# HSEF v5.3 review: Tau Propagation Hypothesis

> Sources: 66 primary reports; claims: 71; verified: 71; unverified: 0. Verification is bounded attribution. Access: 7 partial-body and 59 complete abstract/status examinations. Literature cutoff: 2026-10-06; source examination UTC date: 2026-10-06. No complete-paper audit or blinded calibration claimed.
> **Adversarial review:** Generated by Sol 6.1; adversarially reviewed by Claude Opus 5.5 (Anthropic) on 2026-10-06. 0 corrections applied (see ADVERSARIAL REVIEW AND APPROVAL). Status: **Approved as revised.**

## AT A GLANCE

**Tau transfer and templating are experimentally demonstrable; their necessity as the driver of natural tauopathy neurodegeneration remains unresolved.**

| Level | Confidence | Causal role | Momentum | Stability | Divergence |
|---|---|---|---|---|---|
| Γ — Mechanistically plausible, partial system support | Moderate | reinforcing / stabilizing factor | Mechanistic only | Stable | Contested |

**Deciding experiment:** In spontaneous tauopathy with physiological donor and recipient tau, induce a selective transfer/conversion block after pathology onset and provide mechanistically matched rescue, with source tau burden and neuronal physiology held comparable.

**Belief versus evidence:** The preregistered weakest-link conjunction returns Γ. Longitudinal human network progression, recipient-host conversion experiments and causal modifiers make the claim more than association alone. None of the assembled lines selectively establishes that spontaneous templated neuronal propagation is necessary for the neuronal-loss trajectory across tauopathies. Defined laboratory capability is credited, while selective propagation mediation is the remaining gate.

**Best-supported rival:** Cell-autonomous selective vulnerability. Compare transfer-selective loss and matched rescue with source-tau- and recipient-viability-matched controls, measuring both recipient conversion and blinded neuronal loss. Intrinsic toxicity may coexist; an epistasis design must test mediation rather than rank mutually compatible stories as exclusive.

## COMPETING MECHANISTIC MODELS

**Rank 1: Cell-autonomous selective vulnerability (Ε).** Intrinsic neuronal type, synaptic tau binding and proteostasis help determine which cells degenerate. Synaptogyrin-3 perturbation rescues synaptic function and memory; identical seeds affect different human neuronal subtypes differently. This does not exclude transfer as an additional contributor, and familial/organoid scope is limited.

**Rank 2: Templated neuronal propagation (Γ).** Donor tau transfer recruits recipient substrate and helps advance pathology. Wild-type host conversion, mouse-tau-specific neutralization, temporal seed detection and connected-region models support capability. A selective natural propagation-to-neuron-loss dependency is unresolved; Arc and clinical outcome contrasts prevent automatic mediation.

**Rank 3: Transfer without neurotoxicity (Γ).** Transferred material can move independently of recipient templating or lethal consequences. Human donor tau transfers in a mouse-tau-null recipient model and seeding occurs in neurologically normal brains. Healthy seeds differ from AD seeds; pathogenic seed exposure causes dysfunction in specified recipient models.

**Rank 4: Upstream proteostatic failure (Γ).** Endolysosomal escape and cellular clearance determine tau competence and intrinsic toxicity. RAB7 assays, human-neuron CRISPR proteostasis screens and organoid rescue support relevant mechanisms. Cultured-cell and engineered systems do not establish a common upstream initiator of all tauopathies.

**Rank 5: Shared microenvironment pseudo-spread (Β).** Network activity and glial environments create correlated pathology without obligatory neuron-to-neuron transfer. Connectivity covariance, glial injury and intrinsic susceptibility are compatible with this route. Compatibility alone does not prove it, and direct laboratory donor transfer cannot be explained as covariance alone.

The tournament does not alter the nominal level. Compatible pathways and flexible alternatives are not automatically proved by explaining observations.

## FULL REVIEW

### Registered claim and scope

Pathological tau spreads between anatomically connected neurons by templated seeding, and this cell-to-cell propagation drives the progression of neurodegeneration in tauopathies.

Retain the original user wording. Separate spatial pattern, physical transfer, templated conversion and progression causality. All are required by the conjunction. Refresh earlier tau evidence without reading its previous score as a target.

Selection: public-interest rank 22 from the editorial ranking compiled 2026-09-23; categorical prior verdicts were visible. Private fresh review; earlier documents are preserved.

