defined-consortium precision or robust rescue, a transfer paradigm in vivo is the minimum that crosses this threshold\n\nPer **Cap precedence** above, a gnotobiotic or forced-transfer experiment crosses Δ for the recipient-animal subclaim it was actually run in, while universal cap 5 (seeding or forced-transfer paradigms cap at Γ) still blocks the inference from that result to endogenous human biology — score the two scopes separately rather than choosing between the rules.", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID31504461, PMID34294791, PMID21357860, PMID16428788, PMID29972709, PMID37029659, PMID33122702, PMID24324141, PMID40827724, PMID17329698, PMID31810741", "gamma_hard_rules_triggered": [ "Bounded physiological outcomes, not clinical disease generalization." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Randomized periodontal interventions show context-dependent systemic physiological responses, including endothelial function and blood pressure, together with inflammatory changes. Acute treatment can initially increase inflammation; coronary FMD and PAVE hsCRP nulls map limits. This bounded contribution is not organism-specific proof of human ASCVD or AD causation.", "ceiling_from_boundary_check": "Δ or higher" } ], "thresholds_tested": [ { "subclaim_id": "SC1", "threshold": "Δ", "requirement_quoted": "Requires a transfer paradigm or causal perturbation in vivo.", "satisfied": "no", "supporting_evidence": [], "what_would_cross_it": "Association-only presence is not promoted by more correlated cohorts; a separately registered causal subclaim requires a selective perturbation." }, { "subclaim_id": "SC2", "threshold": "Δ", "requirement_quoted": "Requires a transfer paradigm or causal perturbation in vivo.", "satisfied": "yes", "supporting_evidence": [ "[1] Ligature plus patient plaque and oral F. nucleatum accelerated atheroma in high-cholesterol atheroprone mice; hepatic lipid synthesis was linked to glycolytic signaling.", "[2] Ligature/plaque experiments, gnotobiotic mice, host knockouts and adhesion mutants linked oral pathobionts to B2-cell mobilization and worse experimental infarction; the human arm was associational.", "[7] Four-week Pg/S. gordonii oral lavage in ApoE-deficient mice produced bone loss, hepatic inflammatory expression and impaired aortic acetylcholine relaxation without detected caecal-community differences.", "[11] Pg challenge increased early atheroma, macrophages and local innate markers in ApoE-knockout mice; prior immunization prevented this local response without elevated systemic mediators.", "[16] Cyclic di-AMP prophylaxis reduced periodontal bone loss, lipids and atheroma in Pg-challenged, ligature-treated high-fat ApoE-knockout mice.", "[17] Human gingipain/tau associations accompanied mouse oral-infection brain bacterial/amyloid findings and inhibitor protection in neurotoxicity paradigms.", "[20] Two-month gavage of periodontal-patient salivary communities worsened cognition, amyloid and inflammation in APP/PS1 transgenic mice compared with healthy saliva.", "[21] Gingival exposure to Pg or its EVs impaired mouse memory, unlike oral gavage; labeled-vesicle transport to the ipsilateral trigeminal ganglion was reduced by neurectomy.", "[22] Repeated tail-vein bacteremia increased rat BBB leakage; cellular Cav-1 reduction and Mfsd2a overexpression reversed permeability responses.", "[23] Pg-induced periodontitis impaired cognition in wild-type mice and worsened APP/PS1 decline, with IFN-beta, glial IFITM3 and amyloid changes.", "[24] Ligature periodontitis increased insoluble amyloid in 5xFAD mice, but glial and cytokine effects differed from wild type, including reduced plaque-associated microglia.", "[26] Eight-week oral OMV dosing impaired aged-mouse memory and increased barrier, inflammatory and phospho-tau abnormalities; MCC950 attenuated cellular inflammasome/conditioned-medium effects.", "[27] Daily intraperitoneal Pg LPS worsened memory, synaptic proteins and tau phosphorylation in APP knock-in mice without changing amyloid; cellular GSK3/TNF interventions supported a pathway.", "[32] Oral infection in ApoE-deficient mice yielded Pg brain DNA at 12/24 weeks and neuronal complement-fragment deposition in a subset.", "[34] A month of oral Pg administration impaired mouse cognition with gut-composition, glymphatic, inflammatory and neuronal changes.", "[39] Oral Pg increased phenylephrine vasoconstriction in healthy and ApoE-deficient mice, while acetylcholine and nitroprusside relaxation remained similar.", "[40] Subcutaneous Pg after femoral injury increased neointima and MCP1 in wild-type mice; TLR2 deficiency prevented this response despite antibody induction.", "[41] Oral wild-type Pg increased plaque, bone loss and inflammatory signals in hyperlipidemic Apoe-shl mice relative to gingipain-null and FimA-deficient strains.", "[42] Oral wild-type Pg but not FimA-mutant Pg accelerated periodontal and atherosclerotic pathology in ApoE-null mice; immunization prevented the phenotype.", "[43] Pg impaired endothelial integrity and vasorelaxation; Sirt3 activation reversed mitochondrial and vascular defects in cells and orally exposed mice.", "[44] Wild-type Pg caused endothelial junction loss and leakage in human cells and systemically exposed zebrafish, unlike gingipain-deficient bacteria.", "[45] NOD2 deficiency worsened oral-Pg inflammation, cholesterol and atheroma in ApoE mice; MDP stimulation reduced these phenotypes.", "[54] Oral Pg altered oral and gut communities, barrier measures and AD-like pathology; 3-hydroxykynurenine exposure promoted neuronal apoptosis in model systems.", "[65] Six months of oral Pg after antibiotic conditioning caused poorer water-maze performance, neuronal pathology and altered hippocampal rhythms; cultured-glial AKT activation and Bmal1 knockdown interrogated the clock pathway.", "[66] Twelve-week oral Pg and T. denticola exposures produced differing brain pathology in female mice; coinoculation was less pathogenic than each alone.", "[67] In APP-TgCRND8 mice, chronic oral infection caused bone loss and gliosis without accelerating Aβ; live intracerebral Pg increased Aβ after eight weeks, unlike heat-killed bacteria." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ε", "requirement_quoted": "Requires context-specific causal effect with defined limits. A transferable phenotype exists, but microbial identity or generalizability remains incomplete.", "satisfied": "yes", "supporting_evidence": [ "[1] Ligature plus patient plaque and oral F. nucleatum accelerated atheroma in high-cholesterol atheroprone mice; hepatic lipid synthesis was linked to glycolytic signaling.", "[2] Ligature/plaque experiments, gnotobiotic mice, host knockouts and adhesion mutants linked oral pathobionts to B2-cell mobilization and worse experimental infarction; the human arm was associational.", "[7] Four-week Pg/S. gordonii oral lavage in ApoE-deficient mice produced bone loss, hepatic inflammatory expression and impaired aortic acetylcholine relaxation without detected caecal-community differences.", "[11] Pg challenge increased early atheroma, macrophages and local innate markers in ApoE-knockout mice; prior immunization prevented this local response without elevated systemic mediators.", "[16] Cyclic di-AMP prophylaxis reduced periodontal bone loss, lipids and atheroma in Pg-challenged, ligature-treated high-fat ApoE-knockout mice.", "[17] Human gingipain/tau associations accompanied mouse oral-infection brain bacterial/amyloid findings and inhibitor protection in neurotoxicity paradigms.", "[20] Two-month gavage of periodontal-patient salivary communities worsened cognition, amyloid and inflammation in APP/PS1 transgenic mice compared with healthy saliva.", "[21] Gingival exposure to Pg or its EVs impaired mouse memory, unlike oral gavage; labeled-vesicle transport to the ipsilateral trigeminal ganglion was reduced by neurectomy.", "[22] Repeated tail-vein bacteremia increased rat BBB leakage; cellular Cav-1 reduction and Mfsd2a overexpression reversed permeability responses.", "[23] Pg-induced periodontitis impaired cognition in wild-type mice and worsened APP/PS1 decline, with IFN-beta, glial IFITM3 and amyloid changes.", "[24] Ligature periodontitis increased insoluble amyloid in 5xFAD mice, but glial and cytokine effects differed from wild type, including reduced plaque-associated microglia.", "[26] Eight-week oral OMV dosing impaired aged-mouse memory and increased barrier, inflammatory and phospho-tau abnormalities; MCC950 attenuated cellular inflammasome/conditioned-medium effects.", "[27] Daily intraperitoneal Pg LPS worsened memory, synaptic proteins and tau phosphorylation in APP knock-in mice without changing amyloid; cellular GSK3/TNF interventions supported a pathway.", "[32] Oral infection in ApoE-deficient mice yielded Pg brain DNA at 12/24 weeks and neuronal complement-fragment deposition in a subset.", "[34] A month of oral Pg administration impaired mouse cognition with gut-composition, glymphatic, inflammatory and neuronal changes.", "[39] Oral Pg increased phenylephrine vasoconstriction in healthy and ApoE-deficient mice, while acetylcholine and nitroprusside relaxation remained similar.", "[40] Subcutaneous Pg after femoral injury increased neointima and MCP1 in wild-type mice; TLR2 deficiency prevented this response despite antibody induction.", "[41] Oral wild-type Pg increased plaque, bone loss and inflammatory signals in hyperlipidemic Apoe-shl mice relative to gingipain-null and FimA-deficient strains.", "[42] Oral wild-type Pg but not FimA-mutant Pg accelerated periodontal and atherosclerotic pathology in ApoE-null mice; immunization prevented the phenotype.", "[43] Pg impaired endothelial integrity and vasorelaxation; Sirt3 activation reversed mitochondrial and vascular defects in cells and orally exposed mice.", "[44] Wild-type Pg caused endothelial junction loss and leakage in human cells and systemically exposed zebrafish, unlike gingipain-deficient bacteria.", "[45] NOD2 deficiency worsened oral-Pg inflammation, cholesterol and atheroma in ApoE mice; MDP stimulation reduced these phenotypes.", "[54] Oral Pg altered oral and gut communities, barrier measures and AD-like pathology; 3-hydroxykynurenine exposure promoted neuronal apoptosis in model systems.", "[65] Six months of oral Pg after antibiotic conditioning caused poorer water-maze performance, neuronal pathology and altered hippocampal rhythms; cultured-glial AKT activation and Bmal1 knockdown interrogated the clock pathway.", "[66] Twelve-week oral Pg and T. denticola exposures produced differing brain pathology in female mice; coinoculation was less pathogenic than each alone.", "[67] In APP-TgCRND8 mice, chronic oral infection caused bone loss and gliosis without accelerating Aβ; live intracerebral Pg increased Aβ after eight weeks, unlike heat-killed bacteria." