{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "Prion-like Spread of Misfolded Proteins", "entry_form": "phenomenon", "gradeable_restatement": "Misfolded tau and alpha-synuclein propagate cell to cell by templated conversion, driving progressive neurodegeneration.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Protein species, strain, recipient substrate, cell type, genotype, disease stage and experimental initiation", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "Prion-like Spread of Misfolded Proteins", "central_claim": "Misfolded tau and alpha-synuclein propagate cell to cell by templated conversion, driving progressive neurodegeneration.", "proposed_mechanism": "Misfolded tau and alpha-synuclein propagate cell to cell by templated conversion, driving progressive neurodegeneration.", "claimed_scope": "Misfolded tau and alpha-synuclein propagate cell to cell by templated conversion, driving progressive neurodegeneration.", "claimed_level": [ "progression" ], "is_conjunctive": true, "conjunctive_note": "Use the index nominal tau-and-alpha-synuclein proposition. Unconditional decomposition overrides its stale unitary flag. Canonical PrP transmissibility is a comparator, not interchangeable evidence for ordinary sporadic tauopathy or synucleinopathy." }, "rubric_routing": { "primary_rubric": "01-neurodegeneration.md", "secondary_rubrics": [], "index_notes_applied": [ "Use the index nominal tau-and-alpha-synuclein proposition. Unconditional decomposition overrides its stale unitary flag. Canonical PrP transmissibility is a comparator, not interchangeable evidence for ordinary sporadic tauopathy or synucleinopathy." ], "rubric_fit_note": "Exact archived v5.3 framework. Any stale index empirical framing is rechecked against primary results." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "Misfolded tau and alpha-synuclein template conversion of homologous recipient protein.", "subclaim_type": "mechanism", "scope": "defined tau and alpha-synuclein systems with physiological recipient expression", "claimed_scope": "defined tau and alpha-synuclein systems with physiological recipient expression", "governing_rubric": "01-neurodegeneration.md", "key_evidence_anchor": "Seed-dependent conversion with substrate loss/rescue", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Wild-type neuronal and animal recipients recruit host tau or alpha-synuclein, with species-specific antibody and SNCA-null controls. This is important physiological-substrate capability after forced entry. For the disease-relevant conversion mechanism, positive evidence remains dominated by imposed seeds or engineered sources, triggering the exogenous-seeding-alone ceiling; no claim is made that conversion never occurs." }, { "id": "SC2", "statement": "Endogenous pathological species spread between cells in disease-relevant circuits.", "subclaim_type": "mechanism", "scope": "unforced tauopathies and synucleinopathies", "claimed_scope": "unforced tauopathies and synucleinopathies", "governing_rubric": "01-neurodegeneration.md", "key_evidence_anchor": "Endogenous donor-recipient tracing and selective transfer block", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Human graft pathology, donor-restricted animal protein and endogenous lipid/Arc perturbations strengthen physical transfer. Native molecular lineage in unforced disease remains incompletely distinguished from source overexpression, local generation and correlated vulnerability. PS19 spontaneous pathology retains widespread mutant expression." }, { "id": "SC3", "statement": "Templated intercellular spread is a causal driver of progressive neuronal loss.", "subclaim_type": "necessity", "scope": "functional degeneration in both disease families", "claimed_scope": "functional degeneration in both disease families", "governing_rubric": "01-neurodegeneration.md", "key_evidence_anchor": "Selective propagation block without general substrate removal", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Gut route interruption and receptor/source perturbations couple transmission to injury in models, but also alter substrate, immunity, physiology or initial insult. Arc, human-neuron seeding adaptation and protective glial sharing separate transfer from toxicity. Clinical strategies are null or mixed, without verified universal pathogenic seed blockade." }, { "id": "SC4", "statement": "Prion-like mechanisms explain disease-class progression beyond forced inoculation.", "subclaim_type": "generalization", "scope": "tauopathies and synucleinopathies defined before outcomes", "claimed_scope": "tauopathies and synucleinopathies defined before outcomes", "governing_rubric": "01-neurodegeneration.md", "key_evidence_anchor": "Human/model convergence with host-state and strain boundaries", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Tau/alpha-synuclein strains, native filament structures, recipient phenotypes and clinical responses vary. MSA transmission to sensitized A53T mice does not establish ordinary PD transmission or human contagiousness. SAA kinetics predict some cognitive outcomes but do not measure physical spread. Disease-class progression beyond imposed initiation remains Γ." } ], "aggregation_rule": "weakest-link", "aggregation_preregistered": true, "aggregation_rationale": "Use the index nominal tau-and-alpha-synuclein proposition. Unconditional decomposition overrides its stale unitary flag. Canonical PrP transmissibility is a comparator, not interchangeable evidence for ordinary sporadic tauopathy or synucleinopathy.", "primary_subclaim_id": "SC3", "aggregation_derivation": "The weakest-link conjunction returns Γ. Physiological host substrate can be recruited after imposed seeds, and source-restricted transfer and receptor perturbations demonstrate substantial capabilities. Selective blockade of spontaneous propagation has not established progression necessity in both disease families. Canonical PrP loss/rescue is stronger comparator evidence and is not transferred to the nominal tau/alpha-synuclein claim. Host state, compartment and intracellular toxicity constrain a universal spread-driven account.", "aggregation_alternatives": { "weakest_link_would_return": "Γ", "primary_subclaim_would_return": "Γ", "scope_matched_would_return": "Γ", "note": "Separate narrow successes do not replace the preregistered gate." }, "index_rule_deviation": "" }, "competing_models": { "models_evaluated": [ { "rank_in_tournament": 1, "model_id": "M2", "is_nominal": false, "name": "Selective vulnerability", "core_claim": "Neuronal identity and intrinsic proteostasis condition aggregate susceptibility and injury.", "explains_what_nominal_does_not": "Neuronal identity and intrinsic proteostasis condition aggregate susceptibility and injury.", "strongest_supporting_evidence": [ "SNCA expression/ASO timing, PPN neuron phenotype, human neuronal subtype contrasts and tau synaptic-binding rescue support defined contexts." ], "strongest_contradictory_evidence": [ "These findings can coexist with transfer and do not explain all disease origins." ], "hsef_level_for_this_model": "Ε", "rationale": "SNCA expression/ASO timing, PPN neuron phenotype, human neuronal subtype contrasts and tau synaptic-binding rescue support defined contexts. These findings can coexist with transfer and do not explain all disease origins." }, { "rank_in_tournament": 2, "model_id": "M5", "is_nominal": false, "name": "Host-state determinism", "core_claim": "Substrate amount, lysosomes and intracellular interactions determine pathogenic response.", "explains_what_nominal_does_not": "Substrate amount, lysosomes and intracellular interactions determine pathogenic response.", "strongest_supporting_evidence": [ "SNCA variants, host-null controls, GCase loops, TOM20 and intrinsic tau synaptic effects support specified dependencies." ], "strongest_contradictory_evidence": [ "Mutation-associated disease or substrate suppression does not identify spread as the mediator." ], "hsef_level_for_this_model": "Ε", "rationale": "SNCA variants, host-null controls, GCase loops, TOM20 and intrinsic tau synaptic effects support specified dependencies. Mutation-associated disease or substrate suppression does not identify spread as the mediator." }, { "rank_in_tournament": 3, "model_id": "M1", "is_nominal": true, "name": "Templated protein propagation", "core_claim": "Transferred species recruit host protein and advance regional pathology.", "explains_what_nominal_does_not": "Transferred species recruit host protein and advance regional pathology.", "strongest_supporting_evidence": [ "Wild-type host conversion, species-specific antibody, transport and route contrasts demonstrate experimental capability." ], "strongest_contradictory_evidence": [ "Natural selective progression necessity remains unresolved; forced initiation and clinical engagement gaps limit generality." ], "hsef_level_for_this_model": "Γ", "rationale": "Wild-type host conversion, species-specific antibody, transport and route contrasts demonstrate experimental capability. Natural selective progression necessity remains unresolved; forced initiation and clinical engagement gaps limit generality." }, { "rank_in_tournament": 4, "model_id": "M3", "is_nominal": false, "name": "Spread without toxicity", "core_claim": "Cargo movement or seeded accumulation can occur without sustained neuronal injury.", "explains_what_nominal_does_not": "Cargo movement or seeded accumulation can occur without sustained neuronal injury.", "strongest_supporting_evidence": [ "Tau-null transfer, increased seeding with metabolic recovery, protective microglial transfer and glial sharing separate these events." ], "strongest_contradictory_evidence": [ "The positive PFF neuronal-loss cascade is real, so no universal harmlessness claim follows." ], "hsef_level_for_this_model": "Γ", "rationale": "Tau-null transfer, increased seeding with metabolic recovery, protective microglial transfer and glial sharing separate these events. The positive PFF neuronal-loss cascade is real, so no universal harmlessness claim follows." }, { "rank_in_tournament": 5, "model_id": "M4", "is_nominal": false, "name": "Glial vector propagation", "core_claim": "Microglial vesicles and processing contribute to model spread.", "explains_what_nominal_does_not": "Microglial vesicles and processing contribute to model spread.", "strongest_supporting_evidence": [ "Exosome, TREM2/AEP and transfer experiments show a plausible vector route." ], "strongest_contradictory_evidence": [ "Glia also clear cargo; forced loading, broad depletion and shared inflammatory effects do not establish native dominance." ], "hsef_level_for_this_model": "Γ", "rationale": "Exosome, TREM2/AEP and transfer experiments show a plausible vector route. Glia also clear cargo; forced loading, broad depletion and shared inflammatory effects do not establish native dominance." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. Compare a transfer-only perturbation and matched rescue with substrate lowering, intrinsic-toxicity rescue and clearance controls in spontaneous disease. Measure lineage conversion separately from physical cargo and blinded neuronal survival. Compatible transfer and vulnerability mechanisms must be tested for mediation rather than treated as exclusive stories.", "study_separating_rank1_from_rank2": "Compare a transfer-only perturbation and matched rescue with substrate lowering, intrinsic-toxicity rescue and clearance controls in spontaneous disease. Measure lineage conversion separately from physical cargo and blinded neuronal survival. Compatible transfer and vulnerability mechanisms must be tested for mediation rather than treated as exclusive stories.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "31255487", "title": "Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson's Disease.", "citation": "Kim S, Kwon SH, Kam TI et al. Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson's Disease. Neuron. 2019.", "doi": "10.1016/j.neuron.2019.05.035", "pmcid": "PMC6706297", "url": "https://pubmed.ncbi.nlm.nih.gov/31255487/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31255487/", "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": "PMID31255487", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph1, 1:RESULTS:paragraph2, 1:RESULTS:paragraph3. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Gut PFF injection produces staged brain pathology, dopaminergic loss and motor deficits; vagotomy and SNCA absence prevent the cascade.", "what_it_does_not_show": "Forced gut inoculation and global substrate removal do not identify spontaneous origin. Original Results verify TH plus Nissl stereology; vagotomy also removes 65 percent of DMV ChAT-positive cells and alters ghrelin, intake and gut function, so it is not a transfer-only block.", "confounders_present": [ "Forced gut inoculation and global substrate removal do not identify spontaneous origin. Original Results verify TH plus Nissl stereology; vagotomy also removes 65 percent of DMV ChAT-positive cells and alters ghrelin, intake and gut function, so it is not a transfer-only block." ], "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": "36056345", "title": "LRP1 is a neuronal receptor for α-synuclein uptake and spread.", "citation": "Chen K, Martens YA, Meneses A et al. LRP1 is a neuronal receptor for α-synuclein uptake and spread. Molecular neurodegeneration. 2022.", "doi": "10.1186/s13024-022-00560-w", "pmcid": "PMC9438229", "url": "https://pubmed.ncbi.nlm.nih.gov/36056345/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36056345/", "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": "PMID36056345", "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": "Isogenic LRP1 loss reduces monomer/oligomer uptake more than PFF uptake; neuronal Lrp1 deletion reduces AAV-traced spread.", "what_it_does_not_show": "LRP1 is pleiotropic; transferred AAV-expressed protein, templated conversion and neuron-loss mediation are distinct. No survival/function rescue is credited.", "confounders_present": [ "LRP1 is pleiotropic; transferred AAV-expressed protein, templated conversion and neuron-loss mediation are distinct. No survival/function rescue is credited." ], "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": "32830221", "title": "Brain-first versus body-first Parkinson's disease: a multimodal imaging case-control study.", "citation": "Horsager J, Andersen KB, Knudsen K et al. Brain-first versus body-first Parkinson's disease: a multimodal imaging case-control study. Brain : a journal of neurology. 2020.", "doi": "10.1093/brain/awaa238", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/32830221/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32830221/", "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": "PMID32830221", "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": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "A 37-person de novo PD and 22-person iRBD imaging study shows patterns compatible with brain-first and body-first trajectories.", "what_it_does_not_show": "Cross-sectional group ordering and denervation signals do not directly observe molecular transfer or establish either origin in an individual.", "confounders_present": [ "Cross-sectional group ordering and denervation signals do not directly observe molecular transfer or establish either origin in an individual." ], "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": "21982369", "title": "Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death.", "citation": "Volpicelli-Daley LA, Luk KC, Patel TP et al. Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron. 2011.", "doi": "10.1016/j.neuron.2011.08.033", "pmcid": "PMC3204802", "url": "https://pubmed.ncbi.nlm.nih.gov/21982369/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21982369/", "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": "PMID21982369", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell culture", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "PFFs recruit endogenous alpha-synuclein in primary neurons without overexpression and precede synaptic dysfunction and death.", "what_it_does_not_show": "Exogenous entry and culture timing constrain physiological organismal spread necessity; correlated inclusion formation does not isolate the lethal intermediate.", "confounders_present": [ "Exogenous entry and culture timing constrain physiological organismal spread necessity; correlated inclusion formation does not isolate the lethal intermediate." ], "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": "21700325", "title": "Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies.", "citation": "Mazzulli JR, Xu YH, Sun Y et al. Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell. 2011.", "doi": "10.1016/j.cell.2011.06.001", "pmcid": "PMC3132082", "url": "https://pubmed.ncbi.nlm.nih.gov/21700325/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21700325/", "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": "PMID21700325", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell culture", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "GCase loss impairs degradation and promotes aggregation toxicity; alpha-synuclein also inhibits GCase, producing a bidirectional loop.", "what_it_does_not_show": "The self-propagating loop is intracellular proteostasis feedback, not proof of obligatory intercellular templating in sporadic PD.", "confounders_present": [ "The self-propagating loop is intracellular proteostasis feedback, not proof of obligatory intercellular templating in sporadic PD." ], "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": "39570889", "title": "Lewy pathology formation in patient-derived GBA1 Parkinson's disease midbrain organoids.", "citation": "Frattini E, Faustini G, Lopez G et al. Lewy pathology formation in patient-derived GBA1 Parkinson's disease midbrain organoids. Brain : a journal of neurology. 2025.", "doi": "10.1093/brain/awae365", "pmcid": "PMC11967528", "url": "https://pubmed.ncbi.nlm.nih.gov/39570889/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39570889/", "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": "PMID39570889", "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": "Moderate", "system": "organoid", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "GBA1 patient-derived midbrain organoids form seeding-competent fibrils with dopaminergic loss and transmit pathology to control organoids; GCase-pathway drugs lower pathology.", "what_it_does_not_show": "Organoid toxicity and genetic-risk background lack organismal follow-through; pathology lowering is not verified clinical rescue or selective spread mediation.", "confounders_present": [ "Organoid toxicity and genetic-risk background lack organismal follow-through; pathology lowering is not verified clinical rescue or selective spread 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": 7, "pmid": "41680444", "title": "Glucosylceramide-induced ectosomes propagate pathogenic α-synuclein in Parkinson's disease.", "citation": "Jacquemyn J, Marriott B, Chang J et al. Glucosylceramide-induced ectosomes propagate pathogenic α-synuclein in Parkinson's disease. Nature cell biology. 2026.", "doi": "10.1038/s41556-026-01871-6", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/41680444/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41680444/", "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": "PMID41680444", "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": "Genetically affected and isogenic neurons show glucosylceramide-linked ectosome release; GCase inhibition increases vesicle traffic and alpha-synuclein pathology in mouse brains.", "what_it_does_not_show": "Lipid and lysosomal changes affect donor production and recipient health; a major-route claim does not establish natural disease necessity or neuronal survival mediation.", "confounders_present": [ "Lipid and lysosomal changes affect donor production and recipient health; a major-route claim does not establish natural disease necessity or neuronal survival 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": 8, "pmid": "38327094", "title": "Lymphocyte-Activation Gene 3 Facilitates Pathological Tau Neuron-to-Neuron Transmission.", "citation": "Chen C, Kumbhar R, Wang H et al. Lymphocyte-Activation Gene 3 Facilitates Pathological Tau Neuron-to-Neuron Transmission. Advanced science (Weinheim, Baden-Wurttemberg, Germany). 2024.", "doi": "10.1002/advs.202303775", "pmcid": "PMC11040377", "url": "https://pubmed.ncbi.nlm.nih.gov/38327094/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38327094/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID37293032" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID38327094", "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": "Neuronal LAG3 loss lowers tau PFF internalization, subsequent pathology and behavioral deficits.", "what_it_does_not_show": "Imposed PFF initiation and receptor-expression controversy constrain scope; neuronal LAG3 and broad immune effects require independent confirmation. UpdateOf links a preprint.", "confounders_present": [ "Imposed PFF initiation and receptor-expression controversy constrain scope; neuronal LAG3 and broad immune effects require independent confirmation. UpdateOf links a preprint." ], "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": "40993788", "title": "Facilitated α-synuclein oligomer sharing among glial cells by a centrally acting connexin inhibitor attenuates a rapidly progressive multiple system atrophy-cerebellar type model by reducing the neuronal α-synuclein burden.", "citation": "Harada M, Masaki K, Tanaka T et al. Facilitated α-synuclein oligomer sharing among glial cells by a centrally acting connexin inhibitor attenuates a rapidly progressive multiple system atrophy-cerebellar type model by reducing the neuronal α-synuclein burden. Acta neuropathologica communications. 