### Evidence and causal interpretation

Human tau network patterns are reproducible and predictive in longitudinal samples, but molecular movement is inferred. Atypical AD variants and patient-specific models strengthen temporal anatomy; seed maps and normal-brain seeds complicate a single canonical ordering (PMID40810361, PMID33246962, PMID34635189, PMID38072056).

Source-restricted tau models and wild-type host recipients demonstrate laboratory capability. Donor protein transport, host substrate conversion and injury must remain three separate observations. The Wegmann transfer and severe toxicity experiments use different transgenic systems; tau-null transfer cannot simply be equated with a spread-blocking rescue (PMID22365544, PMID22312444, PMID26538322, PMID33005889, PMID39284839).

Mouse-tau-specific antibody and central-epitope secondary propagation contrasts are stronger than unselective inoculum neutralization. They narrow host recruitment and later propagation after imposed seeds. Uptake receptor and sulfation experiments establish steps in this chain, rather than intact natural progression necessity (PMID39500576, PMID31038156, PMID32296178, PMID39736627, PMID29686391).

Bassoon downregulation preserves total human tau while reducing seed pathology, function defects and atrophy; the separate transfer arm includes source GFP controls. PDDC improves layer density and synaptic markers but also lowers total tau and alters ceramides and gliosis. Arc loss nearly removes transmission but increases intracellular burden and early toxicity. These contrasts credit causal model effects while leaving propagation-specific mediation unsettled (PMID36344699, PMID38049923, PMID42372723).

Selective vulnerability has independent support: identical seeds behave differently across human neuronal types, and Synaptogyrin-3 reduction rescues synaptic function and memory despite continued inflammation. Astrocytic APOE4 deletion can also protect after onset. These pathways can coexist with transfer rather than requiring a single exclusive model (PMID40390134, PMID33472038, PMID33831349).

The Meisl kinetic result concerns the rate of neocortical aggregate accumulation from Braak III onward. Original Results explicitly fold local cell-to-cell transfer into the replication term. It therefore constrains interregional spread as the later rate limiter, while leaving local propagation and earlier initiation unresolved (PMID34714685).

Clinical trials directly test trajectory and deserve weight. PASSPORT, TANGO, tilavonemab PSP/AD, TAURIEL and PERISCOPE do not establish clinical benefit of their tested strategies. LAURIET has a real ADAS-Cog11 benefit but no coprimary functional or global benefit, no PET accumulation difference and no atrophy difference. MAPTRx/BIIB080 demonstrates tau synthesis/biomarker engagement in one small phase1b study and extension, not proven clinical efficacy or selective spread mediation (PMID34385707, PMID38012285, PMID33609476, PMID36730056, PMID35696185, PMID38386949, PMID37643887, PMID37095250, PMID37902726).

Consensus strengthened the gap framework and returned tilavonemab body-level biomarker details that match original Results. Its targeted retrieval missed several available primary trial reports, substituted a TANGO baseline conference report and made inconsistent intermediate full-text coverage claims. Only returned and independently checked passages receive credit; absence in its answer is not literature absence.

## HYPOTHESIS STATE EVALUATION FRAMEWORK (HSEF v5.3)

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### Consensus provenance reconciliation — 9 October 2026

Case-specific Consensus discovery records were located and linked to this final edition. This supplements the review's provenance; it leaves the original assessed claim, grades and source counts intact. Provider summaries and full-text badges do not establish examination of original primary passages by this reviewer. Source access and incorporation retain the limits stated in the original methods and any dated research update.

Recorded evidence artifacts:

- `deliverables/hsef_v53_popularity_ranks_21_25_2026-10-06/tau-propagation-ranked-refresh/consensus/broad-browser-snapshot.txt`
- `deliverables/hsef_v53_popularity_ranks_21_25_2026-10-06/tau-propagation-ranked-refresh/consensus/query-ledger.json`
- `deliverables/hsef_v53_popularity_ranks_21_25_2026-10-06/tau-propagation-ranked-refresh/consensus/reconciliation.md`
- `deliverables/hsef_v53_popularity_ranks_21_25_2026-10-06/tau-propagation-ranked-refresh/consensus/targeted-browser-snapshot.txt`

The located artifacts do not state a reliable source-comparison count. No count is inferred.