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Defined consortium or strain-level causal evidence\n- Rescue logic\n- Replication across at least two relevant models or cohorts", "satisfied": "no", "supporting_evidence": [ "[1] Ligature plus patient plaque and oral F. nucleatum accelerated atheroma in high-cholesterol atheroprone mice; hepatic lipid synthesis was linked to glycolytic signaling.", "[2] Ligature/plaque experiments, gnotobiotic mice, host knockouts and adhesion mutants linked oral pathobionts to B2-cell mobilization and worse experimental infarction; the human arm was associational.", "[7] Four-week Pg/S. gordonii oral lavage in ApoE-deficient mice produced bone loss, hepatic inflammatory expression and impaired aortic acetylcholine relaxation without detected caecal-community differences.", "[11] Pg challenge increased early atheroma, macrophages and local innate markers in ApoE-knockout mice; prior immunization prevented this local response without elevated systemic mediators.", "[16] Cyclic di-AMP prophylaxis reduced periodontal bone loss, lipids and atheroma in Pg-challenged, ligature-treated high-fat ApoE-knockout mice.", "[17] Human gingipain/tau associations accompanied mouse oral-infection brain bacterial/amyloid findings and inhibitor protection in neurotoxicity paradigms.", "[20] Two-month gavage of periodontal-patient salivary communities worsened cognition, amyloid and inflammation in APP/PS1 transgenic mice compared with healthy saliva.", "[21] Gingival exposure to Pg or its EVs impaired mouse memory, unlike oral gavage; labeled-vesicle transport to the ipsilateral trigeminal ganglion was reduced by neurectomy.", "[22] Repeated tail-vein bacteremia increased rat BBB leakage; cellular Cav-1 reduction and Mfsd2a overexpression reversed permeability responses.", "[23] Pg-induced periodontitis impaired cognition in wild-type mice and worsened APP/PS1 decline, with IFN-beta, glial IFITM3 and amyloid changes.", "[24] Ligature periodontitis increased insoluble amyloid in 5xFAD mice, but glial and cytokine effects differed from wild type, including reduced plaque-associated microglia.", "[26] Eight-week oral OMV dosing impaired aged-mouse memory and increased barrier, inflammatory and phospho-tau abnormalities; MCC950 attenuated cellular inflammasome/conditioned-medium effects.", "[27] Daily intraperitoneal Pg LPS worsened memory, synaptic proteins and tau phosphorylation in APP knock-in mice without changing amyloid; cellular GSK3/TNF interventions supported a pathway.", "[32] Oral infection in ApoE-deficient mice yielded Pg brain DNA at 12/24 weeks and neuronal complement-fragment deposition in a subset.", "[34] A month of oral Pg administration impaired mouse cognition with gut-composition, glymphatic, inflammatory and neuronal changes.", "[39] Oral Pg increased phenylephrine vasoconstriction in healthy and ApoE-deficient mice, while acetylcholine and nitroprusside relaxation remained similar.", "[40] Subcutaneous Pg after femoral injury increased neointima and MCP1 in wild-type mice; TLR2 deficiency prevented this response despite antibody induction.", "[41] Oral wild-type Pg increased plaque, bone loss and inflammatory signals in hyperlipidemic Apoe-shl mice relative to gingipain-null and FimA-deficient strains.", "[42] Oral wild-type Pg but not FimA-mutant Pg accelerated periodontal and atherosclerotic pathology in ApoE-null mice; immunization prevented the phenotype.", "[43] Pg impaired endothelial integrity and vasorelaxation; Sirt3 activation reversed mitochondrial and vascular defects in cells and orally exposed mice.", "[44] Wild-type Pg caused endothelial junction loss and leakage in human cells and systemically exposed zebrafish, unlike gingipain-deficient bacteria.", "[45] NOD2 deficiency worsened oral-Pg inflammation, cholesterol and atheroma in ApoE mice; MDP stimulation reduced these phenotypes.", "[54] Oral Pg altered oral and gut communities, barrier measures and AD-like pathology; 3-hydroxykynurenine exposure promoted neuronal apoptosis in model systems.", "[65] Six months of oral Pg after antibiotic conditioning caused poorer water-maze performance, neuronal pathology and altered hippocampal rhythms; cultured-glial AKT activation and Bmal1 knockdown interrogated the clock pathway.", "[66] Twelve-week oral Pg and T. denticola exposures produced differing brain pathology in female mice; coinoculation was less pathogenic than each alone.", "[67] In APP-TgCRND8 mice, chronic oral infection caused bone loss and gliosis without accelerating Aβ; live intracerebral Pg increased Aβ after eight weeks, unlike heat-killed bacteria." ], "what_would_cross_it": "Cross-facility matched-colonization strain subtraction and complementation, with blinded neuronal/vascular function and live organism versus product tracing, would isolate the mediator and test failed contexts." }, { "subclaim_id": "SC3", "threshold": "Δ", "requirement_quoted": "Requires a transfer paradigm or causal perturbation in vivo.", "satisfied": "no", "supporting_evidence": [ "[2] Ligature/plaque experiments, gnotobiotic mice, host knockouts and adhesion mutants linked oral pathobionts to B2-cell mobilization and worse experimental infarction; the human arm was associational.", "[4] Periodontitis-linked genetic instruments and a 101-person hypertensive RCT supported a periodontal-treatment effect on two-month ambulatory BP, with cytokine and T-cell changes.", "[12] A 52-person randomized study found periodontal treatment prevented worsening of platelet activation over three months, with differences in turnover and collagen responses.", "[39] Oral Pg increased phenylephrine vasoconstriction in healthy and ApoE-deficient mice, while acetylcholine and nitroprusside relaxation remained similar.", "[40] Subcutaneous Pg after femoral injury increased neointima and MCP1 in wild-type mice; TLR2 deficiency prevented this response despite antibody induction.", "[43] Pg impaired endothelial integrity and vasorelaxation; Sirt3 activation reversed mitochondrial and vascular defects in cells and orally exposed mice.", "[46] In 135 otherwise healthy periodontal patients, randomized intensive treatment improved FMD and reduced carotid intima-media thickness at 24 months; blood pressure and PWV did not substantially differ.", "[48] Randomized intensive treatment in 120 periodontal patients transiently worsened FMD and inflammation at 24 hours but improved FMD at 60 and 180 days; no cardiovascular events occurred.", "[68] A randomized 48-person recent-STEMI trial improved six-month FMD after periodontal treatment; inflammatory markers and cardiovascular events did not significantly differ." ], "what_would_cross_it": "A clinical-outcome trial or rigorous natural experiment with selective microbial engagement and explicit mediation, sufficient events, and matched dental inflammatory care would cross the human gate." }, { "subclaim_id": "SC4", "threshold": "Δ", "requirement_quoted": "Requires a transfer paradigm or causal perturbation in vivo.", "satisfied": "no", "supporting_evidence": [ "[17] Human gingipain/tau associations accompanied mouse oral-infection brain bacterial/amyloid findings and inhibitor protection in neurotoxicity paradigms.", "[20] Two-month gavage of periodontal-patient salivary communities worsened cognition, amyloid and inflammation in APP/PS1 transgenic mice compared with healthy saliva.", "[21] Gingival exposure to Pg or its EVs impaired mouse memory, unlike oral gavage; labeled-vesicle transport to the ipsilateral trigeminal ganglion was reduced by neurectomy.", "[22] Repeated tail-vein bacteremia increased rat BBB leakage; cellular Cav-1 reduction and Mfsd2a overexpression reversed permeability responses.", "[23] Pg-induced periodontitis impaired cognition in wild-type mice and worsened APP/PS1 decline, with IFN-beta, glial IFITM3 and amyloid changes.", "[24] Ligature periodontitis increased insoluble amyloid in 5xFAD mice, but glial and cytokine effects differed from wild type, including reduced plaque-associated microglia.", "[26] Eight-week oral OMV dosing impaired aged-mouse memory and increased barrier, inflammatory and phospho-tau abnormalities; MCC950 attenuated cellular inflammasome/conditioned-medium effects.", "[27] Daily intraperitoneal Pg LPS worsened memory, synaptic proteins and tau phosphorylation in APP knock-in mice without changing amyloid; cellular GSK3/TNF interventions supported a pathway.", "[32] Oral infection in ApoE-deficient mice yielded Pg brain DNA at 12/24 weeks and neuronal complement-fragment deposition in a subset.", "[34] A month of oral Pg administration impaired mouse cognition with gut-composition, glymphatic, inflammatory and neuronal changes.", "[54] Oral Pg altered oral and gut communities, barrier measures and AD-like pathology; 3-hydroxykynurenine exposure promoted neuronal apoptosis in model systems.", "[65] Six months of oral Pg after