2025.", "doi": "10.1186/s40478-025-02116-7", "pmcid": "PMC12462231", "url": "https://pubmed.ncbi.nlm.nih.gov/40993788/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40993788/", "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": "PMID40993788", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "A pan-connexin blocker improves an induced oligodendroglial A53T MSA-C model while increasing oligomer sharing in glia and reducing neuronal burden.", "what_it_does_not_show": "Sharing can protect in this defined compartment; broad connexin effects, induced overexpression and absent transfer-only rescue prevent universal conclusions. Oligomers rarely colocalize with p-alpha-synuclein.", "confounders_present": [ "Sharing can protect in this defined compartment; broad connexin effects, induced overexpression and absent transfer-only rescue prevent universal conclusions. Oligomers rarely colocalize with p-alpha-synuclein." ], "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": "32449565", "title": "The HSP110/HSP70 disaggregation system generates spreading-competent toxic α-synuclein species.", "citation": "Tittelmeier J, Sandhof CA, Ries HM et al. The HSP110/HSP70 disaggregation system generates spreading-competent toxic α-synuclein species. The EMBO journal. 2020.", "doi": "10.15252/embj.2019103954", "pmcid": "PMC7327497", "url": "https://pubmed.ncbi.nlm.nih.gov/32449565/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32449565/", "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": "PMID32449565", "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": "Worm HSP110 depletion lowers disaggregation, intercellular transmission and alpha-synuclein toxicity.", "what_it_does_not_show": "Overall folding capacity is also impaired; a proteostasis-wide perturbation does not isolate transfer as the mediator or establish mammalian generality.", "confounders_present": [ "Overall folding capacity is also impaired; a proteostasis-wide perturbation does not isolate transfer as the mediator or establish mammalian generality." ], "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": "25095794", "title": "Pathological alpha-synuclein propagates through neural networks.", "citation": "Masuda-Suzukake M, Nonaka T, Hosokawa M et al. Pathological alpha-synuclein propagates through neural networks. Acta neuropathologica communications. 2014.", "doi": "10.1186/s40478-014-0088-8", "pmcid": "PMC4147188", "url": "https://pubmed.ncbi.nlm.nih.gov/25095794/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25095794/", "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": "PMID25095794", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Three inoculation sites produce distinct connected-region pathology and recovered insoluble material reseeds wild-type brains.", "what_it_does_not_show": "Imposed seeds, host pathology and serial transfer are capabilities; direct molecular lineage and natural neuronal-loss dependency remain unresolved.", "confounders_present": [ "Imposed seeds, host pathology and serial transfer are capabilities; direct molecular lineage and natural neuronal-loss dependency remain unresolved." ], "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": "39059388", "title": "Microglia rescue neurons from aggregate-induced neuronal dysfunction and death through tunneling nanotubes.", "citation": "Scheiblich H, Eikens F, Wischhof L et al. Microglia rescue neurons from aggregate-induced neuronal dysfunction and death through tunneling nanotubes. Neuron. 2024.", "doi": "10.1016/j.neuron.2024.06.029", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/39059388/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39059388/", "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": "PMID39059388", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell culture", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Microglial nanotubes remove neuronal tau/alpha-synuclein aggregates and donate healthy mitochondria; mitochondrial inhibition removes neuroprotection.", "what_it_does_not_show": "Protective exchange contrasts with transfer-as-injury, but culture rescue does not establish its dominance in native disease.", "confounders_present": [ "Protective exchange contrasts with transfer-as-injury, but culture rescue does not establish its dominance in native 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": 13, "pmid": "37202391", "title": "Tunnelling nanotubes between neuronal and microglial cells allow bi-directional transfer of α-Synuclein and mitochondria.", "citation": "Chakraborty R, Nonaka T, Hasegawa M et al. Tunnelling nanotubes between neuronal and microglial cells allow bi-directional transfer of α-Synuclein and mitochondria. Cell death & disease. 2023.", "doi": "10.1038/s41419-023-05835-8", "pmcid": "PMC10195781", "url": "https://pubmed.ncbi.nlm.nih.gov/37202391/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37202391/", "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": "PMID37202391", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell culture", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Human neuronal–microglial nanotubes transfer alpha-synuclein predominantly to microglia and mitochondria to burdened neurons.", "what_it_does_not_show": "Observed movement is not necessarily recipient templating; the protective interpretation lacks an organismal progression test.", "confounders_present": [ "Observed movement is not necessarily recipient templating; the protective interpretation lacks an organismal progression test." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 14, "pmid": "38902546", "title": "Target engagement and immunogenicity of an active immunotherapeutic targeting pathological α-synuclein: a phase 1 placebo-controlled trial.", "citation": "Eijsvogel P, Misra P, Concha-Marambio L et al. Target engagement and immunogenicity of an active immunotherapeutic targeting pathological α-synuclein: a phase 1 placebo-controlled trial. Nature medicine. 2024.", "doi": "10.1038/s41591-024-03101-8", "pmcid": "PMC11405261", "url": "https://pubmed.ncbi.nlm.nih.gov/38902546/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38902546/", "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": "PMID38902546", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Twenty-person UB-312 phase1 randomization establishes immunogenicity; CSF antibodies occur in 5 of 13 fully dosed recipients and seed reduction in a subset.", "what_it_does_not_show": "Safety/antibody primary endpoints and exploratory seed effects do not demonstrate clinical benefit, selective spread blockade or an unbiased responding subgroup effect; clinical scales do not differ.", "confounders_present": [ "Safety/antibody primary endpoints and exploratory seed effects do not demonstrate clinical benefit, selective spread blockade or an unbiased responding subgroup effect; clinical scales do not differ." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 15, "pmid": "32075919", "title": "The process of Lewy body formation, rather than simply α-synuclein fibrillization, is one of the major drivers of neurodegeneration.", "citation": "Mahul-Mellier AL, Burtscher J, Maharjan N et al. The process of Lewy body formation, rather than simply α-synuclein fibrillization, is one of the major drivers of neurodegeneration. Proceedings of the National Academy of Sciences of the United States of America. 2020.", "doi": "10.1073/pnas.1913904117", "pmcid": "PMC7060668", "url": "https://pubmed.ncbi.nlm.nih.gov/32075919/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32075919/", "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": "PMID32075919", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell culture", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "A seeded neuronal model links later organelle-rich Lewy-body maturation to mitochondrial and synaptic dysfunction beyond early fibrillization.", "what_it_does_not_show": "The integrated maturation process may mediate injury; culture correlations and forced seeding do not establish selective intercellular transfer necessity.", "confounders_present": [ "The integrated maturation process may mediate injury; culture correlations and forced seeding do not establish selective intercellular transfer necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 16, "pmid": "40541208", "title": "Diagnostic and prognostic value of α-synuclein seed amplification assay kinetic measures in Parkinson's disease: a longitudinal cohort study.", "citation": "Orrú CD, Vaughan DP, Vijiaratnam N et al. Diagnostic and prognostic value of α-synuclein seed amplification assay kinetic measures in Parkinson's disease: a longitudinal cohort study. The Lancet. Neurology. 2025.", "doi": "10.1016/S1474-4422(25)00157-7", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/40541208/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40541208/", "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": "PMID40541208", "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": "Across 1631 participants, faster SAA kinetics predict cognitive decline in independent PD cohort analyses, including an AD-biomarker-negative subset.", "what_it_does_not_show": "SAA is an in-vitro amplification readout, not physical spread rate; it does not establish motor/neuron-loss mediation. PPMI participants overlap other analyses.", "confounders_present": [ "SAA is an in-vitro amplification readout, not physical spread rate; it does not establish motor/neuron-loss mediation. PPMI participants overlap other analyses." ], "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": [ "PPMI/Tubingen data can overlap other prognostic and external comparator studies." ] }, { "n": 17, "pmid": "38499535", "title": "HTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species.", "citation": "Chen S, Puri A, Bell B et al. HTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species. Nature communications. 2024.", "doi": "10.1038/s41467-024-46538-8", "pmcid": "PMC10948756", "url": "https://pubmed.ncbi.nlm.nih.gov/38499535/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38499535/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID37674720" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID38499535", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph17, 1:Results:paragraph26, 1:Results:paragraph28. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell culture", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "HTRA1 and a protease-inactive mutant remodel PFFs and reduce reporter seeding; treated reaction products reduce primary-neuron p-alpha-synuclein and improve MTT signal.", "what_it_does_not_show": "Original Results show mature-PFF reporter seeding decreases about 30–40 percent rather than absolute eradication. MTT at 24 hours precedes one-week inclusion assessment, so selective seeding mediation of survival is not proved; different formation/remodeling arms are kept separate.", "confounders_present": [ "Original Results show mature-PFF reporter seeding decreases about 30–40 percent rather than absolute eradication. MTT at 24 hours precedes one-week inclusion assessment, so selective seeding mediation of survival is not proved; different formation/remodeling arms are kept separate." ], "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": "32025029", "title": "Discriminating α-synuclein strains in Parkinson's disease and multiple system atrophy.", "citation": "Shahnawaz M, Mukherjee A, Pritzkow S et al. Discriminating α-synuclein strains in Parkinson's disease and multiple system atrophy. Nature. 2020.", "doi": "10.1038/s41586-020-1984-7", "pmcid": "PMC7066875", "url": "https://pubmed.ncbi.nlm.nih.gov/32025029/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32025029/", "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": "PMID32025029", "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": "supports", "what_it_shows": "CSF PMCA products discriminate PD and MSA with distinct biochemical/biological properties.", "what_it_does_not_show": "Amplification may select conformers; product identity and clinical diagnosis do not prove faithful in-vivo strain transfer or progressive neurotoxicity.", "confounders_present": [ "Amplification may select conformers; product identity and clinical diagnosis do not prove faithful in-vivo strain transfer or progressive neurotoxicity." ], "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": "27280685", "title": "α-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson's disease.", "citation": "Di Maio R, Barrett PJ, Hoffman EK et al. α-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson's disease. Science translational medicine. 2016.", "doi": "10.1126/scitranslmed.aaf3634", "pmcid": "PMC5016095", "url": "https://pubmed.ncbi.nlm.nih.gov/27280685/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27280685/", "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": "PMID27280685", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Modified alpha-synuclein binds TOM20 and impairs mitochondrial import; modest endogenous knockdown preserves import in an in-vivo model.", "what_it_does_not_show": "Intrinsic mitochondrial toxicity does not require spread; postmortem concordance and import rescue do not establish complete human neuron-survival mediation.", "confounders_present": [ "Intrinsic mitochondrial toxicity does not require spread; postmortem concordance and import rescue do not establish complete human neuron-survival 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": 20, "pmid": "32461689", "title": "Structures of α-synuclein filaments from multiple system atrophy.", "citation": "Schweighauser M, Shi Y, Tarutani A et al. Structures of α-synuclein filaments from multiple system atrophy. Nature. 2020.", "doi": "10.1038/s41586-020-2317-6", "pmcid": "PMC7116528", "url": "https://pubmed.ncbi.nlm.nih.gov/32461689/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32461689/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID41125897" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID32461689", "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 tissue", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Cryo-EM shows distinct native MSA filaments and differences from DLB and recombinant structures.", "what_it_does_not_show": "Structure is not a transmission/necessity experiment. A linked correction exists; its details have not been examined, so fine structural claims are qualified.", "confounders_present": [ "Structure is not a transmission/necessity experiment. A linked correction exists; its details have not been examined, so fine structural claims are qualified." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 21, "pmid": "32355963", "title": "Microglial exosomes facilitate α-synuclein transmission in Parkinson's disease.", "citation": "Guo M, Wang J, Zhao Y et al. Microglial exosomes facilitate α-synuclein transmission in Parkinson's disease. Brain : a journal of neurology. 2020.", "doi": "10.1093/brain/awaa090", "pmcid": "PMC7241957", "url": "https://pubmed.ncbi.nlm.nih.gov/32355963/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32355963/", "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": "PMID32355963", "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": "Microglial PFF-loaded exosomes seed neurons, drive injected mouse pathology/degeneration and are present in patient CSF; exosome inhibition or depletion lowers model transmission.", "what_it_does_not_show": "Forced microglial cargo loading/injection, broad depletion, inflammation and autophagy effects do not isolate spontaneous spread-to-injury mediation.", "confounders_present": [ "Forced microglial cargo loading/injection, broad depletion, inflammation and autophagy effects do not isolate spontaneous spread-to-injury 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": 22, "pmid": "26324905", "title": "Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism.", "citation": "Prusiner SB, Woerman AL, Mordes DA et al. Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism. Proceedings of the National Academy of Sciences of the United States of America. 2015.", "doi": "10.1073/pnas.1514475112", "pmcid": "PMC4586853", "url": "https://pubmed.ncbi.nlm.nih.gov/26324905/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26324905/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID38830111" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID26324905", "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": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Fourteen MSA brain extracts transmit disease to sensitized hemizygous A53T mice and reporter cells; six PD extracts do not in that assay.", "what_it_does_not_show": "Host mutation and assay selectivity limit generalization; natural human transmissibility and common sporadic PD mechanisms are not established. Correction details remain unexamined.", "confounders_present": [ "Host mutation and assay selectivity limit generalization; natural human transmissibility and common sporadic PD mechanisms are not established. Correction details remain unexamined." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "A53T sensitized host/reporter platform, not 14 independent models." ] }, { "n": 23, "pmid": "40812158", "title": "α-synuclein fibrils per se but not α-synuclein seeded aggregation causes mitochondrial dysfunction and cell death in human neurons.", "citation": "Angelova PR, Esteras N, Evans J et al. α-synuclein fibrils per se but not α-synuclein seeded aggregation causes mitochondrial dysfunction and cell death in human neurons. Redox biology. 2025.", "doi": "10.1016/j.redox.2025.103817", "pmcid": "PMC12363591", "url": "https://pubmed.ncbi.nlm.nih.gov/40812158/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40812158/", "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": "PMID40812158", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph2, 2:Results:paragraph9, 2:Results:paragraph12, 2:Results:paragraph22, 2:Results:paragraph25. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell culture", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Isogenic control and SNCA-triplication human neurons show increasing seeding but recovery of mitochondrial function; early fibril exposure raises apoptosis without sustained late seeding toxicity.", "what_it_does_not_show": "Original Results confirm early day1/3 caspase activation returns toward baseline by days14/21, no seeding-associated necrosis, and no 25-day respiration change from PFFs. Cultured cortical neurons, a particular fibril preparation and survival/adaptation cannot generalize to all seeds or nigral disease.", "confounders_present": [ "Original Results confirm early day1/3 caspase activation returns toward baseline by days14/21, no seeding-associated necrosis, and no 25-day respiration change from PFFs. Cultured cortical neurons, a particular fibril preparation and survival/adaptation cannot generalize to all seeds or nigral 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": 24, "pmid": "33177086", "title": "Determinants of seeding and spreading of α-synuclein pathology in the brain.", "citation": "Henrich MT, Geibl FF, Lakshminarasimhan H et al. Determinants of seeding and spreading of α-synuclein pathology in the brain. Science advances. 2020.", "doi": "10.1126/sciadv.abc2487", "pmcid": "PMC7673735", "url": "https://pubmed.ncbi.nlm.nih.gov/33177086/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33177086/", "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": "PMID33177086", "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": "mixed", "what_it_shows": "PPN PFF pathology follows afferent connections but kinetics, magnitude and persistence are not proportional to connection strength; neuronal phenotype matters.", "what_it_does_not_show": "Connectome restriction and cell-specific susceptibility coexist; imposed seeds do not identify unforced native transfer or natural onset.", "confounders_present": [ "Connectome restriction and cell-specific susceptibility coexist; imposed seeds do not identify unforced native transfer or natural onset." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 25, "pmid": "39665233", "title": "Microglia Process α-Synuclein Fibrils and Enhance their Pathogenicity in a TREM2-Dependent Manner.", "citation": "Xiong M, Xia D, Yu H et al. Microglia Process α-Synuclein Fibrils and Enhance their Pathogenicity in a TREM2-Dependent Manner. Advanced science (Weinheim, Baden-Wurttemberg, Germany). 