A dated adversarial approval record exists for the separately identified tau-propagation-ranked-refresh.review.md (2026-10-06; see edition-approval-audit.json). Its scope is that recorded edition. This supplement has no separate approval and no coverage is inferred from topic identity. No score or confidence change is made by this reconciliation.
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### Subclaim matrix and aggregation

| Subclaim | Scope | Level | Decision |
|---|---|---|---|
| SC1 Tau pathology shows reproducible spatial progression along connected brain systems. | defined human tauopathies and staging trajectories | Γ | Longitudinal PET predicts later accumulation along connected systems, supported by anatomical and perturbational models. This is temporal proof beyond static association, but physical propagation is inferred and disease-pattern exceptions remain. The causal explanation of human network progression is Γ. |
| SC2 Pathogenic tau physically transfers between anatomically connected neurons under endogenous conditions. | spontaneous tauopathy conditions without forced seed delivery | Γ | Donor-restricted models, receptor perturbations and activity experiments establish transport capability. Spontaneous PS19 patterns lack injected seeds but retain widespread mutant tau expression. Direct endogenous lineage transfer under natural disease conditions has not been separated from recipient expression and selective vulnerability. |
| SC3 Transferred tau templates pathological conversion of recipient endogenous tau. | recipient neurons with physiological tau expression | Γ | Wild-type recipients, mouse-specific antibody and tau-null/species-specific comparisons strengthen physiological host-tau conversion after imposed seeds. These establish important bounded capabilities. The registered transferred endogenous pathway remains reliant on forced initiation; host recruitment alone does not prove natural disease necessity. |
| SC4 Cell-to-cell templated propagation causally drives neurodegeneration progression. | tauopathy functional and neuronal-loss trajectories | Γ | Bassoon, exosome-pathway, antibody and source-suppression contrasts affect pathology or function, but also source tau, synaptic physiology, ceramides, clearance or inflammation. Arc loss reduces transmission with early toxicity increased; clinical antibody failures and a mixed LAURIET result constrain progression mediation without proving all tau biology irrelevant. |

Preregistered aggregation: weakest-link. The preregistered weakest-link conjunction returns Γ. Longitudinal human network progression, recipient-host conversion experiments and causal modifiers make the claim more than association alone. None of the assembled lines selectively establishes that spontaneous templated neuronal propagation is necessary for the neuronal-loss trajectory across tauopathies. Defined laboratory capability is credited, while selective propagation mediation is the remaining gate. Sensitivities: weakest-link Γ; primary-subclaim Γ; scope-matched Γ.

### Decisive-perturbation inventory and causal tally

[1] 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.

[2] Human neuron assays distinguished aggregate uptake through HSPG-related mechanisms from largely LRP1-dependent monomer accumulation. Recombinant protein exposure and uptake assays do not demonstrate recipient conversion or endogenous human disease progression; the abstract's leading-cause framing exceeds its experiment.

[3] 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.

[5] 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.

[6] Trem2 deletion enhanced AAV-P301L tau dispersion, EV seeding activity, synaptic dysfunction and memory deficits; exosome inhibition reduced release in culture. Microglial clearance and broader immune effects confound selective transfer mediation; pathological human tau expression is imposed, and Trem2 can protect in this context.

[7] Eighteen cell-isolated tau strains induced distinct regional and cellular pathology and different network propagation rates in inoculated PS19 mice. This demonstrates strain capability in a P301S recipient rather than natural human strain origin or propagation-driven neuronal loss.

[9] Endolysosomal permeabilization allowed EV-associated tau seeds to reach biosensor-cell cytosol; RAB7 manipulation changed aggregation. Permeabilization also occurred with tau-free EVs, only a minority of cells aggregated, and RAB7/lysosomal perturbations affect general trafficking.

[10] Human AD EV inoculation in aged wild-type mice induced endogenous tau misfolding with preferential GABAergic pathology and reduced inhibitory synaptic transmission. Forced brain EV delivery bypasses normal release and dose; dysfunction and marker reductions are not an audited neuron-death mediation assay. A linked correction requires qualification.

[11] Donor physiological tau transferred through medium; optogenetic and chemogenetic stimulation increased release and in-vivo tau pathology. Activity also changes intrinsic vulnerability and proteostasis; increased pathology is not proof that transfer-mediated recipient conversion causes degeneration.

[12] 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.

[13] Brain-penetrant nSMase2 inhibition normalized ceramides and reduced PS19 tau pathology, neuronal-layer thinning and glial changes; it separately reduced AAV-mutant contralateral tau transfer. The survival/pathology and transfer experiments use separate systems; ceramide and EV changes have broader effects, so propagation is not the uniquely demonstrated neuroprotective mediator. Original Results show reduced total human tau and loss of the pThr181 difference after total-tau normalization. Layer density/thickness and synaptophysin improve, but no audited total-neuron stereology or behavioral rescue is credited here. The AAV arm normalizes contralateral signal to ipsilateral signal.