antibiotic conditioning caused poorer water-maze performance, neuronal pathology and altered hippocampal rhythms; cultured-glial AKT activation and Bmal1 knockdown interrogated the clock pathway.", "[66] Twelve-week oral Pg and T. denticola exposures produced differing brain pathology in female mice; coinoculation was less pathogenic than each alone.", "[67] In APP-TgCRND8 mice, chronic oral infection caused bone loss and gliosis without accelerating Aβ; live intracerebral Pg increased Aβ after eight weeks, unlike heat-killed bacteria." ], "what_would_cross_it": "A prospectively pathogen-defined AD study with validated CNS infection measurement and selective therapeutic engagement, clinical benefit, multiplicity-controlled interaction and independent replication would cross the gate." }, { "subclaim_id": "SC5", "threshold": "Δ", "requirement_quoted": "Requires a transfer paradigm or causal perturbation in vivo.", "satisfied": "yes", "supporting_evidence": [ "[4] Periodontitis-linked genetic instruments and a 101-person hypertensive RCT supported a periodontal-treatment effect on two-month ambulatory BP, with cytokine and T-cell changes.", "[7] Four-week Pg/S. gordonii oral lavage in ApoE-deficient mice produced bone loss, hepatic inflammatory expression and impaired aortic acetylcholine relaxation without detected caecal-community differences.", "[10] Two-year randomized subantimicrobial doxycycline lowered hs-CRP and MMP-9 in 128 postmenopausal periodontal-maintenance participants, without an overall lipid effect.", "[11] Pg challenge increased early atheroma, macrophages and local innate markers in ApoE-knockout mice; prior immunization prevented this local response without elevated systemic mediators.", "[12] A 52-person randomized study found periodontal treatment prevented worsening of platelet activation over three months, with differences in turnover and collagen responses.", "[16] Cyclic di-AMP prophylaxis reduced periodontal bone loss, lipids and atheroma in Pg-challenged, ligature-treated high-fat ApoE-knockout mice.", "[24] Ligature periodontitis increased insoluble amyloid in 5xFAD mice, but glial and cytokine effects differed from wild type, including reduced plaque-associated microglia.", "[45] NOD2 deficiency worsened oral-Pg inflammation, cholesterol and atheroma in ApoE mice; MDP stimulation reduced these phenotypes.", "[46] In 135 otherwise healthy periodontal patients, randomized intensive treatment improved FMD and reduced carotid intima-media thickness at 24 months; blood pressure and PWV did not substantially differ.", "[48] Randomized intensive treatment in 120 periodontal patients transiently worsened FMD and inflammation at 24 hours but improved FMD at 60 and 180 days; no cardiovascular events occurred.", "[68] A randomized 48-person recent-STEMI trial improved six-month FMD after periodontal treatment; inflammatory markers and cardiovascular events did not significantly differ." ], "what_would_cross_it": "" }, { "subclaim_id": "SC5", "threshold": "Ε", "requirement_quoted": "Requires context-specific causal effect with defined limits. A transferable phenotype exists, but microbial identity or generalizability remains incomplete.", "satisfied": "yes", "supporting_evidence": [ "[4] Periodontitis-linked genetic instruments and a 101-person hypertensive RCT supported a periodontal-treatment effect on two-month ambulatory BP, with cytokine and T-cell changes.", "[7] Four-week Pg/S. gordonii oral lavage in ApoE-deficient mice produced bone loss, hepatic inflammatory expression and impaired aortic acetylcholine relaxation without detected caecal-community differences.", "[10] Two-year randomized subantimicrobial doxycycline lowered hs-CRP and MMP-9 in 128 postmenopausal periodontal-maintenance participants, without an overall lipid effect.", "[11] Pg challenge increased early atheroma, macrophages and local innate markers in ApoE-knockout mice; prior immunization prevented this local response without elevated systemic mediators.", "[12] A 52-person randomized study found periodontal treatment prevented worsening of platelet activation over three months, with differences in turnover and collagen responses.", "[16] Cyclic di-AMP prophylaxis reduced periodontal bone loss, lipids and atheroma in Pg-challenged, ligature-treated high-fat ApoE-knockout mice.", "[24] Ligature periodontitis increased insoluble amyloid in 5xFAD mice, but glial and cytokine effects differed from wild type, including reduced plaque-associated microglia.", "[45] NOD2 deficiency worsened oral-Pg inflammation, cholesterol and atheroma in ApoE mice; MDP stimulation reduced these phenotypes.", "[46] In 135 otherwise healthy periodontal patients, randomized intensive treatment improved FMD and reduced carotid intima-media thickness at 24 months; blood pressure and PWV did not substantially differ.", "[48] Randomized intensive treatment in 120 periodontal patients transiently worsened FMD and inflammation at 24 hours but improved FMD at 60 and 180 days; no cardiovascular events occurred.", "[68] A randomized 48-person recent-STEMI trial improved six-month FMD after periodontal treatment; inflammatory markers and cardiovascular events did not significantly differ." ], "what_would_cross_it": "" }, { "subclaim_id": "SC5", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Defined consortium or strain-level causal evidence\n- Rescue logic\n- Replication across at least two relevant models or cohorts", "satisfied": "no", "supporting_evidence": [ "[4] Periodontitis-linked genetic instruments and a 101-person hypertensive RCT supported a periodontal-treatment effect on two-month ambulatory BP, with cytokine and T-cell changes.", "[7] Four-week Pg/S. gordonii oral lavage in ApoE-deficient mice produced bone loss, hepatic inflammatory expression and impaired aortic acetylcholine relaxation without detected caecal-community differences.", "[10] Two-year randomized subantimicrobial doxycycline lowered hs-CRP and MMP-9 in 128 postmenopausal periodontal-maintenance participants, without an overall lipid effect.", "[11] Pg challenge increased early atheroma, macrophages and local innate markers in ApoE-knockout mice; prior immunization prevented this local response without elevated systemic mediators.", "[12] A 52-person randomized study found periodontal treatment prevented worsening of platelet activation over three months, with differences in turnover and collagen responses.", "[16] Cyclic di-AMP prophylaxis reduced periodontal bone loss, lipids and atheroma in Pg-challenged, ligature-treated high-fat ApoE-knockout mice.", "[24] Ligature periodontitis increased insoluble amyloid in 5xFAD mice, but glial and cytokine effects differed from wild type, including reduced plaque-associated microglia.", "[45] NOD2 deficiency worsened oral-Pg inflammation, cholesterol and atheroma in ApoE mice; MDP stimulation reduced these phenotypes.", "[46] In 135 otherwise healthy periodontal patients, randomized intensive treatment improved FMD and reduced carotid intima-media thickness at 24 months; blood pressure and PWV did not substantially differ.", "[48] Randomized intensive treatment in 120 periodontal patients transiently worsened FMD and inflammation at 24 hours but improved FMD at 60 and 180 days; no cardiovascular events occurred.", "[68] A randomized 48-person recent-STEMI trial improved six-month FMD after periodontal treatment; inflammatory markers and cardiovascular events did not significantly differ." ], "what_would_cross_it": "Mechanistically selective oral inflammatory perturbation, physiological rescue, timing and independent clinical contexts would distinguish shared systemic drug effects from oral mediation." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "Oral infection versus direct intracerebral infection in APP-TgCRND8.", "Live versus heat-killed bacteria.", "FimA/gingipain mutants with colonization caveats.", "Standard active periodontal care in PREMIERS and community crossover in PAVE.", "Stable CAD FMD null versus recent-STEMI or otherwise healthy positive comparisons." ], "note": "Generalization has been tested and failed in specified route, host, pathogen combination, clinical population and endpoint contexts. APP-TgCRND8 oral nulls and weaker coinoculation responses justify an Ε boundary for model capability. They do not refute all oral pathology. Human ASCVD and AD causal mediation remain open rather than proved by the positive mouse contexts." }, "falsification_patterns_met": [ { "pattern": "Expected oral amyloid acceleration failed in a tested host", "evidence": "PMID35328748 oral infection caused dental disease and gliosis without Aβ acceleration, while intracerebral live Pg was positive.", "downgrade_applied": false }, { "pattern": "Uniform treatment response is contradicted", "evidence": "PMID29873864 CAD FMD and PMID19186958 ITT hsCRP were null; PMID17329698 showed early deterioration followed by improvement.", "downgrade_applied": false }, { "pattern": "Hard vascular superiority was not demonstrated", "evidence": "PMID37548008 is a nonsuperior active-comparator phase II result with few events, not an equivalence proof.", "downgrade_applied": false } ], "pitfalls_flagged": [ { "pitfall": "Association and surrogate outcome substituted for clinical microbial mediation", "where": "SC3/SC4; separated in outcome-specific cards." }, { "pitfall": "PCR or antigen presence treated as viable initiating infection", "where": "Dominy controls and low-biomass attribution." }, { "pitfall": "Reports counted as independent studies", "where": "Named cohort groups and genetic-source overlap." }, { "pitfall": "Outcome-defined successful scope", "where": "Host, route, baseline disease and exposure are fixed before results; failures remain included." } ], "causal_tally_audit": { "tally_claimed_by_document": 32, "tally_after_audit": 32, "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 multiple randomized vascular effects, cIMT structural improvement, genetic information and pathogen rescue models. This clearly defeats the view that oral disease has only local effects. Yet a positive vascular response does not isolate Pg or show clinical ASCVD events, and it does not rescue the separate AD gate.", "case_one_rung_lower": "The strongest Β case points to confounding, indirect oral measures, weak MR instruments and low-biomass contamination. It understates actual bacterial virulence and host-pathway perturbations and randomized human physiological effects; the overall mechanistic case exceeds association alone.", "which_rejected": "Reject Δ for the bundled human claim on missing clinical microbial mediation; reject Β for the whole mechanistic claim because recipient and human physiological causal effects are real. Retain Β for SC1, Ε for the bounded successes and Γ for the human gates.