2025.", "doi": "10.1002/advs.202413451", "pmcid": "PMC11831461", "url": "https://pubmed.ncbi.nlm.nih.gov/39665233/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39665233/", "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": "PMID39665233", "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": "TREM2-mediated microglial PFF uptake and AEP truncation enhance seeding; genetic loss or depletion impedes model pathology.", "what_it_does_not_show": "Clearance, inflammatory and substrate-processing changes accompany spread reduction; no audited functional neuronal-loss rescue is credited from the abstract.", "confounders_present": [ "Clearance, inflammatory and substrate-processing changes accompany spread reduction; no audited functional neuronal-loss rescue is credited from 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": 26, "pmid": "27708076", "title": "Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3.", "citation": "Mao X, Ou MT, Karuppagounder SS et al. Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science (New York, N.Y.). 2016.", "doi": "10.1126/science.aah3374", "pmcid": "PMC5510615", "url": "https://pubmed.ncbi.nlm.nih.gov/27708076/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27708076/", "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": "PMID27708076", "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": "LAG3 binding and loss experiments reduce PFF uptake and delay dopaminergic loss and behavioral deficits.", "what_it_does_not_show": "PFF initiation and broad receptor/immune effects limit necessity inference; a later independent expression and survival-null study challenges universal neuronal-receptor attribution.", "confounders_present": [ "PFF initiation and broad receptor/immune effects limit necessity inference; a later independent expression and survival-null study challenges universal neuronal-receptor attribution." ], "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": "35921451", "title": "Trial of Prasinezumab in Early-Stage Parkinson's Disease.", "citation": "Pagano G, Taylor KI, Anzures-Cabrera J et al. Trial of Prasinezumab in Early-Stage Parkinson's Disease. The New England journal of medicine. 2022.", "doi": "10.1056/NEJMoa2202867", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/35921451/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35921451/", "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": "PASADENA-randomization", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "PASADENA randomizes 316 patients; global MDS-UPDRS and DaT-SPECT endpoints do not show meaningful benefit.", "what_it_does_not_show": "Motor-secondary signals do not reverse the primary conclusion; epitope occupancy or plasma binding does not verify blockade of the pathogenic interstitial species. Null is strategy-specific.", "confounders_present": [ "Motor-secondary signals do not reverse the primary conclusion; epitope occupancy or plasma binding does not verify blockade of the pathogenic interstitial species. Null is strategy-specific." ], "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": "39379705", "title": "Sustained effect of prasinezumab on Parkinson's disease motor progression in the open-label extension of the PASADENA trial.", "citation": "Pagano G, Monnet A, Reyes A et al. Sustained effect of prasinezumab on Parkinson's disease motor progression in the open-label extension of the PASADENA trial. Nature medicine. 2024.", "doi": "10.1038/s41591-024-03270-6", "pmcid": "PMC11645263", "url": "https://pubmed.ncbi.nlm.nih.gov/39379705/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39379705/", "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": "PASADENA-randomization-extension", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "PASADENA open-label extension has slower motor worsening than a PPMI external comparator over four years.", "what_it_does_not_show": "This is exploratory nonrandomized follow-up of the same trial, with external-comparator and retention confounding; not an independent randomized efficacy replication.", "confounders_present": [ "This is exploratory nonrandomized follow-up of the same trial, with external-comparator and retention confounding; not an independent randomized efficacy replication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Uses original PASADENA treated cohort plus nonrandomized PPMI external controls." ] }, { "n": 29, "pmid": "42044642", "title": "Safety and efficacy of the anti-α-synuclein monoclonal antibody amlenetug for the treatment of patients with multiple system atrophy (AMULET): a phase 2, randomised, double-blind, multicentre trial.", "citation": "Kjærsgaard L, Wiedemann J, Singer W et al. Safety and efficacy of the anti-α-synuclein monoclonal antibody amlenetug for the treatment of patients with multiple system atrophy (AMULET): a phase 2, randomised, double-blind, multicentre trial. The Lancet. Neurology. 2026.", "doi": "10.1016/S1474-4422(26)00100-6", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/42044642/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42044642/", "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": "PMID42044642", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "AMULET treats 61 participants; estimated progression slowing is 19 percent but Bayesian probability 89.4 percent misses the prespecified 97.5 percent threshold.", "what_it_does_not_show": "Primary endpoint is not met; an uncertain signal and acceptable safety justify further tests, not proof of propagation mediation. Full original body unavailable here.", "confounders_present": [ "Primary endpoint is not met; an uncertain signal and acceptable safety justify further tests, not proof of propagation mediation. Full original body unavailable here." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 30, "pmid": "35921450", "title": "Trial of Cinpanemab in Early Parkinson's Disease.", "citation": "Lang AE, Siderowf AD, Macklin EA et al. Trial of Cinpanemab in Early Parkinson's Disease. The New England journal of medicine. 2022.", "doi": "10.1056/NEJMoa2203395", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/35921450/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35921450/", "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": "SPARK-randomization", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "SPARK randomizes 357 patients; clinical and DaT-SPECT endpoints are null, and trial stops for futility.", "what_it_does_not_show": "The tested extracellular antibody strategy fails; this does not demonstrate universal elimination of pathogenic seeds or refute all intracellular alpha-synuclein biology.", "confounders_present": [ "The tested extracellular antibody strategy fails; this does not demonstrate universal elimination of pathogenic seeds or refute all intracellular alpha-synuclein biology." ], "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": "24382629", "title": "Alpha-synuclein transfers from neurons to oligodendrocytes.", "citation": "Reyes JF, Rey NL, Bousset L et al. Alpha-synuclein transfers from neurons to oligodendrocytes. Glia. 2014.", "doi": "10.1002/glia.22611", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/24382629/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24382629/", "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": "PMID24382629", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Oligodendrocytes take up extracellular alpha-synuclein and grafted rat oligodendroglia contain host-neuronal AAV-expressed human protein.", "what_it_does_not_show": "Transfer of donor protein is not obligatory endogenous recipient conversion; forced source expression and graft environment limit native MSA interpretation.", "confounders_present": [ "Transfer of donor protein is not obligatory endogenous recipient conversion; forced source expression and graft environment limit native MSA interpretation." ], "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": "33813737", "title": "Perampanel Inhibits α-Synuclein Transmission in Parkinson's Disease Models.", "citation": "Ueda J, Uemura N, Sawamura M et al. Perampanel Inhibits α-Synuclein Transmission in Parkinson's Disease Models. Movement disorders : official journal of the Movement Disorder Society. 2021.", "doi": "10.1002/mds.28558", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/33813737/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33813737/", "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": "PMID33813737", "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": "Perampanel reduces neuronal PFF uptake and model pathology through activity-dependent macropinocytosis.", "what_it_does_not_show": "AMPA activity affects physiology and multiple toxic processes; no clinical or audited neuron-survival rescue and no transfer-only intervention are established.", "confounders_present": [ "AMPA activity affects physiology and multiple toxic processes; no clinical or audited neuron-survival rescue and no transfer-only intervention are established." ], "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": "28148299", "title": "Propagation of pathological α-synuclein in marmoset brain.", "citation": "Shimozawa A, Ono M, Takahara D et al. Propagation of pathological α-synuclein in marmoset brain. Acta neuropathologica communications. 2017.", "doi": "10.1186/s40478-017-0413-0", "pmcid": "PMC5289012", "url": "https://pubmed.ncbi.nlm.nih.gov/28148299/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28148299/", "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": "PMID28148299", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Inoculated wild-type marmosets develop connected-region Lewy-like inclusions and fewer ipsilateral TH-positive neurons at three months.", "what_it_does_not_show": "Forced seeds remain; TH-positive counts alone may reflect marker loss without additional stereological identity checks; no full neuronal-loss/function audit was available.", "confounders_present": [ "Forced seeds remain; TH-positive counts alone may reflect marker loss without additional stereological identity checks; no full neuronal-loss/function audit was available." ], "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": "35858558", "title": "Rapid macropinocytic transfer of α-synuclein to lysosomes.", "citation": "Bayati A, Banks E, Han C et al. Rapid macropinocytic transfer of α-synuclein to lysosomes. Cell reports. 2022.", "doi": "10.1016/j.celrep.2022.111102", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/35858558/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35858558/", "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": "PMID35858558", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell culture", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Imaging tracks rapid PFF macropinocytosis to lysosomes and some transfer with exosome markers; inhibitors reduce uptake.", "what_it_does_not_show": "Lysosomal uptake/transport does not demonstrate cytosolic recipient conversion, spontaneous spread or degeneration necessity.", "confounders_present": [ "Lysosomal uptake/transport does not demonstrate cytosolic recipient conversion, spontaneous spread or degeneration necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 35, "pmid": "39977508", "title": "Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson's disease.", "citation": "Wu KM, Xu QH, Liu YQ et al. Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson's disease. Science (New York, N.Y.). 2025.", "doi": "10.1126/science.adp3645", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/39977508/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39977508/", "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": "PMID39977508", "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": "FAM171A2 binds fibrils selectively; neuronal knockdown and bemcentinib reduce uptake and model pathology/neurotoxicity.", "what_it_does_not_show": "Risk-gene association and binding do not identify the full human mediator. Drug pleiotropy, model initiation and matched rescue details remain abstract-only.", "confounders_present": [ "Risk-gene association and binding do not identify the full human mediator. Drug pleiotropy, model initiation and matched rescue details remain abstract-only." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 36, "pmid": "23161999", "title": "Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice.", "citation": "Luk KC, Kehm V, Carroll J et al. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science (New York, N.Y.). 2012.", "doi": "10.1126/science.1227157", "pmcid": "PMC3552321", "url": "https://pubmed.ncbi.nlm.nih.gov/23161999/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23161999/", "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": "PMID23161999", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Main text:paragraph2, 1:Main text:paragraph3, 1:Main text:paragraph6, 1:Main text:paragraph8. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "A single PFF injection into wild-type mice precedes connected pathology, ipsilateral dopamine-neuron loss and rotarod/wire-hang deficits; SNCA-null controls lack these lesions.", "what_it_does_not_show": "Original main text confirms 15 and 35 percent ipsilateral loss at 90/180 days, with monomer/PBS, contralateral and VTA controls. Global substrate absence also removes intrinsic toxicity; imposed initiation does not prove natural spread necessity. Open-field activity and Y-maze are unchanged.", "confounders_present": [ "Original main text confirms 15 and 35 percent ipsilateral loss at 90/180 days, with monomer/PBS, contralateral and VTA controls. Global substrate absence also removes intrinsic toxicity; imposed initiation does not prove natural spread necessity. Open-field activity and Y-maze are unchanged." ], "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": "33682798", "title": "α-Synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson's disease.", "citation": "Cole TA, Zhao H, Collier TJ et al. α-Synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson's disease. JCI insight. 2021.", "doi": "10.1172/jci.insight.135633", "pmcid": "PMC8021121", "url": "https://pubmed.ncbi.nlm.nih.gov/33682798/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33682798/", "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": "PMID33682798", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "SNCA ASOs prevent/reverse established PFF pathology and preserve dopaminergic function; human-target ASOs lower NHP CNS alpha-synuclein.", "what_it_does_not_show": "Global synthesis lowering changes intrinsic substrate and toxicity, not selectively transfer; NHP distribution/CSF engagement is not demonstrated disease efficacy.", "confounders_present": [ "Global synthesis lowering changes intrinsic substrate and toxicity, not selectively transfer; NHP distribution/CSF engagement is not demonstrated disease 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": 38, "pmid": "29502200", "title": "Differential α-synuclein expression contributes to selective vulnerability of hippocampal neuron subpopulations to fibril-induced toxicity.", "citation": "Luna E, Decker SC, Riddle DM et al. Differential α-synuclein expression contributes to selective vulnerability of hippocampal neuron subpopulations to fibril-induced toxicity. Acta neuropathologica. 2018.", "doi": "10.1007/s00401-018-1829-8", "pmcid": "PMC5955788", "url": "https://pubmed.ncbi.nlm.nih.gov/29502200/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29502200/", "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": "PMID29502200", "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": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Endogenous alpha-synuclein levels predict subtype susceptibility; early ASO or glutathione-related rescue protects PFF-vulnerable Math2 neurons.", "what_it_does_not_show": "Late pathology reduction lacks comparable protection, revealing stage thresholds; substrate reduction and redox rescue are not transfer-only tests.", "confounders_present": [ "Late pathology reduction lacks comparable protection, revealing stage thresholds; substrate reduction and redox rescue are not transfer-only tests." ], "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": "34309222", "title": "LAG3 is not expressed in human and murine neurons and does not modulate α-synucleinopathies.", "citation": "Emmenegger M, De Cecco E, Hruska-Plochan M et al. LAG3 is not expressed in human and murine neurons and does not modulate α-synucleinopathies. EMBO molecular medicine. 2021.", "doi": "10.15252/emmm.202114745", "pmcid": "PMC8422075", "url": "https://pubmed.ncbi.nlm.nih.gov/34309222/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34309222/", "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": "PMID34309222", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph12, 1:Results:paragraph20, 1:Results:paragraph60, 1:Results:paragraph67. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Multiple antibody/transcript assays do not detect neuronal LAG3, and LAG3 loss has no A53T survival or seeded-slice pathology effect.", "what_it_does_not_show": "Original Results verify species-specific antibody controls, activated-T-cell positive controls, human snRNAseq, small genotype survival groups and seeded wild-type/A53T slice nulls. A null proposed receptor does not eliminate alternative uptake routes or all propagation.", "confounders_present": [ "Original Results verify species-specific antibody controls, activated-T-cell positive controls, human snRNAseq, small genotype survival groups and seeded wild-type/A53T slice nulls. A null proposed receptor does not eliminate alternative uptake routes or all propagation." ], "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": "38315945", "title": "Cinpanemab in Early Parkinson Disease: Evaluation of Biomarker Results From the Phase 2 SPARK Clinical Trial.", "citation": "Hutchison RM, Fraser K, Yang M et al. Cinpanemab in Early Parkinson Disease: Evaluation of Biomarker Results From the Phase 2 SPARK Clinical Trial. Neurology. 2024.", "doi": "10.1212/WNL.0000000000209137", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/38315945/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38315945/", "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": "SPARK-randomization", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "SPARK biomarker reanalysis finds 93 percent baseline SAA positivity, persistence in 99 percent at week52 and no treatment or progression-linked biomarker effect.", "what_it_does_not_show": "Same 357-person trial; no new randomization. Persistent SAA and absent biomarker effect weaken a claim that cinpanemab verified complete seed blockade.", "confounders_present": [ "Same 357-person trial; no new randomization. Persistent SAA and absent biomarker effect weaken a claim that cinpanemab verified complete seed blockade." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "SPARK participants and biomarker subset; no independent clinical trial." ] }, { "n": 41, "pmid": "42208564", "title": "Efficacy and safety of intravenous prasinezumab in individuals with early-stage Parkinson's disease on stable symptomatic monotherapy (PADOVA): a phase 2b, multicentre, randomised, double-blind, placebo-controlled study.", "citation": "Nikolcheva T, Pagano G, Anzures-Cabrera J et al. Efficacy and safety of intravenous prasinezumab in individuals with early-stage Parkinson's disease on stable symptomatic monotherapy (PADOVA): a phase 2b, multicentre, randomised, double-blind, placebo-controlled study. Lancet (London, England). 2026.", "doi": "10.1016/S0140-6736(26)00865-2", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/42208564/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42208564/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "ErratumIn: PMID42392102" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID42208564", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "PADOVA randomizes 586 patients; motor-progression HR 0.84, 95 percent CI 0.69–1.01, p0.066 misses the primary endpoint.", "what_it_does_not_show": "Exploratory clinical-activity signals merit follow-up but are not confirmatory efficacy. Actual pathogenic extracellular spread blockade is not demonstrated in this abstract; linked correction details remain unexamined.", "confounders_present": [ "Exploratory clinical-activity signals merit follow-up but are not confirmatory efficacy. Actual pathogenic extracellular spread blockade is not demonstrated in this abstract; linked correction details remain unexamined." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 42, "pmid": "8100741", "title": "Mice devoid of PrP are resistant to scrapie.", "citation": "Büeler H, Aguzzi A, Sailer A et al. Mice devoid of PrP are resistant to scrapie. Cell. 1993.", "doi": "10.1016/0092-8674(93)90360-3", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/8100741/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/8100741/", "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": "PMID8100741", "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": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "PrP-null mice resist scrapie whereas host-homologous transgenic reintroduction restores susceptibility.", "what_it_does_not_show": "Canonical PrP substrate dependence is a comparator only; it cannot establish the same mechanism or natural transmission in tau/alpha-synuclein diseases.", "confounders_present": [ "Canonical PrP substrate dependence is a comparator only; it cannot establish the same mechanism or natural transmission in tau/alpha-synuclein diseases." ], "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": "14593181", "title": "Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis.", "citation": "Mallucci G, Dickinson A, Linehan J et al. Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis. Science (New York, N.Y.). 