[14] Removing endogenous mouse tau preserved human-P301L transfer to recipient neurons but reduced neurotoxicity in a separate severe-tauopathy model despite similar tangle numbers. 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.

[15] 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.

[16] Dendrimer-conjugated nSMase2 inhibitor improved exposure and reduced contralateral tau pathology after unilateral mutant-human-tau AAV expression. EV suppression and trafficking are broader than a tau-only mediator; this is an engineered transfer model without a reported clinical or neuronal-loss endpoint.

[18] Seed-competent monomer ensembles encoded reproducible cell strains and distinct PS19-inoculated pathology, with AD and CBD isolates differing. Monomer preparation and reporter selection do not establish spontaneous human strain formation or disease progression dependency.

[19] Injected synthetic tau seeds in P301S mice produced region-dependent spread, impaired synaptic plasticity and corresponding cognitive or motor dysfunction. Forced seeds plus mutant tau create a bounded sufficiency paradigm; functional deficits are not direct proof that naturally transferred seeds cause progressive human neuron death.

[20] Suppressing entorhinal mutant-tau transgene expression resolved inclusions and abnormal sprouting and prevented progressive neuron loss in rTgTauEC mice. Doxycycline lowers the source protein and its cell-autonomous toxicity as well as spread; it is not a propagation-selective mediation test.

[21] The 46-person BIIB080 phase 1b trial and extension showed dose-related fluid tau lowering and reduced PET accumulation in small imaging subsets. Safety was the original primary endpoint; open-label extension and biomarker outcomes do not establish clinical efficacy or selective propagation blockade. Same trial as MAPTRx primary report.

[22] In a randomized 46-person MAPTRx phase 1b study, intrathecal antisense lowered CSF total tau by more than half at higher doses; no treated serious adverse events were reported. The primary endpoint was safety, not clinical disease modification, and total MAPT synthesis lowering cannot identify spread mediation. A linked author correction remains attached. Original Results show no consistent clinical outcome trend and no dose-responsive injury-biomarker effect; ventricular-volume change was greater in active arms. The examined publisher correction changes an author affiliation, not efficacy results (doi:10.1038/s41591-023-02639-3).

[26] Synaptic loss and microgliosis preceded fibrillar tangles in P301S mice; broad FK506 immunosuppression attenuated pathology and increased lifespan. Earlier dysfunction weakens a mature-tangle-only model; broad immunosuppression and mutant expression do not identify spread mediation. A linked erratum lacks an identifier and its details remain unexamined.

[27] Isogenic MAPT-V337M organoids developed splicing/autophagy changes before selective glutamatergic-neuron loss; PIKFYVE inhibition rescued glutamate toxicity. This establishes a familial cell-intrinsic vulnerability route in organoids, not organismal follow-through or intercellular propagation dependency.

[28] Conditional astrocytic APOE4 removal after pathology onset protected against neurodegeneration and synaptic loss in P301S mice and reduced microglial phagocytosis. A real glial causal contribution need not be mediated by tau transfer; mutant-tau and APOE context restrict generalization.

[29] 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.

[30] Whole-brain mapping showed injected fibrils produced a more AD-like pattern than spontaneous P301L pathology; deposits also appeared beyond direct connections and antibody treatment reduced burden. Choosing a seed to improve resemblance is not natural disease validation, and static connectivity plus antibody effects does not isolate physical transfer-driven neuronal loss.

[32] Synaptogyrin-3 reduction in fly and mouse tauopathy restored vesicle mobility and neurotransmission by reducing pathological tau-vesicle association. This narrows a presynaptic toxicity mechanism, not templated propagation; engineered tau systems and conserved synaptic function require separate generalization.

[33] PTEN activation and phosphatidylserine exposure preceded neuronal-structure engulfment in rTg4510 mice; PTEN inhibition reduced microglial uptake. Synaptic tagging and engulfment are rival or downstream toxicity mechanisms, and pharmacology plus mutant overexpression do not isolate templated transfer.

[37] Semorinemab biomarker analyses from TAURIEL and LAURIET showed increased CSF YKL-40 and plasma pTau181, with GFAP stabilization in LAURIET but not TAURIEL. These are reused trial samples and mechanistic biomarker effects, not new independent efficacy trials or direct evidence of beneficial microglial mediation.

[40] 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.

[41] A 25-person bepranemab PSP phase 1b trial reported acceptable safety and about 80 percent reduction in mean free CSF tau. Safety and target occupancy are not clinical disease modification; small phase 1 enrollment cannot settle whether mid-region neutralization blocks propagation-driven degeneration.