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: Run a prospectively pathogen-defined clinical programme with selective Pg suppression versus matched periodontal inflammatory care, documented oral and systemic/CNS engagement, prespecified interactions and independently adjudicated clinical vascular or AD outcomes in separate disease cohorts." }, "final_score": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "69 primary reports with 10 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "Γ, Moderate confidence, for the preregistered human vascular-and-neurodegenerative bundle. Scope-matched aggregation takes the highest subclaim whose scope matches the central claim; only the co-central human subclaims SC3 and SC4 match that scope, and both are Γ. Primary-subclaim sensitivity is Γ; weakest-link sensitivity is Β because the presence/co-occurrence subclaim is observational. Model causality and systemic physiological effects are credited at Ε in their stated scopes rather than allowed to replace human disease causality. The convergence was assessed as a set; the missing link is specific human clinical mediation, not an automatic requirement for an impossible experiment." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": 5, "derivation": "Steps 1–2 do not describe all data: recipient-model subtraction and human randomization show causal effects beyond co-occurrence, and reverse causation is not the only direction. Step 3 lacks human initiation plus prevention plus rate limitation; step 4 lacks universal requirement. Step 5 fits bounded amplification of vascular or neural pathology and systemic inflammatory physiology. This is a conditional role inference, not a claim that human Pg-mediated AD has been proved.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "The 2025 Sirt3 endothelial model and 2026 PI3K/AKT-clock work interrogate model pathways; the two-year cIMT trial adds human physiology. No verified currently running pathogen-selective clinical-outcome study crossing both human gates is asserted.", "justification": "The 2025 Sirt3 endothelial model and 2026 PI3K/AKT-clock work interrogate model pathways; the two-year cIMT trial adds human physiology. No verified currently running pathogen-selective clinical-outcome study crossing both human gates is asserted." }, "stability": { "value": "Stable", "trigger": "No named pending result was verified that is likely to move the co-central human score imminently. A new target-engaged clinical result would matter, but a hypothetical trigger does not set Rising.", "justification": "No named pending result was verified that is likely to move the co-central human score imminently. A new target-engaged clinical result would matter, but a hypothetical trigger does not set Rising." }, "divergence": { "implied_level": null, "implied_level_basis": "No single field-implied level is defensible from conflicting framings.", "assessed_level": "Γ", "gap_in_rungs": null, "value": "Contested", "justification": "No manufactured field consensus or arithmetic gap." }, "calibration_note": "M/S/D never modify HSEF level or confidence." }, "change_record": { "applies": false, "prior_level": "Ranking categorical verdict visible; no prior letter used as a target", "prior_confidence": null, "prior_source": null, "derived_before_consulting_prior": false, "new_level": "Γ", "direction": "newly assigned", "what_moved_it": "Fresh primary evidence appraisal; not blinded.", "divergence_from_other_reviewers": null }, "proposed_decisive_experiments": [ { "name": "Registered boundary experiment", "experiment": "Run a prospectively pathogen-defined clinical programme with selective Pg suppression versus matched periodontal inflammatory care, documented oral and systemic/CNS engagement, prespecified interactions and independently adjudicated clinical vascular or AD outcomes in separate disease cohorts.", "readout": "Clinical event or cognitive/functional trajectory with organism load, viability-sensitive measures and mediator timing", "critical_control": "Matched dental inflammation improvement, placebo/active comparator, non-Pg pathogen comparison, blinded outcomes, contamination/spike-in controls and multiplicity plan", "supporting_result": "Selective sustained engagement changes the registered clinical trajectory beyond matched inflammation control and replicates in the prespecified pathogen-defined population", "falsifying_result": "Adequate engagement with sufficiently precise clinical nulls, or equal benefit from nonspecific inflammation control without pathogen mediation" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Separate direct microbial invasion from systemic inflammatory, gut-metabolic and barrier routes; inhibitor benefit coupled to lower load cannot identify one mediator.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Determine whether viable CNS organisms precede AD pathology with sensitive contamination-controlled assays; postmortem DNA is insufficient.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Resolve clinical event benefit after periodontal treatment with adequate event counts; positive FMD or cIMT should motivate, not substitute for, that study.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Verify GAIN subgroup definitions, effect estimates, multiplicity, interactions and safety from complete primary results before pathogen-defined benefit is used causally.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Test complemented bacterial mutants at matched colonization across independent facilities, both sexes and prespecified host backgrounds.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 6", "statement": "Model protective immune signaling and acute treatment-related inflammatory spikes rather than treating all activation as harmful.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-06", "reviewer": "Codex", "evidence_base_note": "69 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": true, "why_not_sufficient": "Eradication with hard outcomes, strain-level complemented rescue and orthogonal human causal instruments were considered. Defined virulence controls establish bounded model capability. Human treatment studies do not selectively isolate microbial mediation, and the hard-event randomized contrast was nonsuperior with limited precision. Thus higher levels remain reachable without an all-purpose RCT demand." }, { "kind": "natural_experiment", "available": true, "why_not_sufficient": "Eradication with hard outcomes, strain-level complemented rescue and orthogonal human causal instruments were considered. Defined virulence controls establish bounded model capability. Human treatment studies do not selectively isolate microbial mediation, and the hard-event randomized contrast was nonsuperior with limited precision. Thus higher levels remain reachable without an all-purpose RCT demand." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "Eradication with hard outcomes, strain-level complemented rescue and orthogonal human causal instruments were considered. Defined virulence controls establish bounded model capability. Human treatment studies do not selectively isolate microbial mediation, and the hard-event randomized contrast was nonsuperior with limited precision. Thus higher levels remain reachable without an all-purpose RCT demand." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Eradication with hard outcomes, strain-level complemented rescue and orthogonal human causal instruments were considered. Defined virulence controls establish bounded model capability. Human treatment studies do not selectively isolate microbial mediation, and the hard-event randomized contrast was nonsuperior with limited precision. Thus higher levels remain reachable without an all-purpose RCT demand." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": true, "why_not_sufficient": "Eradication with hard outcomes, strain-level complemented rescue and orthogonal human causal instruments were considered. Defined virulence controls establish bounded model capability. Human treatment studies do not selectively isolate microbial mediation, and the hard-event randomized contrast was nonsuperior with limited precision. Thus higher levels remain reachable without an all-purpose RCT demand." } ], "convergence_present": true, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 69, "claims_total": 75, "claims_verified": 75, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 69, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "Ligature plus patient plaque and oral F. nucleatum accelerated atheroma in high-cholesterol atheroprone mice; hepatic lipid synthesis was linked to glycolytic signaling. Forced exposure, ApoE/diet context and in-vitro pathway inhibition do not establish pathogen-specific human ASCVD mediation.", "carries_number": false, "load_bearing_for": [ "SC2" ], "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": "Ligature/plaque experiments, gnotobiotic mice, host knockouts and adhesion mutants linked oral pathobionts to B2-cell mobilization and worse experimental infarction; the human arm was associational. This tests aggravation after induced MI, not spontaneous human coronary initiation or proof that Pg alone is necessary.