2003.", "doi": "10.1126/science.1090187", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/14593181/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/14593181/", "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": "conditional-neuronal-PrP-platform", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Post-invasion neuronal PrP depletion reverses spongiosis and prevents clinical disease despite accumulating extraneuronal PrPSc.", "what_it_does_not_show": "Neuron-specific conversion dependence is stronger than aggregate presence; nonneuronal propagation can be nonpathogenic. Neither PrP result is interchangeable with tau or alpha-synuclein necessity.", "confounders_present": [ "Neuron-specific conversion dependence is stronger than aggregate presence; nonneuronal propagation can be nonpathogenic. Neither PrP result is interchangeable with tau or alpha-synuclein necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Conditional PrP depletion platform shared with PMID17270731." ] }, { "n": 44, "pmid": "17270731", "title": "Targeting cellular prion protein reverses early cognitive deficits and neurophysiological dysfunction in prion-infected mice.", "citation": "Mallucci GR, White MD, Farmer M et al. Targeting cellular prion protein reverses early cognitive deficits and neurophysiological dysfunction in prion-infected mice. Neuron. 2007.", "doi": "10.1016/j.neuron.2007.01.005", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/17270731/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17270731/", "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": "conditional-neuronal-PrP-platform", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Neuronal PrP depletion rescues early cognition and electrophysiology before large deposits accumulate.", "what_it_does_not_show": "Same conditional PrP platform as the earlier depletion study; functional rescue does not demonstrate non-PrP disease mechanisms.", "confounders_present": [ "Same conditional PrP platform as the earlier depletion study; functional rescue does not demonstrate non-PrP disease mechanisms." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 45, "pmid": "9197268", "title": "Mutation in the alpha-synuclein gene identified in families with Parkinson's disease.", "citation": "Polymeropoulos MH, Lavedan C, Leroy E et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science (New York, N.Y.). 1997.", "doi": "10.1126/science.276.5321.2045", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/9197268/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/9197268/", "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": "PMID9197268", "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 genetics", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "A segregating SNCA mutation occurs in an Italian kindred and three unrelated Greek families with dominant PD.", "what_it_does_not_show": "Inherited gene causality supports protein relevance, not selective propagation mediation or direct generalization to sporadic disease.", "confounders_present": [ "Inherited gene causality supports protein relevance, not selective propagation mediation or direct generalization to sporadic 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": 46, "pmid": "18391962", "title": "Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease.", "citation": "Kordower JH, Chu Y, Hauser RA et al. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease. Nature medicine. 2008.", "doi": "10.1038/nm1747", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/18391962/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18391962/", "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": "PMID18391962", "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": "Weak", "system": "human tissue", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Fourteen-year-old human nigral grafts have Lewy-like alpha-synuclein/ubiquitin inclusions and reduced DAT staining.", "what_it_does_not_show": "A natural host-to-graft lead, but graft stress, shared milieu and de-novo aggregation remain alternatives; donor–recipient protein lineage and lethal templating were not directly measured.", "confounders_present": [ "A natural host-to-graft lead, but graft stress, shared milieu and de-novo aggregation remain alternatives; donor–recipient protein lineage and lethal templating were not directly measured." ], "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": "19651612", "title": "Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein.", "citation": "Desplats P, Lee HJ, Bae EJ et al. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proceedings of the National Academy of Sciences of the United States of America. 2009.", "doi": "10.1073/pnas.0903691106", "pmcid": "PMC2722313", "url": "https://pubmed.ncbi.nlm.nih.gov/19651612/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19651612/", "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": "PMID19651612", "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": "Neuron-derived alpha-synuclein enters neighboring cells and grafted precursors with inclusion/apoptosis markers; lysosomal failure increases accumulation.", "what_it_does_not_show": "Transgenic source and apoptosis markers do not identify a physiological templated, transfer-specific degeneration dependency. Linked erratum has no PMID supplied and remains unresolved.", "confounders_present": [ "Transgenic source and apoptosis markers do not identify a physiological templated, transfer-specific degeneration dependency. Linked erratum has no PMID supplied and remains unresolved." ], "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": "23109146", "title": "Neuron-to-neuron transmission of α-synuclein fibrils through axonal transport.", "citation": "Freundt EC, Maynard N, Clancy EK et al. Neuron-to-neuron transmission of α-synuclein fibrils through axonal transport. Annals of neurology. 2012.", "doi": "10.1002/ana.23747", "pmcid": "PMC3490229", "url": "https://pubmed.ncbi.nlm.nih.gov/23109146/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23109146/", "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": "PMID23109146", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell culture", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Microfluidic imaging tracks fibrils along axons into second-order neurons; transfer does not appear to require synapses.", "what_it_does_not_show": "Physical cargo transfer under imposed exposure is not recipient endogenous conversion or organismal neuron-loss mediation.", "confounders_present": [ "Physical cargo transfer under imposed exposure is not recipient endogenous conversion or organismal neuron-loss mediation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 49, "pmid": "26436904", "title": "Depletion of microglia and inhibition of exosome synthesis halt tau propagation.", "citation": "Asai H, Ikezu S, Tsunoda S et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nature neuroscience. 2015.", "doi": "10.1038/nn.4132", "pmcid": "PMC4694577", "url": "https://pubmed.ncbi.nlm.nih.gov/26436904/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26436904/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID26436904", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Microglial depletion and exosome-synthesis inhibition reduced tau propagation in an AAV entorhinal-to-dentate model and changed dentate excitability.", "what_it_does_not_show": "AAV expression and broad microglial/exosome effects do not isolate spontaneous tau templating as the mediator of neuron death. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "confounders_present": [ "AAV expression and broad microglial/exosome effects do not isolate spontaneous tau templating as the mediator of neuron death. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 50, "pmid": "42372723", "title": "Arc mediates intercellular tau transmission via extracellular vesicles.", "citation": "Tyagi M, de Hoog E, Grega M et al. Arc mediates intercellular tau transmission via extracellular vesicles. Cell. 2026.", "doi": "10.1016/j.cell.2026.06.008", "pmcid": "PMC13315601", "url": "https://pubmed.ncbi.nlm.nih.gov/42372723/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42372723/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID39484489" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID42372723", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Arc knockout nearly abolished intercellular transmission in mutant-tau mice while reducing EV tau and increasing intracellular accumulation with modest early toxicity.", "what_it_does_not_show": "Transmission reduction did not yield uniform neuroprotection; developmental Arc functions and mutant transgenic expression complicate selective spread mediation. UpdateOf links the preceding version, not a separate replication. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "confounders_present": [ "Transmission reduction did not yield uniform neuroprotection; developmental Arc functions and mutant transgenic expression complicate selective spread mediation. UpdateOf links the preceding version, not a separate replication. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 51, "pmid": "32296178", "title": "LRP1 is a master regulator of tau uptake and spread.", "citation": "Rauch JN, Luna G, Guzman E et al. LRP1 is a master regulator of tau uptake and spread. Nature. 2020.", "doi": "10.1038/s41586-020-2156-5", "pmcid": "PMC7687380", "url": "https://pubmed.ncbi.nlm.nih.gov/32296178/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32296178/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID32296178", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "LRP1 knockdown reduced tau uptake in human-derived cells and reduced neuronal tau spread in a mouse model.", "what_it_does_not_show": "Receptor uptake is not identical to recipient conversion; LRP1 has broader trafficking functions and the abstract does not establish neuronal-loss prevention. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "confounders_present": [ "Receptor uptake is not identical to recipient conversion; LRP1 has broader trafficking functions and the abstract does not establish neuronal-loss prevention. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 52, "pmid": "24857020", "title": "Distinct tau prion strains propagate in cells and mice and define different tauopathies.", "citation": "Sanders DW, Kaufman SK, DeVos SL et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron. 2014.", "doi": "10.1016/j.neuron.2014.04.047", "pmcid": "PMC4171396", "url": "https://pubmed.ncbi.nlm.nih.gov/24857020/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24857020/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID24857020", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Cell-derived tau conformations retained strain-like characteristics across three inoculated transgenic-mouse generations and patient-derived biosensor isolates differed by tauopathy.", "what_it_does_not_show": "Repeat-domain reporters and imposed serial inoculation establish templating capability, not natural human intercellular disease causation or infectivity equivalence to PrP. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "confounders_present": [ "Repeat-domain reporters and imposed serial inoculation establish templating capability, not natural human intercellular disease causation or infectivity equivalence to PrP. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 53, "pmid": "26538322", "title": "Removing endogenous tau does not prevent tau propagation yet reduces its neurotoxicity.", "citation": "Wegmann S, Maury EA, Kirk MJ et al. Removing endogenous tau does not prevent tau propagation yet reduces its neurotoxicity. The EMBO journal. 2015.", "doi": "10.15252/embj.201592748", "pmcid": "PMC4687785", "url": "https://pubmed.ncbi.nlm.nih.gov/26538322/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26538322/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID26538322", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Removing endogenous mouse tau preserved human-P301L transfer to recipient neurons but reduced neurotoxicity in a separate severe-tauopathy model despite similar tangle numbers.", "what_it_does_not_show": "Donor-protein movement can occur without host templating, and tangle burden can dissociate from toxicity; human transgenes and tau-null physiology limit natural disease generalization. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "confounders_present": [ "Donor-protein movement can occur without host templating, and tangle burden can dissociate from toxicity; human transgenes and tau-null physiology limit natural disease generalization. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 54, "pmid": "39500576", "title": "Targeting Endogenous Tau in Seeded Tauopathy Models Inhibits Tau Spread.", "citation": "Jang E, Hoxha K, Mozier D et al. Targeting Endogenous Tau in Seeded Tauopathy Models Inhibits Tau Spread. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2024.", "doi": "10.1523/JNEUROSCI.0877-24.2024", "pmcid": "PMC11604146", "url": "https://pubmed.ncbi.nlm.nih.gov/39500576/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39500576/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID39500576", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "A mouse-tau-specific antibody reduced human AD-tau-seeded pathology in female wild-type mice despite not binding the human inoculum.", "what_it_does_not_show": "This narrows recipient-substrate involvement but still begins with imposed seeds; the abstract infers intraneuronal elongation and does not establish selective spread-mediated neuron survival. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "confounders_present": [ "This narrows recipient-substrate involvement but still begins with imposed seeds; the abstract infers intraneuronal elongation and does not establish selective spread-mediated neuron survival. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 55, "pmid": "33472038", "title": "Lowering Synaptogyrin-3 expression rescues Tau-induced memory defects and synaptic loss in the presence of microglial activation.", "citation": "Largo-Barrientos P, Apóstolo N, Creemers E et al. Lowering Synaptogyrin-3 expression rescues Tau-induced memory defects and synaptic loss in the presence of microglial activation. Neuron. 2021.", "doi": "10.1016/j.neuron.2020.12.016", "pmcid": "PMC7927913", "url": "https://pubmed.ncbi.nlm.nih.gov/33472038/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33472038/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID33472038", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Reducing Synaptogyrin-3 rescued mutant-tau synaptic plasticity, memory and synapse loss while neuroinflammation remained elevated.", "what_it_does_not_show": "The contrast identifies synaptic toxicity independent of persistent glial activation; it does not directly test pathological species transfer. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "confounders_present": [ "The contrast identifies synaptic toxicity independent of persistent glial activation; it does not directly test pathological species transfer. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 56, "pmid": "38012285", "title": "TANGO: a placebo-controlled randomized phase 2 study of efficacy and safety of the anti-tau monoclonal antibody gosuranemab in early Alzheimer's disease.", "citation": "Shulman M, Kong J, O'Gorman J et al. TANGO: a placebo-controlled randomized phase 2 study of efficacy and safety of the anti-tau monoclonal antibody gosuranemab in early Alzheimer's disease. Nature aging. 2023.", "doi": "10.1038/s43587-023-00523-w", "pmcid": "PMC10724064", "url": "https://pubmed.ncbi.nlm.nih.gov/38012285/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38012285/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID38012285", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph19, 1:Results:paragraph23, 1:Results:paragraph28, 1:Results:paragraph33, 1:Results:paragraph38. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "null", "what_it_shows": "TANGO randomized 654 early-AD participants and showed no favorable cognitive/functional CDR-SB change with gosuranemab despite reduced unbound N-terminal CSF tau.", "what_it_does_not_show": "Safety was primary and clinical efficacy secondary; drug engagement of a soluble N-terminal pool does not demonstrate selective blockade of all tau propagation. Original Results confirm 80.1–92.6 percent unbound N-terminal CSF tau reduction, no tau-PET dose response and no favorable atrophy response. An isolated exploratory cognitive result was worse, without a dose response; it is not treated as a definitive toxicity test. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "confounders_present": [ "Safety was primary and clinical efficacy secondary; drug engagement of a soluble N-terminal pool does not demonstrate selective blockade of all tau propagation. Original Results confirm 80.1–92.6 percent unbound N-terminal CSF tau reduction, no tau-PET dose response and no favorable atrophy response. An isolated exploratory cognitive result was worse, without a dose response; it is not treated as a definitive toxicity test. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 57, "pmid": "37643887", "title": "Randomized Phase II Study of the Safety and Efficacy of Semorinemab in Participants With Mild-to-Moderate Alzheimer Disease: Lauriet.", "citation": "Monteiro C, Toth B, Brunstein F et al. Randomized Phase II Study of the Safety and Efficacy of Semorinemab in Participants With Mild-to-Moderate Alzheimer Disease: Lauriet. Neurology. 2023.", "doi": "10.1212/WNL.0000000000207663", "pmcid": "PMC10573141", "url": "https://pubmed.ncbi.nlm.nih.gov/37643887/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37643887/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID37643887", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph8, 2:Results:paragraph15, 2:Results:paragraph17, 2:Results:paragraph19, 2:Results:paragraph20. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "LAURIET semorinemab improved ADAS-Cog11 decline at week 49 but not the coprimary activities-of-daily-living endpoint or global secondary measures.", "what_it_does_not_show": "The prespecified coprimary trial result was negative; isolated cognitive benefit is credited without being relabeled overall efficacy or propagation-mediated neuroprotection. Original Results confirm a 2.89-point ADAS-Cog11 difference at week 49, with the largest post hoc item effect in word recognition. CSF tau fell but PET accumulation and atrophy rates did not differ. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "confounders_present": [ "The prespecified coprimary trial result was negative; isolated cognitive benefit is credited without being relabeled overall efficacy or propagation-mediated neuroprotection. Original Results confirm a 2.89-point ADAS-Cog11 difference at week 49, with the largest post hoc item effect in word recognition. CSF tau fell but PET accumulation and atrophy rates did not differ. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 58, "pmid": "19503072", "title": "Transmission and spreading of tauopathy in transgenic mouse brain.", "citation": "Clavaguera F, Bolmont T, Crowther RA et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nature cell biology. 2009.", "doi": "10.1038/ncb1901", "pmcid": "PMC2726961", "url": "https://pubmed.ncbi.nlm.nih.gov/19503072/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19503072/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID19503072", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Mutant-P301S brain extract induced filament assembly of wild-type human tau and regional pathology in inoculated transgenic recipients.", "what_it_does_not_show": "The recipients express human tau and receive artificial intracerebral exposure; capability is not natural cell-to-cell necessity or neurodegeneration mediation. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "confounders_present": [ "The recipients express human tau and receive artificial intracerebral exposure; capability is not natural cell-to-cell necessity or neurodegeneration mediation. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 59, "pmid": "22365544", "title": "Propagation of tau pathology in a model of early Alzheimer's disease.", "citation": "de Calignon A, Polydoro M, Suárez-Calvet M et al. Propagation of tau pathology in a model of early Alzheimer's disease. Neuron. 2012.", "doi": "10.1016/j.neuron.2011.11.033", "pmcid": "PMC3292759", "url": "https://pubmed.ncbi.nlm.nih.gov/22365544/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22365544/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID22365544", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Entorhinal-restricted P301L expression was followed by human tau in connected neurons lacking detectable transgene, coaggregation with mouse tau, synapse degeneration and EC loss.", "what_it_does_not_show": "Low-level expression detection and source-cell deafferentation complicate inference; mutant overexpression does not isolate selective endogenous templating. Linked erratum details are unexamined. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "confounders_present": [ "Low-level expression detection and source-cell deafferentation complicate inference; mutant overexpression does not isolate selective endogenous templating. Linked erratum details are unexamined. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Related restricted-EC tau constructs overlap conceptual methods in PMID22312444." ] }, { "n": 60, "pmid": "40390134", "title": "hiPSC-neurons recapitulate the subtype-specific cell intrinsic nature of susceptibility to neurodegenerative disease-relevant aggregation.", "citation": "Weidling I, Preiss CN, Chancellor SE et al. hiPSC-neurons recapitulate the subtype-specific cell intrinsic nature of susceptibility to neurodegenerative disease-relevant aggregation. Acta neuropathologica communications. 2025.", "doi": "10.1186/s40478-025-02000-4", "pmcid": "PMC12087151", "url": "https://pubmed.ncbi.nlm.nih.gov/40390134/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40390134/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID40390134", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell culture", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Different human iPSC neuronal subtypes showed distinct susceptibility to identical tau or synuclein seeds; uptake/degradation did not explain the tau differences.", "what_it_does_not_show": "This supports intrinsic vulnerability as a contributor to regional patterns; imposed aggregates and cultured neurons do not establish the full human progression mechanism. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "confounders_present": [ "This supports intrinsic vulnerability as a contributor to regional patterns; imposed aggregates and cultured neurons do not establish the full human progression mechanism. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 61, "pmid": "36344699", "title": "Bassoon contributes to tau-seed propagation and neurotoxicity.", "citation": "Martinez P, Patel H, You Y et al. Bassoon contributes to tau-seed propagation and neurotoxicity. Nature neuroscience. 2022.", "doi": "10.1038/s41593-022-01191-6", "pmcid": "PMC9708566", "url": "https://pubmed.ncbi.nlm.nih.gov/36344699/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36344699/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID36344699", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph21, 1:Results:paragraph26, 1:Results:paragraph33, 1:Results:paragraph36, 1:Results:paragraph44. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Bassoon downregulation reduced tau seed-associated pathology and spread and rescued synaptic/behavioral defects and atrophy in experimental tauopathy systems.", "what_it_does_not_show": "Bassoon regulates presynaptic function and seed stability as well as transport; matching source toxicity and selective recipient conversion remains essential to propagation mediation. Original Results show unchanged total human tau after preventive P0 Bassoon shRNA, and source GFP controls in the separate AAV transfer arm. These controls strengthen seed-mediated contribution but do not make presynaptic Bassoon a transfer-only intervention. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "confounders_present": [ "Bassoon regulates presynaptic function and seed stability as well as transport; matching source toxicity and selective recipient conversion remains essential to propagation mediation. Original Results show unchanged total human tau after preventive P0 Bassoon shRNA, and source GFP controls in the separate AAV transfer arm. These controls strengthen seed-mediated contribution but do not make presynaptic Bassoon a transfer-only intervention. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 62, "pmid": "40886860", "title": "Spontaneous pathology in PS19 tauopathy mice progresses via brain networks.", "citation": "Ramirez DMO, Whitesell JD, Bhagwat N et al. Spontaneous pathology in PS19 tauopathy mice progresses via brain networks. Neurobiology of disease. 2025.", "doi": "10.1016/j.nbd.2025.107072", "pmcid": "PMC13411113", "url": "https://pubmed.ncbi.nlm.nih.gov/40886860/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40886860/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID37293074" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID40886860", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Whole-brain age-series maps of pan-neuronal P301S PS19 mice fitted retrograde-biased connectivity models without injected seeds.", "what_it_does_not_show": "Spontaneous pathology is valuable but still occurs with widespread mutant human tau expression; modeled phospho-tau progression is not directly traced protein transfer or selective spread blockade. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "confounders_present": [ "Spontaneous pathology is valuable but still occurs with widespread mutant human tau expression; modeled phospho-tau progression is not directly traced protein transfer or selective spread blockade. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 63, "pmid": "34714685", "title": "In vivo rate-determining steps of tau seed accumulation in Alzheimer's disease.", "citation": "Meisl G, Hidari E, Allinson K et al. In vivo rate-determining steps of tau seed accumulation in Alzheimer's disease. Science advances. 2021.", "doi": "10.1126/sciadv.abh1448", "pmcid": "PMC8555892", "url": "https://pubmed.ncbi.nlm.nih.gov/34714685/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34714685/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID34714685", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph3, 1:RESULTS:paragraph4, 1:RESULTS:paragraph5, 1:RESULTS:paragraph13, 1:RESULTS:paragraph14, 1:RESULTS:paragraph15, 1:RESULTS:paragraph16, 1:RESULTS:paragraph17. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Kinetic fits across multiple human seed/tau measures suggested local replication, rather than interregional spread, limits neocortical accumulation from Braak III onward.", "what_it_does_not_show": "The inferred approximately five-year seed doubling is model-dependent and stage-specific; it does not show early seeding is irrelevant or experimentally identify a clinical rate-limiting mediator. Original Results explicitly subsume local cell-to-cell transfer into the replication term. The contrast concerns interregional spread, not all transfer; extrapolation before Braak III is untested. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "confounders_present": [ "The inferred approximately five-year seed doubling is model-dependent and stage-specific; it does not show early seeding is irrelevant or experimentally identify a clinical rate-limiting mediator. Original Results explicitly subsume local cell-to-cell transfer into the replication term. The contrast concerns interregional spread, not all transfer; extrapolation before Braak III is untested. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 64, "pmid": "39284839", "title": "The cellular prion protein does not affect tau seeding and spreading of sarkosyl-insoluble fractions from Alzheimer's disease.", "citation": "Sala-Jarque J, Gil V, Andrés-Benito P et al. The cellular prion protein does not affect tau seeding and spreading of sarkosyl-insoluble fractions from Alzheimer's disease. Scientific reports. 2024.", "doi": "10.1038/s41598-024-72232-2", "pmcid": "PMC11405773", "url": "https://pubmed.ncbi.nlm.nih.gov/39284839/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39284839/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID39284839", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Human AD insoluble tau induced host-tau pathology in mice across Prnp genotypes; tau-null and species-specific antibody comparisons supported recipient tau origin, while PrP genotype did not change seeding/spread.", "what_it_does_not_show": "Forced inoculation establishes host conversion capability and excludes an obligatory PrP receptor in this setting, not natural human tau propagation necessity. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "confounders_present": [ "Forced inoculation establishes host conversion capability and excludes an obligatory PrP receptor in this setting, not natural human tau propagation necessity. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 65, "pmid": "22312444", "title": "Trans-synaptic spread of tau pathology in vivo.", "citation": "Liu L, Drouet V, Wu JW et al. Trans-synaptic spread of tau pathology in vivo. PloS one. 2012.", "doi": "10.1371/journal.pone.0031302", "pmcid": "PMC3270029", "url": "https://pubmed.ncbi.nlm.nih.gov/22312444/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22312444/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID22312444", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Entorhinal-biased human-tau transgenic mice developed human tau staining and mature pathology in connected hippocampal and cortical regions with age.", "what_it_does_not_show": "Distribution and expression restriction support transfer but do not directly visualize a precursor-product lineage or separate low-level transgene expression from recipient conversion. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "confounders_present": [ "Distribution and expression restriction support transfer but do not directly visualize a precursor-product lineage or separate low-level transgene expression from recipient conversion. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 66, "pmid": "33005889", "title": "Dextran sulphate-induced tau assemblies cause endogenous tau aggregation and propagation in wild-type mice.", "citation": "Masuda-Suzukake M, Suzuki G, Hosokawa M et al. Dextran sulphate-induced tau assemblies cause endogenous tau aggregation and propagation in wild-type mice. Brain communications. 2020.", "doi": "10.1093/braincomms/fcaa091", "pmcid": "PMC7519727", "url": "https://pubmed.ncbi.nlm.nih.gov/33005889/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33005889/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID33005889", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Dextran-sulfate-assembled full-length tau induced host mouse-tau aggregation and connected-region pathology in nontransgenic mice after intracerebral injection.", "what_it_does_not_show": "This removes a recipient overexpression requirement but retains artificial seed creation and forced entry; it is not observation of spontaneous human transmission. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "confounders_present": [ "This removes a recipient overexpression requirement but retains artificial seed creation and forced entry; it is not observation of spontaneous human transmission. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] } ], "verification_summary": { "load_bearing_claims_checked": 71, "verified": 71, "unverified": 0, "contradicted": 0, "note": "Verified attribution is distinct from mechanism truth or complete body access." }, "factual_issues_found": [], "cap_rules_applied": [ { "subclaim_id": "SC1", "cap": "Γ", "cap_source": "rubric", "triggered": true, "trigger_text_quoted": "Exogenous seeding models alone", "specific_trigger": "Wild-type neuronal and animal recipients recruit host tau or alpha-synuclein, with species-specific antibody and SNCA-null controls. This is important physiological-substrate capability after forced entry. For the disease-relevant conversion mechanism, positive evidence remains dominated by imposed seeds or engineered sources, triggering the exogenous-seeding-alone ceiling; no claim is made that conversion never occurs.", "resulting_ceiling": "Γ" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Misfolded tau and alpha-synuclein propagate cell to cell by templated conversion, driving progressive neurodegeneration.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "The neurodegeneration rubric credits disease-relevant mediator perturbation within its tested scope, but exogenous seeding alone remains capped for the natural disease inference. Wild-type recipients remove overexpression of the host substrate, not imposed initiation. LAG3/LRP1, vagotomy and ASO results are real perturbations but do not selectively isolate natural transfer-to-injury necessity in both protein families. PrP knockout/reintroduction and post-onset depletion support their own mechanism; no comparator grade is imported into tau/alpha-synuclein. The complete set is assessed for complementary errors, not re-capped simply because one component is weak.", "note": "Convergent lines are assessed as a set; one weak leg is not re-capped over the assembled case." } ], "boundary_check_BGD": [ { "subclaim_id": "SC1", "field_valid_perturbation_quote": "\n- Endogenous genetic deletion, suppression, or degron depletion of the proposed mediator in vivo\n- Selective pathway inhibition that changes onset/progression while preserving broader viability\n- Vagotomy-type natural experiment, only if confounding is rigorously controlled AND effect is disease-initiation relevant rather than merely associated", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "PMID31255487, PMID21982369, PMID39570889, PMID38499535, PMID40812158, PMID23161999, PMID33682798, PMID29502200, PMID8100741, PMID14593181, PMID24857020, PMID26538322, PMID39500576, PMID19503072, PMID22365544, PMID40390134, PMID36344699, PMID39284839, PMID33005889", "gamma_hard_rules_triggered": [ "Exogenous seeding alone cannot establish natural disease progression necessity.", "Physiological recipient expression does not make imposed initiation physiological.", "Protein transfer, host conversion and neuronal loss are three separate observations.", "Substrate depletion also changes intrinsic toxicity; PrP mechanisms are not inherited by non-PrP proteins." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Wild-type neuronal and animal recipients recruit host tau or alpha-synuclein, with species-specific antibody and SNCA-null controls. This is important physiological-substrate capability after forced entry. For the disease-relevant conversion mechanism, positive evidence remains dominated by imposed seeds or engineered sources, triggering the exogenous-seeding-alone ceiling; no claim is made that conversion never occurs.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC2", "field_valid_perturbation_quote": "\n- Endogenous genetic deletion, suppression, or degron depletion of the proposed mediator in vivo\n- Selective pathway inhibition that changes onset/progression while preserving broader viability\n- Vagotomy-type natural experiment, only if confounding is rigorously controlled AND effect is disease-initiation relevant rather than merely associated", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "PMID31255487, PMID36056345, PMID41680444, PMID38327094, PMID40993788, PMID32449565, PMID39059388, PMID32355963, PMID39665233, PMID27708076, PMID33813737, PMID35858558, PMID39977508, PMID23161999, PMID34309222, PMID19651612, PMID26436904, PMID42372723, PMID32296178, PMID26538322, PMID22365544, PMID40390134, PMID36344699, PMID33005889", "gamma_hard_rules_triggered": [ "Exogenous seeding alone cannot establish natural disease progression necessity.", "Physiological recipient expression does not make imposed initiation physiological.", "Protein transfer, host conversion and neuronal loss are three separate observations.", "Substrate depletion also changes intrinsic toxicity; PrP mechanisms are not inherited by non-PrP proteins." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Human graft pathology, donor-restricted animal protein and endogenous lipid/Arc perturbations strengthen physical transfer. Native molecular lineage in unforced disease remains incompletely distinguished from source overexpression, local generation and correlated vulnerability. PS19 spontaneous pathology retains widespread mutant expression.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC3", "field_valid_perturbation_quote": "\n- Endogenous genetic deletion, suppression, or degron depletion of the proposed mediator in vivo\n- Selective pathway inhibition that changes onset/progression while preserving broader viability\n- Vagotomy-type natural experiment, only if confounding is rigorously controlled AND effect is disease-initiation relevant rather than merely associated", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "PMID31255487, PMID21982369, PMID21700325, PMID39570889, PMID38327094, PMID40993788, PMID32449565, PMID39059388, PMID38902546, PMID38499535, PMID27280685, PMID32355963, PMID40812158, PMID39665233, PMID27708076, PMID35921451, PMID42044642, PMID35921450, PMID33813737, PMID39977508, PMID23161999, PMID33682798, PMID29502200, PMID34309222, PMID38315945, PMID42208564, PMID8100741, PMID14593181, PMID17270731, PMID19651612, PMID26436904, PMID42372723, PMID26538322, PMID33472038, PMID37643887, PMID22365544, PMID36344699", "gamma_hard_rules_triggered": [ "Exogenous seeding alone cannot establish natural disease progression necessity.", "Physiological recipient expression does not make imposed initiation physiological.", "Protein transfer, host conversion and neuronal loss are three separate observations.", "Substrate depletion also changes intrinsic toxicity; PrP mechanisms are not inherited by non-PrP proteins." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Gut route interruption and receptor/source perturbations couple transmission to injury in models, but also alter substrate, immunity, physiology or initial insult. Arc, human-neuron seeding adaptation and protective glial sharing separate transfer from toxicity. Clinical strategies are null or mixed, without verified universal pathogenic seed blockade.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC4", "field_valid_perturbation_quote": "\n- Endogenous genetic deletion, suppression, or degron depletion of the proposed mediator in vivo\n- Selective pathway inhibition that changes onset/progression while preserving broader viability\n- Vagotomy-type natural experiment, only if confounding is rigorously controlled AND effect is disease-initiation relevant rather than merely associated", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "PMID31255487, PMID21700325, PMID39570889, PMID41680444, PMID40993788, PMID38902546, PMID35921451, PMID42044642, PMID35921450, PMID29502200, PMID34309222, PMID38315945, PMID42208564", "gamma_hard_rules_triggered": [ "Exogenous seeding alone cannot establish natural disease progression necessity.", "Physiological recipient expression does not make imposed initiation physiological.", "Protein transfer, host conversion and neuronal loss are three separate observations.", "Substrate depletion also changes intrinsic toxicity; PrP mechanisms are not inherited by non-PrP proteins." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Tau/alpha-synuclein strains, native filament structures, recipient phenotypes and clinical responses vary. MSA transmission to sensitized A53T mice does not establish ordinary PD transmission or human contagiousness. SAA kinetics predict some cognitive outcomes but do not measure physical spread. Disease-class progression beyond imposed initiation remains Γ.", "ceiling_from_boundary_check": "Γ" } ], "thresholds_tested": [ { "subclaim_id": "SC1", "threshold": "Δ", "requirement_quoted": "Requires at least one genuine causal perturbation in a disease-relevant in vivo system, or equivalent human natural experiment that materially supports the mechanism.", "satisfied": "no", "supporting_evidence": [ "[1] Gut PFF injection produces staged brain pathology, dopaminergic loss and motor deficits; vagotomy and SNCA absence prevent the cascade.", "[4] PFFs recruit endogenous alpha-synuclein in primary neurons without overexpression and precede synaptic dysfunction and death.", "[6] GBA1 patient-derived midbrain organoids form seeding-competent fibrils with dopaminergic loss and transmit pathology to control organoids; GCase-pathway drugs lower pathology.", "[17] HTRA1 and a protease-inactive mutant remodel PFFs and reduce reporter seeding; treated reaction products reduce primary-neuron p-alpha-synuclein and improve MTT signal.", "[23] Isogenic control and SNCA-triplication human neurons show increasing seeding but recovery of mitochondrial function; early fibril exposure raises apoptosis without sustained late seeding toxicity.", "[36] A single PFF injection into wild-type mice precedes connected pathology, ipsilateral dopamine-neuron loss and rotarod/wire-hang deficits; SNCA-null controls lack these lesions.", "[37] SNCA ASOs prevent/reverse established PFF pathology and preserve dopaminergic function; human-target ASOs lower NHP CNS alpha-synuclein.", "[38] Endogenous alpha-synuclein levels predict subtype susceptibility; early ASO or glutathione-related rescue protects PFF-vulnerable Math2 neurons.", "[42] PrP-null mice resist scrapie whereas host-homologous transgenic reintroduction restores susceptibility.", "[43] Post-invasion neuronal PrP depletion reverses spongiosis and prevents clinical disease despite accumulating extraneuronal PrPSc.", "[52] Cell-derived tau conformations retained strain-like characteristics across three inoculated transgenic-mouse generations and patient-derived biosensor isolates differed by tauopathy.", "[53] Removing endogenous mouse tau preserved human-P301L transfer to recipient neurons but reduced neurotoxicity in a separate severe-tauopathy model despite similar tangle numbers.", "[54] A mouse-tau-specific antibody reduced human AD-tau-seeded pathology in female wild-type mice despite not binding the human inoculum.", "[58] Mutant-P301S brain extract induced filament assembly of wild-type human tau and regional pathology in inoculated transgenic recipients.", "[59] Entorhinal-restricted P301L expression was followed by human tau in connected neurons lacking detectable transgene, coaggregation with mouse tau, synapse degeneration and EC loss.", "[60] Different human iPSC neuronal subtypes showed distinct susceptibility to identical tau or synuclein seeds; uptake/degradation did not explain the tau differences.", "[61] Bassoon downregulation reduced tau seed-associated pathology and spread and rescued synaptic/behavioral defects and atrophy in experimental tauopathy systems.", "[64] Human AD insoluble tau induced host-tau pathology in mice across Prnp genotypes; tau-null and species-specific antibody comparisons supported recipient tau origin, while PrP genotype did not change seeding/spread.", "[66] Dextran-sulfate-assembled full-length tau induced host mouse-tau aggregation and connected-region pathology in nontransgenic mice after intracerebral injection." ], "what_would_cross_it": "Direct native donor–recipient lineage conversion at physiological expression, with substrate-selective loss and matched rescue, would extend imposed-seed capability to the registered disease mechanism." }, { "subclaim_id": "SC2", "threshold": "Δ", "requirement_quoted": "Requires at least one genuine causal perturbation in a disease-relevant in vivo system, or equivalent human natural experiment that materially supports the mechanism.", "satisfied": "no", "supporting_evidence": [ "[1] Gut PFF injection produces staged brain pathology, dopaminergic loss and motor deficits; vagotomy and SNCA absence prevent the cascade.", "[2] Isogenic LRP1 loss reduces monomer/oligomer uptake more than PFF uptake; neuronal Lrp1 deletion reduces AAV-traced spread.", "[7] Genetically affected and isogenic neurons show glucosylceramide-linked ectosome release; GCase inhibition increases vesicle traffic and alpha-synuclein pathology in mouse brains.", "[8] Neuronal LAG3 loss lowers tau PFF internalization, subsequent pathology and behavioral deficits.", "[9] A pan-connexin blocker improves an induced oligodendroglial A53T MSA-C model while increasing oligomer sharing in glia and reducing neuronal burden.", "[10] Worm HSP110 depletion lowers disaggregation, intercellular transmission and alpha-synuclein toxicity.", "[12] Microglial nanotubes remove neuronal tau/alpha-synuclein aggregates and donate healthy mitochondria; mitochondrial inhibition removes neuroprotection.", "[21] Microglial PFF-loaded exosomes seed neurons, drive injected mouse pathology/degeneration and are present in patient CSF; exosome inhibition or depletion lowers model transmission.", "[25] TREM2-mediated microglial PFF uptake and AEP truncation enhance seeding; genetic loss or depletion impedes model pathology.", "[26] LAG3 binding and loss experiments reduce PFF uptake and delay dopaminergic loss and behavioral deficits.", "[32] Perampanel reduces neuronal PFF uptake and model pathology through activity-dependent macropinocytosis.", "[34] Imaging tracks rapid PFF macropinocytosis to lysosomes and some transfer with exosome markers; inhibitors reduce uptake.", "[35] FAM171A2 binds fibrils selectively; neuronal knockdown and bemcentinib reduce uptake and model pathology/neurotoxicity.", "[36] A single PFF injection into wild-type mice precedes connected pathology, ipsilateral dopamine-neuron loss and rotarod/wire-hang deficits; SNCA-null controls lack these lesions.", "[39] Multiple antibody/transcript assays do not detect neuronal LAG3, and LAG3 loss has no A53T survival or seeded-slice pathology effect.", "[47] Neuron-derived alpha-synuclein enters neighboring cells and grafted precursors with inclusion/apoptosis markers; lysosomal failure increases accumulation.", "[49] Microglial depletion and exosome-synthesis inhibition reduced tau propagation in an AAV entorhinal-to-dentate model and changed dentate excitability.", "[50] Arc knockout nearly abolished intercellular transmission in mutant-tau mice while reducing EV tau and increasing intracellular accumulation with modest early toxicity.", "[51] LRP1 knockdown reduced tau uptake in human-derived cells and reduced neuronal tau spread in a mouse model.", "[53] Removing endogenous mouse tau preserved human-P301L transfer to recipient neurons but reduced neurotoxicity in a separate severe-tauopathy model despite similar tangle numbers.", "[59] Entorhinal-restricted P301L expression was followed by human tau in connected neurons lacking detectable transgene, coaggregation with mouse tau, synapse degeneration and EC loss.", "[60] Different human iPSC neuronal subtypes showed distinct susceptibility to identical tau or synuclein seeds; uptake/degradation did not explain the tau differences.", "[61] Bassoon downregulation reduced tau seed-associated pathology and spread and rescued synaptic/behavioral defects and atrophy in experimental tauopathy systems.", "[66] Dextran-sulfate-assembled full-length tau induced host mouse-tau aggregation and connected-region pathology in nontransgenic mice after intracerebral injection." ], "what_would_cross_it": "Trace spontaneously formed donor species into distinguished recipient protein in unforced disease, then selectively interrupt transfer without altering source burden or baseline viability." }, { "subclaim_id": "SC3", "threshold": "Δ", "requirement_quoted": "Requires at least one genuine causal perturbation in a disease-relevant in vivo system, or equivalent human natural experiment that materially supports the mechanism.", "satisfied": "no", "supporting_evidence": [ "[1] Gut PFF injection produces staged brain pathology, dopaminergic loss and motor deficits; vagotomy and SNCA absence prevent the cascade.", "[4] PFFs recruit endogenous alpha-synuclein in primary neurons without overexpression and precede synaptic dysfunction and death.", "[5] GCase loss impairs degradation and promotes aggregation toxicity; alpha-synuclein also inhibits GCase, producing a bidirectional loop.", "[6] GBA1 patient-derived midbrain organoids form seeding-competent fibrils with dopaminergic loss and transmit pathology to control organoids; GCase-pathway drugs lower pathology.", "[8] Neuronal LAG3 loss lowers tau PFF internalization, subsequent pathology and behavioral deficits.", "[9] A pan-connexin blocker improves an induced oligodendroglial A53T MSA-C model while increasing oligomer sharing in glia and reducing neuronal burden.", "[10] Worm HSP110 depletion lowers disaggregation, intercellular transmission and alpha-synuclein toxicity.", "[12] Microglial nanotubes remove neuronal tau/alpha-synuclein aggregates and donate healthy mitochondria; mitochondrial inhibition removes neuroprotection.", "[14] Twenty-person UB-312 phase1 randomization establishes immunogenicity; CSF antibodies occur in 5 of 13 fully dosed recipients and seed reduction in a subset.", "[17] HTRA1 and a protease-inactive mutant remodel PFFs and reduce reporter seeding; treated reaction products reduce primary-neuron p-alpha-synuclein and improve MTT signal.", "[19] Modified alpha-synuclein binds TOM20 and impairs mitochondrial import; modest endogenous knockdown preserves import in an in-vivo model.", "[21] Microglial PFF-loaded exosomes seed neurons, drive injected mouse pathology/degeneration and are present in patient CSF; exosome inhibition or depletion lowers model transmission.", "[23] Isogenic control and SNCA-triplication human neurons show increasing seeding but recovery of mitochondrial function; early fibril exposure raises apoptosis without sustained late seeding toxicity.", "[25] TREM2-mediated microglial PFF uptake and AEP truncation enhance seeding; genetic loss or depletion impedes model pathology.", "[26] LAG3 binding and loss experiments reduce PFF uptake and delay dopaminergic loss and behavioral deficits.", "[27] PASADENA randomizes 316 patients; global MDS-UPDRS and DaT-SPECT endpoints do not show meaningful benefit.", "[29] AMULET treats 61 participants; estimated progression slowing is 19 percent but Bayesian probability 89.4 percent misses the prespecified 97.5 percent threshold.", "[30] SPARK randomizes 357 patients; clinical and DaT-SPECT endpoints are null, and trial stops for futility.", "[32] Perampanel reduces neuronal PFF uptake and model pathology through activity-dependent macropinocytosis.", "[35] FAM171A2 binds fibrils selectively; neuronal knockdown and bemcentinib reduce uptake and model pathology/neurotoxicity.", "[36] A single PFF injection into wild-type mice precedes connected pathology, ipsilateral dopamine-neuron loss and rotarod/wire-hang deficits; SNCA-null controls lack these lesions.", "[37] SNCA ASOs prevent/reverse established PFF pathology and preserve dopaminergic function; human-target ASOs lower NHP CNS alpha-synuclein.", "[38] Endogenous alpha-synuclein levels predict subtype susceptibility; early ASO or glutathione-related rescue protects PFF-vulnerable Math2 neurons.", "[39] Multiple antibody/transcript assays do not detect neuronal LAG3, and LAG3 loss has no A53T survival or seeded-slice pathology effect.", "[40] SPARK biomarker reanalysis finds 93 percent baseline SAA positivity, persistence in 99 percent at week52 and no treatment or progression-linked biomarker effect.", "[41] PADOVA randomizes 586 patients; motor-progression HR 0.84, 95 percent CI 0.69–1.01, p0.066 misses the primary endpoint.", "[42] PrP-null mice resist scrapie whereas host-homologous transgenic reintroduction restores susceptibility.", "[43] Post-invasion neuronal PrP depletion reverses spongiosis and prevents clinical disease despite accumulating extraneuronal PrPSc.", "[44] Neuronal PrP depletion rescues early cognition and electrophysiology before large deposits accumulate.", "[47] Neuron-derived alpha-synuclein enters neighboring cells and grafted precursors with inclusion/apoptosis markers; lysosomal failure increases accumulation.", "[49] Microglial depletion and exosome-synthesis inhibition reduced tau propagation in an AAV entorhinal-to-dentate model and changed dentate excitability.", "[50] Arc knockout nearly abolished intercellular transmission in mutant-tau mice while reducing EV tau and increasing intracellular accumulation with modest early toxicity.", "[53] Removing endogenous mouse tau preserved human-P301L transfer to recipient neurons but reduced neurotoxicity in a separate severe-tauopathy model despite similar tangle numbers.", "[55] Reducing Synaptogyrin-3 rescued mutant-tau synaptic plasticity, memory and synapse loss while neuroinflammation remained elevated.", "[57] LAURIET semorinemab improved ADAS-Cog11 decline at week 49 but not the coprimary activities-of-daily-living endpoint or global secondary measures.", "[59] Entorhinal-restricted P301L expression was followed by human tau in connected neurons lacking detectable transgene, coaggregation with mouse tau, synapse degeneration and EC loss.", "[61] Bassoon downregulation reduced tau seed-associated pathology and spread and rescued synaptic/behavioral defects and atrophy in experimental tauopathy systems." ], "what_would_cross_it": "Post-onset transfer/conversion-specific suppression must alter neuron survival and function, with matched rescue restoring both spread and injury while intracellular toxicity is controlled." }, { "subclaim_id": "SC4", "threshold": "Δ", "requirement_quoted": "Requires at least one genuine causal perturbation in a disease-relevant in vivo system, or equivalent human natural experiment that materially supports the mechanism.", "satisfied": "no", "supporting_evidence": [ "[1] Gut PFF injection produces staged brain pathology, dopaminergic loss and motor deficits; vagotomy and SNCA absence prevent the cascade.", "[5] GCase loss impairs degradation and promotes aggregation toxicity; alpha-synuclein also inhibits GCase, producing a bidirectional loop.", "[6] GBA1 patient-derived midbrain organoids form seeding-competent fibrils with dopaminergic loss and transmit pathology to control organoids; GCase-pathway drugs lower pathology.", "[7] Genetically affected and isogenic neurons show glucosylceramide-linked ectosome release; GCase inhibition increases vesicle traffic and alpha-synuclein pathology in mouse brains.", "[9] A pan-connexin blocker improves an induced oligodendroglial A53T MSA-C model while increasing oligomer sharing in glia and reducing neuronal burden.", "[14] Twenty-person UB-312 phase1 randomization establishes immunogenicity; CSF antibodies occur in 5 of 13 fully dosed recipients and seed reduction in a subset.", "[27] PASADENA randomizes 316 patients; global MDS-UPDRS and DaT-SPECT endpoints do not show meaningful benefit.", "[29] AMULET treats 61 participants; estimated progression slowing is 19 percent but Bayesian probability 89.4 percent misses the prespecified 97.5 percent threshold.", "[30] SPARK randomizes 357 patients; clinical and DaT-SPECT endpoints are null, and trial stops for futility.", "[38] Endogenous alpha-synuclein levels predict subtype susceptibility; early ASO or glutathione-related rescue protects PFF-vulnerable Math2 neurons.", "[39] Multiple antibody/transcript assays do not detect neuronal LAG3, and LAG3 loss has no A53T survival or seeded-slice pathology effect.", "[40] SPARK biomarker reanalysis finds 93 percent baseline SAA positivity, persistence in 99 percent at week52 and no treatment or progression-linked biomarker effect.", "[41] PADOVA randomizes 586 patients; motor-progression HR 0.84, 95 percent CI 0.69–1.01, p0.066 misses the primary endpoint." ], "what_would_cross_it": "Replicate causal mediation across prospectively defined tauopathy and synucleinopathy subtypes, strains and stages, with human mechanism-sensitive clinical or genetic convergence." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "Monomer/PBS, contralateral hemisphere and VTA controls in wild-type PFF mice.", "SNCA-null recipients and host tau-specific antibodies.", "Vagotomy systemic/DMV injury measured alongside protection.", "LAG3 antibody species controls and activated-T-cell positive controls.", "LAG3-null survival and seeded-slice negative results.", "Acute fibril apoptosis versus later seeding with recovery.", "Protective glial sharing and nanotube clearance.", "Arc transfer loss with modest early toxicity increase.", "Clinical primary endpoint versus exploratory/external-comparator signals." ], "note": "Evidence covers tau and alpha-synuclein, amyloid versus pure tau, PD versus MSA, native versus recombinant structures, human recipients, wild-type and sensitized hosts, and clinical interventions. Host substrate necessity after inoculation is not spontaneous origin. Prion-like templating is not a claim of ordinary human contagiousness. Native disease-class mediation remains the unclosed gate." }, "falsification_patterns_met": [ { "pattern": "Transfer and toxicity do not map one to one", "evidence": "Arc loss, human-neuron adaptation and protective glial sharing dissociate transfer/seeding from injury.", "downgrade_applied": false }, { "pattern": "One proposed receptor is not universally required", "evidence": "LAG3 absence/expression controls and null survival/slice results challenge a broad neuronal LAG3 account.", "downgrade_applied": false }, { "pattern": "Clinical strategy outcomes are not confirmed progression benefit", "evidence": "SPARK, PASADENA, PADOVA and AMULET miss primary endpoints; LAURIET has a real cognitive signal with negative functional/global outcomes.", "downgrade_applied": false } ], "pitfalls_flagged": [ { "pitfall": "PrP causality imported into non-PrP disease", "where": "Comparator knockout/depletion versus nominal tau/alpha-synuclein." }, { "pitfall": "Protein cargo transfer equated with recipient templating", "where": "Grafts, axonal tracking and tau-null systems." }, { "pitfall": "Primary clinical failure called complete seed-blockade falsification", "where": "Human CNS species/compartment engagement remains incomplete." }, { "pitfall": "Provider year-filter or empty cells used as systematic gap proof", "where": "Initial Consensus incorrectly selected only 2026; its matrices contradict some extracted controls." }, { "pitfall": "All disaggregation called harmless", "where": "HSP70/HSP110 can release toxic species; HTRA1 has distinct reaction arms and assays." } ], "causal_tally_audit": { "tally_claimed_by_document": 47, "tally_after_audit": 47, "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/Ε case combines wild-type host conversion with gut/vagal interruption, receptor loss, source restriction and neuroprotection. The physiological host and original neuronal counts deserve full weight. Yet global substrate loss, vagotomy injury, receptor pleiotropy and imposed seed initiation leave natural propagation-specific mediation unisolated; tau Arc and clinical contrasts prevent assuming a shared universal driver.", "case_one_rung_lower": "The strongest Β case calls the literature only postmortem staging and metaphor. Direct axonal transfer, host-origin conversion, temporal neuronal-loss cascades and route perturbations exceed static association. Γ preserves these experimental capabilities without upgrading them to demonstrated broad endogenous necessity.", "which_rejected": "Reject Β for the actual mechanistic/temporal evidence and reject Δ for the unclosed full-scope selective mediator gate. Stronger PrP and narrowly defined substrate or vulnerability claims are acknowledged separately.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: In independently generated spontaneous tau and alpha-synuclein disease systems with physiological donor/recipient substrate, interrupt a selective transfer or recipient-conversion step after onset and restore it with matched rescue." }, "final_score": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "66 primary reports with 9 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "The weakest-link conjunction returns Γ. Physiological host substrate can be recruited after imposed seeds, and source-restricted transfer and receptor perturbations demonstrate substantial capabilities. Selective blockade of spontaneous propagation has not established progression necessity in both disease families. Canonical PrP loss/rescue is stronger comparator evidence and is not transferred to the nominal tau/alpha-synuclein claim. Host state, compartment and intracellular toxicity constrain a universal spread-driven account." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": 5, "derivation": "Transfer and templating can amplify pathology in specified systems. Selective natural degeneration necessity and rate limitation across both families remain unresolved, so the broad role is conditional reinforcement. Clearance transfer may protect; physiological substrate recruitment after an imposed seed does not establish spontaneous initiation.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "Completed PADOVA/AMULET primary reports and recent ectosome, Arc and human-neuron experiments refine progression and host-state boundaries. Phase3 programs are mentioned by trial authors but fresh registry status is not independently checked here.", "justification": "Completed PADOVA/AMULET primary reports and recent ectosome, Arc and human-neuron experiments refine progression and host-state boundaries. Phase3 programs are mentioned by trial authors but fresh registry status is not independently checked here." }, "stability": { "value": "Stable", "trigger": "No verified pending study is asserted as an imminent score-changing result.", "justification": "No verified pending study is asserted as an imminent score-changing result." }, "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": "In independently generated spontaneous tau and alpha-synuclein disease systems with physiological donor/recipient substrate, interrupt a selective transfer or recipient-conversion step after onset and restore it with matched rescue.", "readout": "Direct donor–recipient lineage, recipient conversion, regional pathology, blinded neuron survival and functional trajectory", "critical_control": "Source protein load, host physiology, intracellular toxicity, clearance and peripheral/glial responses", "supporting_result": "Verified selective suppression slows recipient conversion and subsequent neuron loss; matched rescue reinstates both in each prespecified system", "falsifying_result": "Verified selective suppression leaves progression unchanged or increases intracellular injury despite less transfer" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Identify native transmitted species and precursor–product conversion independently of uptake or pSer129 staining.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Test spontaneous donor–recipient transfer at physiological expression, without forced PFF entry or pan-neuronal mutant expression.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Develop selective post-onset transfer loss/rescue with matched source load, intracellular toxicity and clearance.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Resolve receptor expression and assay specificity independently across neuronal subtypes; retain LAG3 conflicting results.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Verify actual pathogenic species/compartment blockade in humans before interpreting negative clinical antibodies as propagation elimination.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 6", "statement": "Map strain, neuronal subtype, glial compartment and disease stage prospectively; transfer can be pathogenic, neutral or protective.