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C3", "text": "In 206602 Korean participants, frequent brushing was associated with lower incident stroke during median 10.4-year follow-up. Dental-care behavior, socioeconomic factors and health behaviors confound mediation; stroke subtypes overlap and the result is not a randomized pathogen intervention.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "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": "Periodontitis-linked genetic instruments and a 101-person hypertensive RCT supported a periodontal-treatment effect on two-month ambulatory BP, with cytokine and T-cell changes. Short-term BP/endothelial effects are narrower than atherosclerotic events; host-instrument pleiotropy and nonspecific treatment do not isolate Pg.", "carries_number": true, "load_bearing_for": [ "SC3", "SC5" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Methods:paragraph1, 1:Methods:paragraph2, 1:Methods:paragraph4, 1:Methods:paragraph5, 1:Methods:paragraph11. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C5", "text": "An eight-year CAD follow-up found no significant association between baseline periodontal severity and later MI, revascularization or CAD death. A modest established-CAD cohort can miss effects; the null does not prove no periodontal contribution in other stages.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "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": "ARIC periodontal severity and dental-care use were associated with incident AF; statistical mediation suggested AF might explain part of the periodontal-stroke association. Shared ARIC reports are not independent causal lines, and observational mediation does not identify a microbial cause.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "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": "Four-week Pg/S. gordonii oral lavage in ApoE-deficient mice produced bone loss, hepatic inflammatory expression and impaired aortic acetylcholine relaxation without detected caecal-community differences. Mixed-pathogen exposure and atheroprone genotype do not isolate a human Pg pathway; endothelial function is not a hard clinical event.", "carries_number": false, "load_bearing_for": [ "SC2", "SC5" ], "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": "Among 1850 Thai adults followed 13 years, severe periodontitis predicted CHD, but not total cardiovascular events or stroke, after adjustment. The CHD interval was wide and endpoints differed; association cannot establish pathogen mediation or generalize to every vascular event.", "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": "Northern Finland cohort data associated F. alocis, periodontal pockets, phosphorylcholine antibody responses and carotid thickness. Cross-sectional microbial/antibody mediation is not causal mediation and is an alternative to a Pg-specific explanation.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC5" ], "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": "Two-year randomized subantimicrobial doxycycline lowered hs-CRP and MMP-9 in 128 postmenopausal periodontal-maintenance participants, without an overall lipid effect. Systemic doxycycline is a host-modulating drug, so the effect cannot be assigned to elimination of oral microbes; no CAD event benefit was tested.", "carries_number": true, "load_bearing_for": [ "SC5" ], "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": "Pg challenge increased early atheroma, macrophages and local innate markers in ApoE-knockout mice; prior immunization prevented this local response without elevated systemic mediators. Artificial challenge and prophylactic immunization demonstrate model capacity, not spontaneous human disease or an obligatory systemic-CRP pathway.", "carries_number": false, "load_bearing_for": [ "SC2", "SC5" ], "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": "A 52-person randomized study found periodontal treatment prevented worsening of platelet activation over three months, with differences in turnover and collagen responses. The treated arm was largely unchanged rather than normalized; platelet assays do not demonstrate prevention of MI or stroke.", "carries_number": true, "load_bearing_for": [ "SC3", "SC5" ], "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": "NHANES III mortality follow-up associated severe periodontitis with cardiovascular/all-cause death in men aged 30–64, but not older men or women. Subgroup heterogeneity, residual health-behavior confounding and shared NHANES material limit causal and independence claims.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 13 ], "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": "C14", "text": "In 518 older dentate Northern Irish men, detectable subgingival Pg was associated with higher CRP after selected adjustments. The cross-sectional finding cannot establish direction or exclude all obesity, smoking and host-susceptibility pathways.", "carries_number": true, "load_bearing_for": [ "SC1", "SC5" ], "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": "Genetic proxies for chronic/aggressive periodontitis were null for overall ischemic stroke; a nominal chronic-periodontitis cardioembolic association contrasted with null large-artery and small-vessel results. Limited periodontal instruments, multiple subtype tests and host pleiotropy prevent interpreting the isolated nominal result as microbial mediation.", "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": "Cyclic di-AMP prophylaxis reduced periodontal bone loss, lipids and atheroma in Pg-challenged, ligature-treated high-fat ApoE-knockout mice. A broad STING/trained-immunity adjuvant is not pathogen-specific rescue or proof of necessary human Pg infection.", "carries_number": false, "load_bearing_for": [ "SC2", "SC5" ], "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": "Human gingipain/tau associations accompanied mouse oral-infection brain bacterial/amyloid findings and inhibitor protection in neurotoxicity paradigms. Postmortem detection cannot establish antecedent oral-to-brain transit in humans; the routes, outcomes and controls of distinct mouse experiments must remain separate. Original sections show PCR positivity also in five of six nondemented controls, no healthy CSF comparison in the ten-AD-person pilot, direct hippocampal gingipain injection in one toxicity experiment, and oral inhibitor effects coupled to reduced pathogen burden. Gad67-positive interneuron counts are not a complete unbiased neuron-survival audit.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:INTRODUCTION:paragraph13, 0:INTRODUCTION:paragraph14, 0:INTRODUCTION:paragraph26, 0:INTRODUCTION:paragraph27, 0:INTRODUCTION:paragraph30, 0:INTRODUCTION:paragraph31. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C18", "text": "A six-month observational cohort of 60 mild/moderate AD participants linked baseline periodontitis to faster ADAS-cog decline and increased inflammatory tone. This is established-AD progression, not initiation, and frailty/caregiving or disease severity can affect oral health despite baseline adjustment.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4", "SC5" ], "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": "WHICAP oral-health data in 468 people associated periodontal/tooth and microbial-response features with brain MRI atrophy and vascular markers. The analysis does not show AD causality; bacterial-specific associations differed and MRI endpoints are not a randomized clinical trajectory.", "carries_number": true, "load_bearing_for": [ "SC1", "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": "Two-month gavage of periodontal-patient salivary communities worsened cognition, amyloid and inflammation in APP/PS1 transgenic mice compared with healthy saliva. Crude transfer does not identify a necessary Pg strain, separate gut/community/inflammation mediation, or establish endogenous human AD.", "carries_number": true, "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": "Gingival exposure to Pg or its EVs impaired mouse memory, unlike oral gavage; labeled-vesicle transport to the ipsilateral trigeminal ganglion was reduced by neurectomy. Label movement is not intact replicating-organism transit; neuronal markers are not stereological loss, and route-specific inoculation bounds generalization.", "carries_number": false, "load_bearing_for": [ "SC2", "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": "Repeated tail-vein bacteremia increased rat BBB leakage; cellular Cav-1 reduction and Mfsd2a overexpression reversed permeability responses. Forced bloodstream delivery and cell-level rescue do not establish an oral initiating route or rescue of human dementia.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C23", "text": "Pg-induced periodontitis impaired cognition in wild-type mice and worsened APP/PS1 decline, with IFN-beta, glial IFITM3 and amyloid changes. The abstract does not report IFITM3-specific loss/rescue; correlated pathway activation does not isolate the mediator or establish human initiation.", "carries_number": true, "load_bearing_for": [ "SC2", "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": "Ligature periodontitis increased insoluble amyloid in 5xFAD mice, but glial and cytokine effects differed from wild type, including reduced plaque-associated microglia. State-specific responses oppose a simple uniform activation account; amyloid/glial changes do not demonstrate cognitive rescue or a Pg-specific cause.