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-06", "reviewer": "Codex", "evidence_base_note": "66 primary reports; literature cutoff 2026-10-06; source examination UTC date 2026-10-06; bounded critical review, not exhaustive systematic review.", "literature_tools_available": true, "literature_tools_note": "Life Sciences Literature PubMed/Entrez; attempted Europe PMC XML and successful public NCBI PMC direct HTTPS access are separately logged. Signed-in Consensus browser discovery and targeted indexed full-text checks are reconciled with original sections; failed matches and source substitutions remain explicit. Zero Consensus API calls.", "skill_version": "5.3", "validator_run": "exact archived v5.3 validator 2.3; see validator.txt", "validator_warnings_addressed": "Phenomenon entry was restated as the preregistered causal claim. No real phenomenon is labelled refuted; warning is explicitly justified.", "consensus_consistency_audit": "2026-10-09; supplementary provenance/source reconciliation; original grading retained; prior grades visible." }, "is_calibration_entry": { "value": false, "entry_role": "not_calibration", "blind_graded": null, "completed_blinded_calibration": false, "expected_band_sealed_at": "", "target_sha256": "", "target_authorship": "not applicable", "target_author_saw_review": null, "future_run_status": "not prepared", "unblinded_reason": "Ranking categorical verdict and index guidance were visible. No completed blinded calibration claimed." }, "upper_ladder_check": { "final_level_below_zeta": true, "equivalents_considered": [ { "kind": "mendelian_randomization", "available": false, "why_not_sufficient": "Familial SNCA evidence, human graft observations, clinical anti-tau/anti-alpha-synuclein trials and natural host-state contrasts were considered. They respectively establish protein relevance, natural pathological transfer leads or tested-strategy outcomes, not a common selective propagation mediator. Randomized efficacy is not an obligatory unique gate, but the assembled equivalents do not demonstrate broad natural progression necessity. Canonical PrP evidence has much stronger causal specificity within its own separate scope." }, { "kind": "natural_experiment", "available": true, "why_not_sufficient": "Familial SNCA evidence, human graft observations, clinical anti-tau/anti-alpha-synuclein trials and natural host-state contrasts were considered. They respectively establish protein relevance, natural pathological transfer leads or tested-strategy outcomes, not a common selective propagation mediator. Randomized efficacy is not an obligatory unique gate, but the assembled equivalents do not demonstrate broad natural progression necessity. Canonical PrP evidence has much stronger causal specificity within its own separate scope." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "Familial SNCA evidence, human graft observations, clinical anti-tau/anti-alpha-synuclein trials and natural host-state contrasts were considered. They respectively establish protein relevance, natural pathological transfer leads or tested-strategy outcomes, not a common selective propagation mediator. Randomized efficacy is not an obligatory unique gate, but the assembled equivalents do not demonstrate broad natural progression necessity. Canonical PrP evidence has much stronger causal specificity within its own separate scope." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Familial SNCA evidence, human graft observations, clinical anti-tau/anti-alpha-synuclein trials and natural host-state contrasts were considered. They respectively establish protein relevance, natural pathological transfer leads or tested-strategy outcomes, not a common selective propagation mediator. Randomized efficacy is not an obligatory unique gate, but the assembled equivalents do not demonstrate broad natural progression necessity. Canonical PrP evidence has much stronger causal specificity within its own separate scope." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": true, "why_not_sufficient": "Familial SNCA evidence, human graft observations, clinical anti-tau/anti-alpha-synuclein trials and natural host-state contrasts were considered. They respectively establish protein relevance, natural pathological transfer leads or tested-strategy outcomes, not a common selective propagation mediator. Randomized efficacy is not an obligatory unique gate, but the assembled equivalents do not demonstrate broad natural progression necessity. Canonical PrP evidence has much stronger causal specificity within its own separate scope." } ], "convergence_present": true, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 66, "claims_total": 71, "claims_verified": 71, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 66, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "Gut PFF injection produces staged brain pathology, dopaminergic loss and motor deficits; vagotomy and SNCA absence prevent the cascade. Forced gut inoculation and global substrate removal do not identify spontaneous origin. Original Results verify TH plus Nissl stereology; vagotomy also removes 65 percent of DMV ChAT-positive cells and alters ghrelin, intake and gut function, so it is not a transfer-only block.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3", "SC4" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph1, 1:RESULTS:paragraph2, 1:RESULTS:paragraph3. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C2", "text": "Isogenic LRP1 loss reduces monomer/oligomer uptake more than PFF uptake; neuronal Lrp1 deletion reduces AAV-traced spread. LRP1 is pleiotropic; transferred AAV-expressed protein, templated conversion and neuron-loss mediation are distinct. No survival/function rescue is credited.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C3", "text": "A 37-person de novo PD and 22-person iRBD imaging study shows patterns compatible with brain-first and body-first trajectories. Cross-sectional group ordering and denervation signals do not directly observe molecular transfer or establish either origin in an individual.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C4", "text": "PFFs recruit endogenous alpha-synuclein in primary neurons without overexpression and precede synaptic dysfunction and death. Exogenous entry and culture timing constrain physiological organismal spread necessity; correlated inclusion formation does not isolate the lethal intermediate.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C5", "text": "GCase loss impairs degradation and promotes aggregation toxicity; alpha-synuclein also inhibits GCase, producing a bidirectional loop. The self-propagating loop is intracellular proteostasis feedback, not proof of obligatory intercellular templating in sporadic PD.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "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": "GBA1 patient-derived midbrain organoids form seeding-competent fibrils with dopaminergic loss and transmit pathology to control organoids; GCase-pathway drugs lower pathology. Organoid toxicity and genetic-risk background lack organismal follow-through; pathology lowering is not verified clinical rescue or selective spread mediation.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C7", "text": "Genetically affected and isogenic neurons show glucosylceramide-linked ectosome release; GCase inhibition increases vesicle traffic and alpha-synuclein pathology in mouse brains. Lipid and lysosomal changes affect donor production and recipient health; a major-route claim does not establish natural disease necessity or neuronal survival mediation.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "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": "Neuronal LAG3 loss lowers tau PFF internalization, subsequent pathology and behavioral deficits. Imposed PFF initiation and receptor-expression controversy constrain scope; neuronal LAG3 and broad immune effects require independent confirmation. UpdateOf links a preprint.", "carries_number": true, "load_bearing_for": [ "SC2", "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": "A pan-connexin blocker improves an induced oligodendroglial A53T MSA-C model while increasing oligomer sharing in glia and reducing neuronal burden. Sharing can protect in this defined compartment; broad connexin effects, induced overexpression and absent transfer-only rescue prevent universal conclusions. Oligomers rarely colocalize with p-alpha-synuclein.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "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": "Worm HSP110 depletion lowers disaggregation, intercellular transmission and alpha-synuclein toxicity. Overall folding capacity is also impaired; a proteostasis-wide perturbation does not isolate transfer as the mediator or establish mammalian generality.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C11", "text": "Three inoculation sites produce distinct connected-region pathology and recovered insoluble material reseeds wild-type brains. Imposed seeds, host pathology and serial transfer are capabilities; direct molecular lineage and natural neuronal-loss dependency remain unresolved.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "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": "Microglial nanotubes remove neuronal tau/alpha-synuclein aggregates and donate healthy mitochondria; mitochondrial inhibition removes neuroprotection. Protective exchange contrasts with transfer-as-injury, but culture rescue does not establish its dominance in native disease.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C13", "text": "Human neuronal–microglial nanotubes transfer alpha-synuclein predominantly to microglia and mitochondria to burdened neurons. Observed movement is not necessarily recipient templating; the protective interpretation lacks an organismal progression test.", "carries_number": false, "load_bearing_for": [ "SC2", "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": "Twenty-person UB-312 phase1 randomization establishes immunogenicity; CSF antibodies occur in 5 of 13 fully dosed recipients and seed reduction in a subset. Safety/antibody primary endpoints and exploratory seed effects do not demonstrate clinical benefit, selective spread blockade or an unbiased responding subgroup effect; clinical scales do not differ.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C15", "text": "A seeded neuronal model links later organelle-rich Lewy-body maturation to mitochondrial and synaptic dysfunction beyond early fibrillization. The integrated maturation process may mediate injury; culture correlations and forced seeding do not establish selective intercellular transfer necessity.", "carries_number": false, "load_bearing_for": [ "SC1", "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": "Across 1631 participants, faster SAA kinetics predict cognitive decline in independent PD cohort analyses, including an AD-biomarker-negative subset. SAA is an in-vitro amplification readout, not physical spread rate; it does not establish motor/neuron-loss mediation. PPMI participants overlap other analyses.", "carries_number": true, "load_bearing_for": [ "SC4" ], "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": "HTRA1 and a protease-inactive mutant remodel PFFs and reduce reporter seeding; treated reaction products reduce primary-neuron p-alpha-synuclein and improve MTT signal. Original Results show mature-PFF reporter seeding decreases about 30–40 percent rather than absolute eradication. MTT at 24 hours precedes one-week inclusion assessment, so selective seeding mediation of survival is not proved; different formation/remodeling arms are kept separate.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph17, 1:Results:paragraph26, 1:Results:paragraph28. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C18", "text": "CSF PMCA products discriminate PD and MSA with distinct biochemical/biological properties. Amplification may select conformers; product identity and clinical diagnosis do not prove faithful in-vivo strain transfer or progressive neurotoxicity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "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": "Modified alpha-synuclein binds TOM20 and impairs mitochondrial import; modest endogenous knockdown preserves import in an in-vivo model. Intrinsic mitochondrial toxicity does not require spread; postmortem concordance and import rescue do not establish complete human neuron-survival mediation.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C20", "text": "Cryo-EM shows distinct native MSA filaments and differences from DLB and recombinant structures. Structure is not a transmission/necessity experiment. A linked correction exists; its details have not been examined, so fine structural claims are qualified.", "carries_number": false, "load_bearing_for": [ "SC1", "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": "Microglial PFF-loaded exosomes seed neurons, drive injected mouse pathology/degeneration and are present in patient CSF; exosome inhibition or depletion lowers model transmission. Forced microglial cargo loading/injection, broad depletion, inflammation and autophagy effects do not isolate spontaneous spread-to-injury mediation.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C22", "text": "Fourteen MSA brain extracts transmit disease to sensitized hemizygous A53T mice and reporter cells; six PD extracts do not in that assay. Host mutation and assay selectivity limit generalization; natural human transmissibility and common sporadic PD mechanisms are not established. Correction details remain unexamined.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3", "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": "Isogenic control and SNCA-triplication human neurons show increasing seeding but recovery of mitochondrial function; early fibril exposure raises apoptosis without sustained late seeding toxicity. Original Results confirm early day1/3 caspase activation returns toward baseline by days14/21, no seeding-associated necrosis, and no 25-day respiration change from PFFs. Cultured cortical neurons, a particular fibril preparation and survival/adaptation cannot generalize to all seeds or nigral disease.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph2, 2:Results:paragraph9, 2:Results:paragraph12, 2:Results:paragraph22, 2:Results:paragraph25. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C24", "text": "PPN PFF pathology follows afferent connections but kinetics, magnitude and persistence are not proportional to connection strength; neuronal phenotype matters. Connectome restriction and cell-specific susceptibility coexist; imposed seeds do not identify unforced native transfer or natural onset.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "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": "TREM2-mediated microglial PFF uptake and AEP truncation enhance seeding; genetic loss or depletion impedes model pathology. Clearance, inflammatory and substrate-processing changes accompany spread reduction; no audited functional neuronal-loss rescue is credited from the abstract.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "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": "LAG3 binding and loss experiments reduce PFF uptake and delay dopaminergic loss and behavioral deficits. PFF initiation and broad receptor/immune effects limit necessity inference; a later independent expression and survival-null study challenges universal neuronal-receptor attribution.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "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": "PASADENA randomizes 316 patients; global MDS-UPDRS and DaT-SPECT endpoints do not show meaningful benefit. Motor-secondary signals do not reverse the primary conclusion; epitope occupancy or plasma binding does not verify blockade of the pathogenic interstitial species. Null is strategy-specific.", "carries_number": true, "load_bearing_for": [ "SC3", "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": "PASADENA open-label extension has slower motor worsening than a PPMI external comparator over four years. This is exploratory nonrandomized follow-up of the same trial, with external-comparator and retention confounding; not an independent randomized efficacy replication.", "carries_number": false, "load_bearing_for": [ "SC3", "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": "AMULET treats 61 participants; estimated progression slowing is 19 percent but Bayesian probability 89.4 percent misses the prespecified 97.5 percent threshold. Primary endpoint is not met; an uncertain signal and acceptable safety justify further tests, not proof of propagation mediation. Full original body unavailable here.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C30", "text": "SPARK randomizes 357 patients; clinical and DaT-SPECT endpoints are null, and trial stops for futility. The tested extracellular antibody strategy fails; this does not demonstrate universal elimination of pathogenic seeds or refute all intracellular alpha-synuclein biology.", "carries_number": true, "load_bearing_for": [ "SC3", "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": "Oligodendrocytes take up extracellular alpha-synuclein and grafted rat oligodendroglia contain host-neuronal AAV-expressed human protein. Transfer of donor protein is not obligatory endogenous recipient conversion; forced source expression and graft environment limit native MSA interpretation.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C32", "text": "Perampanel reduces neuronal PFF uptake and model pathology through activity-dependent macropinocytosis. AMPA activity affects physiology and multiple toxic processes; no clinical or audited neuron-survival rescue and no transfer-only intervention are established.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "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": "Inoculated wild-type marmosets develop connected-region Lewy-like inclusions and fewer ipsilateral TH-positive neurons at three months. Forced seeds remain; TH-positive counts alone may reflect marker loss without additional stereological identity checks; no full neuronal-loss/function audit was available.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C34", "text": "Imaging tracks rapid PFF macropinocytosis to lysosomes and some transfer with exosome markers; inhibitors reduce uptake. Lysosomal uptake/transport does not demonstrate cytosolic recipient conversion, spontaneous spread or degeneration necessity.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C35", "text": "FAM171A2 binds fibrils selectively; neuronal knockdown and bemcentinib reduce uptake and model pathology/neurotoxicity. Risk-gene association and binding do not identify the full human mediator. Drug pleiotropy, model initiation and matched rescue details remain abstract-only.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "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": "A single PFF injection into wild-type mice precedes connected pathology, ipsilateral dopamine-neuron loss and rotarod/wire-hang deficits; SNCA-null controls lack these lesions. Original main text confirms 15 and 35 percent ipsilateral loss at 90/180 days, with monomer/PBS, contralateral and VTA controls. Global substrate absence also removes intrinsic toxicity; imposed initiation does not prove natural spread necessity. Open-field activity and Y-maze are unchanged.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Main text:paragraph2, 1:Main text:paragraph3, 1:Main text:paragraph6, 1:Main text:paragraph8. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C37", "text": "SNCA ASOs prevent/reverse established PFF pathology and preserve dopaminergic function; human-target ASOs lower NHP CNS alpha-synuclein. Global synthesis lowering changes intrinsic substrate and toxicity, not selectively transfer; NHP distribution/CSF engagement is not demonstrated disease efficacy.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "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": "Endogenous alpha-synuclein levels predict subtype susceptibility; early ASO or glutathione-related rescue protects PFF-vulnerable Math2 neurons. Late pathology reduction lacks comparable protection, revealing stage thresholds; substrate reduction and redox rescue are not transfer-only tests.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "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": "Multiple antibody/transcript assays do not detect neuronal LAG3, and LAG3 loss has no A53T survival or seeded-slice pathology effect. Original Results verify species-specific antibody controls, activated-T-cell positive controls, human snRNAseq, small genotype survival groups and seeded wild-type/A53T slice nulls. A null proposed receptor does not eliminate alternative uptake routes or all propagation.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph12, 1:Results:paragraph20, 1:Results:paragraph60, 1:Results:paragraph67. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C40", "text": "SPARK biomarker reanalysis finds 93 percent baseline SAA positivity, persistence in 99 percent at week52 and no treatment or progression-linked biomarker effect. Same 357-person trial; no new randomization. Persistent SAA and absent biomarker effect weaken a claim that cinpanemab verified complete seed blockade.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4" ], "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": "PADOVA randomizes 586 patients; motor-progression HR 0.84, 95 percent CI 0.69–1.01, p0.066 misses the primary endpoint. Exploratory clinical-activity signals merit follow-up but are not confirmatory efficacy. Actual pathogenic extracellular spread blockade is not demonstrated in this abstract; linked correction details remain unexamined.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C42", "text": "PrP-null mice resist scrapie whereas host-homologous transgenic reintroduction restores susceptibility. Canonical PrP substrate dependence is a comparator only; it cannot establish the same mechanism or natural transmission in tau/alpha-synuclein diseases.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C43", "text": "Post-invasion neuronal PrP depletion reverses spongiosis and prevents clinical disease despite accumulating extraneuronal PrPSc. Neuron-specific conversion dependence is stronger than aggregate presence; nonneuronal propagation can be nonpathogenic. Neither PrP result is interchangeable with tau or alpha-synuclein necessity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C44", "text": "Neuronal PrP depletion rescues early cognition and electrophysiology before large deposits accumulate. Same conditional PrP platform as the earlier depletion study; functional rescue does not demonstrate non-PrP disease mechanisms.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 44 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C45", "text": "A segregating SNCA mutation occurs in an Italian kindred and three unrelated Greek families with dominant PD. Inherited gene causality supports protein relevance, not selective propagation mediation or direct generalization to sporadic disease.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C46", "text": "Fourteen-year-old human nigral grafts have Lewy-like alpha-synuclein/ubiquitin inclusions and reduced DAT staining. A natural host-to-graft lead, but graft stress, shared milieu and de-novo aggregation remain alternatives; donor–recipient protein lineage and lethal templating were not directly measured.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "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": "Neuron-derived alpha-synuclein enters neighboring cells and grafted precursors with inclusion/apoptosis markers; lysosomal failure increases accumulation. Transgenic source and apoptosis markers do not identify a physiological templated, transfer-specific degeneration dependency. Linked erratum has no PMID supplied and remains unresolved.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C48", "text": "Microfluidic imaging tracks fibrils along axons into second-order neurons; transfer does not appear to require synapses. Physical cargo transfer under imposed exposure is not recipient endogenous conversion or organismal neuron-loss mediation.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C49", "text": "Microglial depletion and exosome-synthesis inhibition reduced tau propagation in an AAV entorhinal-to-dentate model and changed dentate excitability. AAV expression and broad microglial/exosome effects do not isolate spontaneous tau templating as the mediator of neuron death. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "carries_number": false, "load_bearing_for": [ "SC2", "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": "Arc knockout nearly abolished intercellular transmission in mutant-tau mice while reducing EV tau and increasing intracellular accumulation with modest early toxicity. Transmission reduction did not yield uniform neuroprotection; developmental Arc functions and mutant transgenic expression complicate selective spread mediation. UpdateOf links the preceding version, not a separate replication. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C51", "text": "LRP1 knockdown reduced tau uptake in human-derived cells and reduced neuronal tau spread in a mouse model. Receptor uptake is not identical to recipient conversion; LRP1 has broader trafficking functions and the abstract does not establish neuronal-loss prevention. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "carries_number": true, "load_bearing_for": [ "SC2" ], "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": "Cell-derived tau conformations retained strain-like characteristics across three inoculated transgenic-mouse generations and patient-derived biosensor isolates differed by tauopathy. Repeat-domain reporters and imposed serial inoculation establish templating capability, not natural human intercellular disease causation or infectivity equivalence to PrP. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C53", "text": "Removing endogenous mouse tau preserved human-P301L transfer to recipient neurons but reduced neurotoxicity in a separate severe-tauopathy model despite similar tangle numbers. Donor-protein movement can occur without host templating, and tangle burden can dissociate from toxicity; human transgenes and tau-null physiology limit natural disease generalization. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "carries_number": true, "load_bearing_for": [ "SC2", "SC1", "SC3" ], "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": "A mouse-tau-specific antibody reduced human AD-tau-seeded pathology in female wild-type mice despite not binding the human inoculum. This narrows recipient-substrate involvement but still begins with imposed seeds; the abstract infers intraneuronal elongation and does not establish selective spread-mediated neuron survival. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "carries_number": false, "load_bearing_for": [ "SC1" ], "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": "Reducing Synaptogyrin-3 rescued mutant-tau synaptic plasticity, memory and synapse loss while neuroinflammation remained elevated. The contrast identifies synaptic toxicity independent of persistent glial activation; it does not directly test pathological species transfer. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C56", "text": "TANGO randomized 654 early-AD participants and showed no favorable cognitive/functional CDR-SB change with gosuranemab despite reduced unbound N-terminal CSF tau. Safety was primary and clinical efficacy secondary; drug engagement of a soluble N-terminal pool does not demonstrate selective blockade of all tau propagation. Original Results confirm 80.1–92.6 percent unbound N-terminal CSF tau reduction, no tau-PET dose response and no favorable atrophy response. An isolated exploratory cognitive result was worse, without a dose response; it is not treated as a definitive toxicity test. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph19, 1:Results:paragraph23, 1:Results:paragraph28, 1:Results:paragraph33, 1:Results:paragraph38. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C57", "text": "LAURIET semorinemab improved ADAS-Cog11 decline at week 49 but not the coprimary activities-of-daily-living endpoint or global secondary measures. The prespecified coprimary trial result was negative; isolated cognitive benefit is credited without being relabeled overall efficacy or propagation-mediated neuroprotection. Original Results confirm a 2.89-point ADAS-Cog11 difference at week 49, with the largest post hoc item effect in word recognition. CSF tau fell but PET accumulation and atrophy rates did not differ. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph8, 2:Results:paragraph15, 2:Results:paragraph17, 2:Results:paragraph19, 2:Results:paragraph20. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C58", "text": "Mutant-P301S brain extract induced filament assembly of wild-type human tau and regional pathology in inoculated transgenic recipients. The recipients express human tau and receive artificial intracerebral exposure; capability is not natural cell-to-cell necessity or neurodegeneration mediation. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "carries_number": true, "load_bearing_for": [ "SC1" ], "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": "Entorhinal-restricted P301L expression was followed by human tau in connected neurons lacking detectable transgene, coaggregation with mouse tau, synapse degeneration and EC loss. Low-level expression detection and source-cell deafferentation complicate inference; mutant overexpression does not isolate selective endogenous templating. Linked erratum details are unexamined. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "carries_number": true, "load_bearing_for": [ "SC2", "SC1", "SC3" ], "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": "Different human iPSC neuronal subtypes showed distinct susceptibility to identical tau or synuclein seeds; uptake/degradation did not explain the tau differences. This supports intrinsic vulnerability as a contributor to regional patterns; imposed aggregates and cultured neurons do not establish the full human progression mechanism. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "carries_number": false, "load_bearing_for": [ "SC2", "SC1" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C61", "text": "Bassoon downregulation reduced tau seed-associated pathology and spread and rescued synaptic/behavioral defects and atrophy in experimental tauopathy systems. Bassoon regulates presynaptic function and seed stability as well as transport; matching source toxicity and selective recipient conversion remains essential to propagation mediation. Original Results show unchanged total human tau after preventive P0 Bassoon shRNA, and source GFP controls in the separate AAV transfer arm. These controls strengthen seed-mediated contribution but do not make presynaptic Bassoon a transfer-only intervention. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "carries_number": false, "load_bearing_for": [ "SC2", "SC1", "SC3" ], "source_ns": [ 61 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph21, 1:Results:paragraph26, 1:Results:paragraph33, 1:Results:paragraph36, 1:Results:paragraph44. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C62", "text": "Whole-brain age-series maps of pan-neuronal P301S PS19 mice fitted retrograde-biased connectivity models without injected seeds. Spontaneous pathology is valuable but still occurs with widespread mutant human tau expression; modeled phospho-tau progression is not directly traced protein transfer or selective spread blockade. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "carries_number": true, "load_bearing_for": [ "SC2" ], "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": "Kinetic fits across multiple human seed/tau measures suggested local replication, rather than interregional spread, limits neocortical accumulation from Braak III onward. The inferred approximately five-year seed doubling is model-dependent and stage-specific; it does not show early seeding is irrelevant or experimentally identify a clinical rate-limiting mediator. Original Results explicitly subsume local cell-to-cell transfer into the replication term. The contrast concerns interregional spread, not all transfer; extrapolation before Braak III is untested. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 63 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph3, 1:RESULTS:paragraph4, 1:RESULTS:paragraph5, 1:RESULTS:paragraph13, 1:RESULTS:paragraph14, 1:RESULTS:paragraph15, 1:RESULTS:paragraph16, 1:RESULTS:paragraph17. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C64", "text": "Human AD insoluble tau induced host-tau pathology in mice across Prnp genotypes; tau-null and species-specific antibody comparisons supported recipient tau origin, while PrP genotype did not change seeding/spread. Forced inoculation establishes host conversion capability and excludes an obligatory PrP receptor in this setting, not natural human tau propagation necessity. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 64 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C65", "text": "Entorhinal-biased human-tau transgenic mice developed human tau staining and mature pathology in connected hippocampal and cortical regions with age. Distribution and expression restriction support transfer but do not directly visualize a precursor-product lineage or separate low-level transgene expression from recipient conversion. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 65 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C66", "text": "Dextran-sulfate-assembled full-length tau induced host mouse-tau aggregation and connected-region pathology in nontransgenic mice after intracerebral injection. This removes a recipient overexpression requirement but retains artificial seed creation and forced entry; it is not observation of spontaneous human transmission. Reappraised for the tau-and-alpha-synuclein conjunction; prior single-protein body checks are reusable source evidence, not an independent replication.", "carries_number": false, "load_bearing_for": [ "SC2", "SC1" ], "source_ns": [ 66 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "CSC1", "text": "Wild-type neuronal and animal recipients recruit host tau or alpha-synuclein, with species-specific antibody and SNCA-null controls. This is important physiological-substrate capability after forced entry. For the disease-relevant conversion mechanism, positive evidence remains dominated by imposed seeds or engineered sources, triggering the exogenous-seeding-alone ceiling; no claim is made that conversion never occurs.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 1, 4, 6, 11, 15, 17, 18, 20, 22, 23, 33, 36, 37, 38, 42, 43, 52, 53, 54, 58, 59, 60, 61, 64, 66 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-06", "note": "" }, { "id": "CSC2", "text": "Human graft pathology, donor-restricted animal protein and endogenous lipid/Arc perturbations strengthen physical transfer. Native molecular lineage in unforced disease remains incompletely distinguished from source overexpression, local generation and correlated vulnerability. PS19 spontaneous pathology retains widespread mutant expression.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 1, 2, 3, 7, 8, 9, 10, 11, 12, 13, 21, 24, 25, 26, 31, 32, 33, 34, 35, 36, 39, 46, 47, 48, 49, 50, 51, 53, 59, 60, 61, 62, 63, 65, 66 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-06", "note": "" }, { "id": "CSC3", "text": "Gut route interruption and receptor/source perturbations couple transmission to injury in models, but also alter substrate, immunity, physiology or initial insult. Arc, human-neuron seeding adaptation and protective glial sharing separate transfer from toxicity. Clinical strategies are null or mixed, without verified universal pathogenic seed blockade.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 1, 4, 5, 6, 8, 9, 10, 12, 13, 14, 15, 17, 19, 21, 22, 23, 25, 26, 27, 28, 29, 30, 32, 33, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 47, 49, 50, 53, 55, 56, 57, 59, 61, 63 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-06", "note": "" }, { "id": "CSC4", "text": "Tau/alpha-synuclein strains, native filament structures, recipient phenotypes and clinical responses vary. MSA transmission to sensitized A53T mice does not establish ordinary PD transmission or human contagiousness. SAA kinetics predict some cognitive outcomes but do not measure physical spread. Disease-class progression beyond imposed initiation remains Γ.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 1, 3, 5, 6, 7, 9, 14, 16, 18, 20, 22, 24, 27, 28, 29, 30, 38, 39, 40, 41, 45, 46 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-06", "note": "" }, { "id": "CH", "text": "Tau and alpha-synuclein transfer and seed host protein in experiments; a selective natural propagation-to-neuronal-loss dependency is unresolved.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 36, 1, 66, 50, 23, 41 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-06", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Kim S, Kwon SH, Kam TI et al. Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson's Disease. Neuron. 2019.", "tier": "A", "kind": "primary", "pmid": "31255487", "doi": "10.1016/j.neuron.2019.05.035", "url": "https://pubmed.ncbi.nlm.nih.gov/31255487/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID31255487", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph1, 1:RESULTS:paragraph2, 1:RESULTS:paragraph3. No complete-paper or supplement audit claimed.", "carries_claims": [ "C1", "CSC1", "CSC2", "CSC3", "CSC4", "CH" ] }, { "n": 2, "citation": "Chen K, Martens YA, Meneses A et al. LRP1 is a neuronal receptor for α-synuclein uptake and spread. 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Nature medicine. 2024.", "tier": "A", "kind": "rct", "pmid": "38902546", "doi": "10.1038/s41591-024-03101-8", "url": "https://pubmed.ncbi.nlm.nih.gov/38902546/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID38902546", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C14", "CSC3", "CSC4" ] }, { "n": 15, "citation": "Mahul-Mellier AL, Burtscher J, Maharjan N et al. The process of Lewy body formation, rather than simply α-synuclein fibrillization, is one of the major drivers of neurodegeneration. Proceedings of the National Academy of Sciences of the United States of America. 2020.", "tier": "A", "kind": "primary", "pmid": "32075919", "doi": "10.1073/pnas.1913904117", "url": "https://pubmed.ncbi.nlm.nih.gov/32075919/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID32075919", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C15", "CSC1", "CSC3" ] }, { "n": 16, "citation": "Orrú CD, Vaughan DP, Vijiaratnam N et al. Diagnostic and prognostic value of α-synuclein seed amplification assay kinetic measures in Parkinson's disease: a longitudinal cohort study. The Lancet. Neurology. 2025.", "tier": "A", "kind": "primary", "pmid": "40541208", "doi": "10.1016/S1474-4422(25)00157-7", "url": "https://pubmed.ncbi.nlm.nih.gov/40541208/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID40541208", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C16", "CSC4" ] }, { "n": 17, "citation": "Chen S, Puri A, Bell B et al. HTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species. Nature communications. 2024.", "tier": "A", "kind": "primary", "pmid": "38499535", "doi": "10.1038/s41467-024-46538-8", "url": "https://pubmed.ncbi.nlm.nih.gov/38499535/", "status_flags": [ "UpdateOf: PMID37674720" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID38499535", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph17, 1:Results:paragraph26, 1:Results:paragraph28. No complete-paper or supplement audit claimed.", "carries_claims": [ "C17", "CSC1", "CSC3" ] }, { "n": 18, "citation": "Shahnawaz M, Mukherjee A, Pritzkow S et al. Discriminating α-synuclein strains in Parkinson's disease and multiple system atrophy. Nature. 2020.", "tier": "A", "kind": "primary", "pmid": "32025029", "doi": "10.1038/s41586-020-1984-7", "url": "https://pubmed.ncbi.nlm.nih.gov/32025029/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID32025029", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C18", "CSC1", "CSC4" ] }, { "n": 19, "citation": "Di Maio R, Barrett PJ, Hoffman EK et al. α-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson's disease. Science translational medicine. 2016.", "tier": "A", "kind": "primary", "pmid": "27280685", "doi": "10.1126/scitranslmed.aaf3634", "url": "https://pubmed.ncbi.nlm.nih.gov/27280685/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID27280685", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C19", "CSC3" ] }, { "n": 20, "citation": "Schweighauser M, Shi Y, Tarutani A et al. Structures of α-synuclein filaments from multiple system atrophy. Nature. 2020.", "tier": "A", "kind": "primary", "pmid": "32461689", "doi": "10.1038/s41586-020-2317-6", "url": "https://pubmed.ncbi.nlm.nih.gov/32461689/", "status_flags": [ "ErratumIn: PMID41125897" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID32461689", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C20", "CSC1", "CSC4" ] }, { "n": 21, "citation": "Guo M, Wang J, Zhao Y et al. Microglial exosomes facilitate α-synuclein transmission in Parkinson's disease. Brain : a journal of neurology. 2020.", "tier": "A", "kind": "primary", "pmid": "32355963", "doi": "10.1093/brain/awaa090", "url": "https://pubmed.ncbi.nlm.nih.gov/32355963/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID32355963", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C21", "CSC2", "CSC3" ] }, { "n": 22, "citation": "Prusiner SB, Woerman AL, Mordes DA et al. Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism. Proceedings of the National Academy of Sciences of the United States of America. 2015.", "tier": "A", "kind": "primary", "pmid": "26324905", "doi": "10.1073/pnas.1514475112", "url": "https://pubmed.ncbi.nlm.nih.gov/26324905/", "status_flags": [ "ErratumIn: PMID38830111" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID26324905", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C22", "CSC1", "CSC3", "CSC4" ] }, { "n": 23, "citation": "Angelova PR, Esteras N, Evans J et al. α-synuclein fibrils per se but not α-synuclein seeded aggregation causes mitochondrial dysfunction and cell death in human neurons. 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