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4", "SC5" ], "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": "NHANES III linked periodontal pockets and multi-pathogen IgG composites to incident dementia/AD mortality over long follow-up, particularly in older adults. Composite antibodies and administrative outcomes do not identify active CNS infection; multiple analyses of the same NHANES cohort are one study family.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "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": "Eight-week oral OMV dosing impaired aged-mouse memory and increased barrier, inflammatory and phospho-tau abnormalities; MCC950 attenuated cellular inflammasome/conditioned-medium effects. The NLRP3 inhibition was in vitro, not a demonstrated in-vivo cognitive rescue; forced vesicle dose and substrate assays do not establish human AD.", "carries_number": true, "load_bearing_for": [ "SC2", "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": "Daily intraperitoneal Pg LPS worsened memory, synaptic proteins and tau phosphorylation in APP knock-in mice without changing amyloid; cellular GSK3/TNF interventions supported a pathway. A systemic endotoxin regimen is not oral infection, and cell-level inhibition is not organismal mediator-specific rescue.", "carries_number": true, "load_bearing_for": [ "SC2", "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": "A Canadian case-control cohort found altered oral microbiota and greater Pg prevalence in AD, but no significant oral or gut microbial association with cognition. A 45-case/54-control cross-section cannot establish direction; the lack of a cognition signature limits a simple abundance-to-progression inference.", "carries_number": false, "load_bearing_for": [ "SC1", "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": "Before/after dental care in 29 mild-AD patients improved pain, periodontal indices, quality of life and reported functional impairment. An uncontrolled multicomponent intervention with symptomatic dental benefits cannot establish disease modification or microbial mediation.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "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": "Clinical attachment loss was associated with greater amyloid PET uptake in 38 cognitively normal older people after selected adjustment. Small observational amyloid imaging does not establish a causal infectious origin or clinical trajectory change.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "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": "Oral Pg exposure in obese diabetic db/db mice produced glial/tau immunoreactivity and signaling changes, but silver staining detected neither amyloid plaques nor neurofibrillary tangles. This is a constrained comorbidity model; transcriptional pathway activation and immunoreactivity cannot be equated with full AD or proven neuronal loss.", "carries_number": false, "load_bearing_for": [ "SC2", "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": "Oral infection in ApoE-deficient mice yielded Pg brain DNA at 12/24 weeks and neuronal complement-fragment deposition in a subset. Bacterial DNA and complement staining do not prove viable CNS replication, generalized neuronal death or spontaneous human initiation.", "carries_number": true, "load_bearing_for": [ "SC2", "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": "Spike-in and meningitis-positive controls worked in 176 archived CSF specimens, while ordinary samples yielded negligible bacterial reads consistent with contamination/error. This limits a resident-CSF microbiome claim; it does not exclude transient infection, focal brain organisms or every oral inflammatory pathway.", "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": "A month of oral Pg administration impaired mouse cognition with gut-composition, glymphatic, inflammatory and neuronal changes. Co-occurring routes and pathways were not separately rescued in the abstract; alpha diversity was unchanged and an induced model is not human mediation.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C35", "text": "A trial-emulation comparison of 177 treated and 409 untreated cohort members associated periodontal care with less AD-pattern brain atrophy after median 7.3 years. Treatment was not randomized, the groups came from different cohorts, and MRI atrophy is neither AD diagnosis nor a clinical dementia endpoint.", "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": "Kentucky longitudinal samples showed elevated antibodies to F. nucleatum and P. intermedia before AD conversion, after selected adjustment. The principal positive species were not Pg; antibody antecedence to symptoms does not establish antecedence to preclinical brain disease or causality.", "carries_number": false, "load_bearing_for": [ "SC1", "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": "Full-mouth scaling in 31 patients improved periodontal/bacterial measures by six weeks but produced an acute next-day systemic inflammatory response. The uncontrolled before/after design and procedure-induced acute inflammation do not establish chronic pathogenic mediation or vascular-event prevention.", "carries_number": true, "load_bearing_for": [ "SC5" ], "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": "A small stroke case-control study found worse periodontal health and more Pg-contaminated sites in stroke patients. The title's in-vivo wording does not make this an intervention; post-stroke sampling and a very wide association interval permit reverse causation/confounding.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C39", "text": "Oral Pg increased phenylephrine vasoconstriction in healthy and ApoE-deficient mice, while acetylcholine and nitroprusside relaxation remained similar. The receptor-specific response is not uniform endothelial failure and does not demonstrate human clinical-event causality.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "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": "Subcutaneous Pg after femoral injury increased neointima and MCP1 in wild-type mice; TLR2 deficiency prevented this response despite antibody induction. Arterial injury and forced systemic exposure establish a recipient-model dependency, not spontaneous oral-pathogen-mediated human ASCVD.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C41", "text": "Oral wild-type Pg increased plaque, bone loss and inflammatory signals in hyperlipidemic Apoe-shl mice relative to gingipain-null and FimA-deficient strains. Virulence mutations also change dissemination and burden; NLRP3 expression was measured without a reported NLRP3 necessity manipulation in the abstract.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C42", "text": "Oral wild-type Pg but not FimA-mutant Pg accelerated periodontal and atherosclerotic pathology in ApoE-null mice; immunization prevented the phenotype. Both strains were detected by PCR in blood and aorta; coupled changes in periodontal disease and virulence do not isolate invasion as the sole mediator.", "carries_number": false, "load_bearing_for": [ "SC2" ], "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": "Pg impaired endothelial integrity and vasorelaxation; Sirt3 activation reversed mitochondrial and vascular defects in cells and orally exposed mice. Honokiol activation is not equivalent to a selective genetic rescue, and vascular physiology does not establish human clinical event prevention.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C44", "text": "Wild-type Pg caused endothelial junction loss and leakage in human cells and systemically exposed zebrafish, unlike gingipain-deficient bacteria. Cell culture and forced systemic zebrafish infection do not reproduce endogenous human oral-to-vascular mediation.", "carries_number": false, "load_bearing_for": [ "SC2" ], "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": "NOD2 deficiency worsened oral-Pg inflammation, cholesterol and atheroma in ApoE mice; MDP stimulation reduced these phenotypes. NOD2 signaling was protective here; systemic MDP also affected weight and metabolic inflammation. The linked correction concerns an author name, not a new study.", "carries_number": true, "load_bearing_for": [ "SC2", "SC5" ], "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": "In 135 otherwise healthy periodontal patients, randomized intensive treatment improved FMD and reduced carotid intima-media thickness at 24 months; blood pressure and PWV did not substantially differ. The primary outcome was vascular structure, not MI, stroke or death; the PubMed abstract confidence interval is malformed and is not reproduced.", "carries_number": true, "load_bearing_for": [ "SC3", "SC5" ], "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": "Cross-sectional baseline analysis of 280 PREMIERS participants associated severe periodontitis with post-stroke cognitive impairment. This report is not a randomized cognitive-treatment result; stroke severity, education and race-related factors remain relevant, and it shares the PREMIERS trial population. Publication-type labeling was overridden to observational baseline analysis.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "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": "Randomized intensive treatment in 120 periodontal patients transiently worsened FMD and inflammation at 24 hours but improved FMD at 60 and 180 days; no cardiovascular events occurred. Healthy participants and a surrogate endpoint limit clinical ASCVD inference; the parent paper has a correction to tPA variability reporting and a figure day label.", "carries_number": true, "load_bearing_for": [ "SC3", "SC5" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: Original web Methods: enrollment and vascular assessment; linked correction NEJMx180022. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C49", "text": "Two-sample Mendelian randomization found no supported periodontitis effect on major cardiovascular outcomes across several estimators. Genetic liability instruments are not pathogen-specific eradication experiments and may not capture acquired infection severity or timing.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C50", "text": "Bidirectional genetic analyses did not support oral disease liability causing AD; a reverse AD-risk association was reported for oral cancer. This does not isolate Pg infection, and instrument validity and phenotype specificity restrict a universal absence conclusion.", "carries_number": false, "load_bearing_for": [ "SC4" ], "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": "Candidate-gene analysis linked aggressive periodontitis and CAD susceptibility through shared ANRIL and PLG-related loci. Shared genetic susceptibility can support common causes; it is not Mendelian randomization or a randomized clinical intervention despite its database trial tag. Publication-type labeling was overridden to genetic association.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "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": "Periodontitis-to-AD Mendelian randomization using FinnGen and two AD datasets produced null estimates with reported sensitivity analyses. Host liability instruments and relaxed selection thresholds do not exclude all microbial causal effects, and summary datasets are reused across MR reports. Original Methods use p<1e-5 instruments and a small clinically ascertained AD case count in one outcome; nonsignificant Egger tests do not prove absence of pleiotropy.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:METHOD, 2:RESULTS. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C53", "text": "NHANES III antibody and infection-burden models associated Pg-related interactions with incident AD over linked follow-up. Antibody exposure, multiple interactions and CMS outcome ascertainment do not prove CNS infection; other NHANES III reports are not independent cohorts.", "carries_number": false, "load_bearing_for": [ "SC1", "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": "Oral Pg altered oral and gut communities, barrier measures and AD-like pathology; 3-hydroxykynurenine exposure promoted neuronal apoptosis in model systems. The abstract does not report necessity blockade of the entire oral-to-brain pathway; indirect metabolic mediation remains distinct from direct CNS infection.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C55", "text": "Among 8275 ARIC participants followed for an average 18.4 years, severe periodontitis showed a modest association with incident dementia. Some tooth-loss and cognitive endpoints had intervals spanning no association; confounding and shared ARIC participants preclude an independent causal line.", "carries_number": true, "load_bearing_for": [ "SC1", "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": "A Swedish matched cohort of 7992 deep-pocket patients and 29182 controls found similar dementia incidence over mean 7.6 years and no adjusted association. The exposure is a periodontitis proxy; the wide adjusted interval does not demonstrate equivalence or rule out all pathogen-defined effects.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C57", "text": "An ARIC subset showed lower cognitive performance with complete tooth loss but no greater eight-year cognitive decline predicted by periodontal disease, tooth count or edentulism. This shares the ARIC source population and evaluates limited cognitive tests rather than biomarker-defined AD or Pg exposure.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C58", "text": "In the Gothenburg women's cohort, most adjusted tooth-count comparisons over 37 years were not associated with dementia; one examination remained positive. Tooth count is an indirect exposure and selective positive time points do not establish periodontal microbial mediation.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C59", "text": "In a 219-person WHICAP case-cohort, high A. naeslundii IgG predicted higher AD risk and E. nodatum IgG lower risk after adjustment. The reported positive pathogen was not Pg; baseline age differed markedly, antibody response is indirect, and other WHICAP reports reuse the cohort.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "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": "PREMIERS randomized 280 recent stroke or TIA patients to intensive or standard periodontal care; 12-month death, MI or stroke occurred in 11 versus 17, without significant superiority. Both arms received active care, the phase II trial had few events and broad uncertainty; nonsuperiority is not proof of no clinical effect or pathogen irrelevance. Original Methods show an open-label masked-endpoint trial, standard-arm rescue treatment for periodontal worsening, a low observed event rate relative to planning, baseline diabetes/BMI imbalance, and no missing primary time-to-event data.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: Original web Methods: Design, Treatment, Statistical considerations; Results: Trial population and events. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C61", "text": "Bidirectional and multivariable MR did not support direct periodontitis-CVD causality, while colocalization and cross-trait analyses identified shared loci and immune-metabolic pathways. Shared variants and pathway annotation do not establish oral infection mediation; phenotype instruments and reused summary data constrain independence.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 61 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Materials and methods:paragraph2, 1:Materials and methods:paragraph4, 1:Materials and methods:paragraph5, 1:Materials and methods:paragraph8. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C62", "text": "Candidate-gene analysis identified shared 9p21 susceptibility for aggressive periodontitis and coronary disease, distinct from a nearby diabetes variant. Shared ANRIL-region association does not resolve disease direction or prove pathogen-mediated coronary disease.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 62 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C63", "text": "In UK Biobank, self-reported periodontal disease was associated with cardiac remodeling and incident CAD; its polygenic score also associated with CAD. The polygenic-score analysis is not a valid pathogen-specific causal instrument; weak liability and pleiotropy prevent treating it as decisive Mendelian randomization. Original Discussion expressly says MR was avoided because of instrument weakness and acknowledges horizontal or indirect pleiotropy.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 63 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Discussion:paragraph7, 2:Discussion:paragraph8, 2:Discussion:paragraph10. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C64", "text": "The 303-person PAVE pilot improved periodontal measures but showed no intention-to-treat reduction in hsCRP at six months; nearly half of community controls obtained dental care. Post-randomization any-care and obesity subgroup comparisons do not retain the randomized contrast; this feasibility pilot was not powered for clinical cardiovascular efficacy.", "carries_number": true, "load_bearing_for": [ "SC3", "SC5" ], "source_ns": [ 64 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: Original web Introduction/Methods: pilot aims and randomization. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C65", "text": "Six months of oral Pg after antibiotic conditioning caused poorer water-maze performance, neuronal pathology and altered hippocampal rhythms; cultured-glial AKT activation and Bmal1 knockdown interrogated the clock pathway. Original Methods/Results specify twice-weekly exposure for 24 weeks after kanamycin, matched oral handling, and cell-line rather than in-vivo pathway rescue. Cognitive pathology is present; in-vivo clock-mediated necessity remains untested in the examined sections.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 65 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:METHODS:paragraph6, 1:METHODS:paragraph7, 1:METHODS:paragraph12, 1:METHODS:paragraph17, 2:RESULTS:paragraph0, 2:RESULTS:paragraph6, 2:RESULTS:paragraph8. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C66", "text": "Twelve-week oral Pg and T. denticola exposures produced differing brain pathology in female mice; coinoculation was less pathogenic than each alone. Pathogen combination and host context alter outcomes; AD-like histology is not human AD, and a stronger universal synergistic prediction failed in this context.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "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": "C67", "text": "In APP-TgCRND8 mice, chronic oral infection caused bone loss and gliosis without accelerating Aβ; live intracerebral Pg increased Aβ after eight weeks, unlike heat-killed bacteria. Direct brain injection bypasses the proposed oral route; peripheral and central results provide a route boundary rather than a general oral-infection proof.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 67 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:2. Results:paragraph0, 1:2. Results:paragraph5, 1:2. Results:paragraph9, 1:2. Results:paragraph10. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C68", "text": "A randomized 48-person recent-STEMI trial improved six-month FMD after periodontal treatment; inflammatory markers and cardiovascular events did not significantly differ. The small trial's primary endpoint was endothelial physiology; it cannot establish prevention of recurrent clinical events or Pg-specific mediation.", "carries_number": true, "load_bearing_for": [ "SC3", "SC5" ], "source_ns": [ 68 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C69", "text": "In 69 stable coronary patients, periodontal treatment improved dental status but did not improve three-month FMD relative to control; some vascular inflammatory markers were maintained. Short follow-up and limited size constrain inference; positive adhesion-marker comparisons do not replace the null vasodilation contrast.", "carries_number": true, "load_bearing_for": [ "SC3", "SC5" ], "source_ns": [ 69 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "CSC1", "text": "Prospective cohorts support co-occurrence, with substantial endpoint and population heterogeneity. Swedish dementia, ARIC cognitive decline, adjusted tooth-count and selected cardiovascular comparisons are null or mixed. Association is established as a recurring observation, not a universal risk relation or a microbial causal pathway.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 3, 5, 6, 8, 9, 13, 14, 18, 19, 25, 28, 30, 36, 38, 47, 51, 53, 55, 56, 57, 58, 59, 61, 62, 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": "Defined oral exposures, bacterial virulence subtraction and host-pathway perturbations produce vascular and neural phenotypes in particular rodent systems. Oral versus intracerebral infection and single versus dual inoculation map important failures. Recipient-model causality is credited, but a single conserved organism-specific mediator across both organ systems is not independently isolated.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 1, 2, 7, 11, 16, 17, 20, 21, 22, 23, 24, 26, 27, 31, 32, 34, 39, 40, 41, 42, 43, 44, 45, 54, 65, 66, 67 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-06", "note": "" }, { "id": "CSC3", "text": "Periodontal treatment causally changes blood pressure or vascular function in some populations, and a two-year randomized trial changes carotid structure. These are positive human effects. However, Pg-specific mediation of clinical atherosclerotic events is not established: PREMIERS did not show superiority on hard events, PAVE was a feasibility pilot with crossover, and genetic liability studies do not provide a specific infection instrument.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 2, 3, 4, 5, 6, 8, 9, 12, 13, 15, 38, 39, 40, 43, 46, 47, 48, 49, 51, 60, 61, 62, 63, 64, 68, 69 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-06", "note": "" }, { "id": "CSC4", "text": "Human periodontal associations and low-biomass pathogen detection do not establish an antecedent oral cause of AD. Rodent toxicity/rescue is route- and host-dependent. Genetic analyses are null but imperfect infection instruments. The supplementary GAIN sponsor summary reports no overall efficacy and a positive pathogen-defined subgroup whose effect sizes and multiplicity could not be independently checked; it does not carry a positive threshold.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 47, 50, 52, 53, 54, 55, 56, 57, 58, 59, 65, 66, 67 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-06", "note": "" }, { "id": "CSC5", "text": "Randomized periodontal interventions show context-dependent systemic physiological responses, including endothelial function and blood pressure, together with inflammatory changes. Acute treatment can initially increase inflammation; coronary FMD and PAVE hsCRP nulls map limits. This bounded contribution is not organism-specific proof of human ASCVD or AD causation.", "carries_number": false, "load_bearing_for": [ "SC5" ], "source_ns": [ 4, 7, 9, 10, 11, 12, 14, 16, 18, 24, 29, 37, 45, 46, 48, 64, 68, 69 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-06", "note": "" }, { "id": "CH", "text": "Oral inflammation has systemic effects; oral pathogens are not yet established as causal drivers of human ASCVD and Alzheimer disease.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 4, 46, 60, 17, 67, 63 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-06", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Zhou LJ, Lin WZ, Meng XQ et al. Periodontitis exacerbates atherosclerosis through Fusobacterium nucleatum-promoted hepatic glycolysis and lipogenesis. Cardiovascular research. 2023.", "tier": "A", "kind": "primary", "pmid": "36943793", "doi": "10.1093/cvr/cvad045", "url": "https://pubmed.ncbi.nlm.nih.gov/36943793/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID36943793", "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" ] }, { "n": 2, "citation": "Chen BY, Zhu H, Li YL et al. Oral Pathobionts Aggravate Myocardial Infarction Through Mobilization of B2 Cells. Circulation. 2025.", "tier": "A", "kind": "primary", "pmid": "40859845", "doi": "10.1161/CIRCULATIONAHA.125.074837", "url": "https://pubmed.ncbi.nlm.nih.gov/40859845/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID40859845", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C2", "CSC2", "CSC3" ] }, { "n": 3, "citation": "Chang Y, Woo HG, Lee JS et al. Better oral hygiene is associated with lower risk of stroke. Journal of periodontology. 2021.", "tier": "A", "kind": "primary", "pmid": "32432793", "doi": "10.1002/JPER.20-0053", "url": "https://pubmed.ncbi.nlm.nih.gov/32432793/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID32432793", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C3", "CSC1", "CSC3" ] }, { "n": 4, "citation": "Czesnikiewicz-Guzik M, Osmenda G, Siedlinski M et al. Causal association between periodontitis and hypertension: evidence from Mendelian randomization and a randomized controlled trial of non-surgical periodontal therapy. European heart journal. 2019.", "tier": "A", "kind": "rct", "pmid": "31504461", "doi": "10.1093/eurheartj/ehz646", "url": "https://pubmed.ncbi.nlm.nih.gov/31504461/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID31504461", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Methods:paragraph1, 1:Methods:paragraph2, 1:Methods:paragraph4, 1:Methods:paragraph5, 1:Methods:paragraph11. No complete-paper or supplement audit claimed.", "carries_claims": [ "C4", "CSC3", "CSC5", "CH" ] }, { "n": 5, "citation": "Johansson CS, Ravald N, Pagonis C et al. Periodontitis in patients with coronary artery disease: an 8-year follow-up. Journal of periodontology. 2014.", "tier": "A", "kind": "primary", "pmid": "23725030", "doi": "10.1902/jop.2013.120730", "url": "https://pubmed.ncbi.nlm.nih.gov/23725030/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID23725030", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C5", "CSC1", "CSC3" ] }, { "n": 6, "citation": "Sen S, Redd K, Trivedi T et al. Periodontal Disease, Atrial Fibrillation and Stroke. American heart journal. 2021.", "tier": "A", "kind": "primary", "pmid": "33503409", "doi": "10.1016/j.ahj.2021.01.009", "url": "https://pubmed.ncbi.nlm.nih.gov/33503409/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "ARIC", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C6", "CSC1", "CSC3" ] }, { "n": 7, "citation": "Parvaneh M, Witting PK, Ku J et al. Periodontitis induces endothelial dysfunction in mice. Scientific reports. 2021.", "tier": "A", "kind": "primary", "pmid": "34294791", "doi": "10.1038/s41598-021-94418-8", "url": "https://pubmed.ncbi.nlm.nih.gov/34294791/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID34294791", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C7", "CSC2", "CSC5" ] }, { "n": 8, "citation": "Tiensripojamarn N, Lertpimonchai A, Tavedhikul K et al. Periodontitis is associated with cardiovascular diseases: A 13-year study. Journal of clinical periodontology. 2021.", "tier": "A", "kind": "primary", "pmid": "33386631", "doi": "10.1111/jcpe.13418", "url": "https://pubmed.ncbi.nlm.nih.gov/33386631/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID33386631", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C8", "CSC1", "CSC3" ] }, { "n": 9, "citation": "Akhi R, Lavrinienko A, Hakula M et al. Oral Microbiota Linking Humoral Response, Periodontitis and Atherosclerosis. Journal of clinical periodontology. 2025.", "tier": "A", "kind": "primary", "pmid": "40796367", "doi": "10.1111/jcpe.70001", "url": "https://pubmed.ncbi.nlm.nih.gov/40796367/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID40796367", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C9", "CSC1", "CSC3", "CSC5" ] }, { "n": 10, "citation": "Payne JB, Golub LM, Stoner JA et al. The effect of subantimicrobial-dose-doxycycline periodontal therapy on serum biomarkers of systemic inflammation: a randomized, double-masked, placebo-controlled clinical trial. Journal of the American Dental Association (1939). 2011.", "tier": "A", "kind": "rct", "pmid": "21357860", "doi": "10.14219/jada.archive.2011.0165", "url": "https://pubmed.ncbi.nlm.nih.gov/21357860/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID21357860", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C10", "CSC5" ] }, { "n": 11, "citation": "Miyamoto T, Yumoto H, Takahashi Y et al. Pathogen-accelerated atherosclerosis occurs early after exposure and can be prevented via immunization. Infection and immunity. 2006.", "tier": "A", "kind": "primary", "pmid": "16428788", "doi": "10.1128/IAI.74.2.1376-1380.2006", "url": "https://pubmed.ncbi.nlm.nih.gov/16428788/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID16428788", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C11", "CSC2", "CSC5" ] }, { "n": 12, "citation": "Laky M, Anscheringer I, Wolschner L et al. Periodontal treatment limits platelet activation in patients with periodontitis-a controlled-randomized intervention trial. Journal of clinical periodontology. 2018.", "tier": "A", "kind": "rct", "pmid": "29972709", "doi": "10.1111/jcpe.12980", "url": "https://pubmed.ncbi.nlm.nih.gov/29972709/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID29972709", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C12", "CSC3", "CSC5" ] }, { "n": 13, "citation": "Xu F, Lu B et al. Prospective association of periodontal disease with cardiovascular and all-cause mortality: NHANES III follow-up study. 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