[42] Galectin-3 deletion in THY-Tau22 mice reduced activation, tau pathology and synaptic loss and rescued memory; cell studies linked Gal3 to EV release and fibrillation. Genetic removal also changes broad immune responses; the two arms do not isolate propagation as the uniquely causal neuroprotective mediator.

[43] ApoE3-Christchurch reduced tau uptake and fragmentation, seeded spread, inflammatory signals and cognitive defects relative to wild-type ApoE3 in amyloid and P301S models. APOE changes several uptake, inflammatory and proteolytic pathways, and PFF initiation remains imposed; a natural human variant does not isolate propagation mediation here.

[44] 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.

[45] Entorhinal-restricted P301L expression was followed by human tau in connected neurons lacking detectable transgene, coaggregation with mouse tau, synapse degeneration and EC loss. Low-level expression detection and source-cell deafferentation complicate inference; mutant overexpression does not isolate selective endogenous templating. Linked erratum details are unexamined.

[46] 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.

[49] Human-neuron CRISPR screens identified tau proteostasis dependencies including UFMylation, GPI biosynthesis and CRL5-SOCS4, with mitochondrial disruption generating altered tau fragments. Cellular aggregation control and disease correlation do not demonstrate intercellular spread or clinical neuroprotection; the linked preprint is not a second study.

[53] Microglial depletion reduced AAV-tau spread in wild-type and APP-knock-in mice but increased plaques and plaque-associated dystrophic-neurite tau; tagged microglial EVs carried tau. Depletion changes clearance and injury as well as transfer, so reduced distal signal cannot be relabeled uniform protection. A linked correction remains attached.

[54] 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.

[55] TREM2 deficiency or microglial ablation increased amyloid-associated tau seeding/spread, and repopulated microglia did not recover the protective activation state. This shows protective microglial function in an amyloid-seeded context and contradicts universal beneficial depletion; seed burden is not equivalent to neuron-loss causality.

[56] CRISPRi and sulfation manipulation identified HSPG 6-O-sulfation dependence of tau uptake across cells, human-derived neurons and mouse slices. Uptake is one step; these experiments do not establish intact-animal endogenous transfer, conversion or degeneration dependency.

[57] Fractionated recombinant and AD-derived tau assemblies of at least three units underwent uptake and seeded biosensor aggregation, with HSPG-sensitive entry. The minimum size depends on preparation and assay; extracellular exposure and reporter amplification do not prove a universal naturally propagating toxic species.

[58] Tau antibodies differed in promoting Fc-mediated microglial uptake versus blocking neuronal uptake according to epitope and aggregate preparation/size. An antibody's pathology benefit cannot be assigned automatically to transfer blockade; this is cultured-cell mechanism analysis, not new in-vivo disease causality.

[61] Human AD insoluble tau induced host-tau pathology in mice across Prnp genotypes; tau-null and species-specific antibody comparisons supported recipient tau origin, while PrP genotype did not change seeding/spread. Forced inoculation establishes host conversion capability and excludes an obligatory PrP receptor in this setting, not natural human tau propagation necessity.

[62] A repeat-domain antibody reduced seed-competent/aggregated tau and injury biomarkers when started early in Line66 mice, but later treatment did not remove established aggregates below baseline. The endpoints were aggregation and fluid injury markers, without a reported functional trajectory test; epitope and timing matter but do not establish spread-mediated neuroprotection.

[64] A central-epitope antibody neutralized human AD-extract seeding and reduced distal pathology after K18-P301L fibrils, outperforming one N-terminal comparator. Imposed seeds and transgenic substrate limit inference; reducing secondary pathology is more specific than inoculum neutralization but not proof of clinical neuronal-loss mediation.

[65] A neuronal reporter model visualized K18/AD-seeded aggregate formation and contact-dependent transfer with new deposits in neighboring cells, including nanotube-associated material. Endogenously formed refers to aggregates formed inside reporter cells after seeding, not native unseeded human disease; tau-fragment reporters and cultures restrict generalization.

[66] 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.

Tally: 46 discriminating contrasts. 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.

### Cap audit, precedence and Β/Γ/Δ boundary

The neurodegeneration rubric credits endogenous mediator perturbation only within the actual tested system. Recipient physiological tau conversion after injected seeds is real capability but remains subject to the exogenous-seeding ceiling for the natural propagation subclaim. Longitudinal human temporal data exceed a static-association-only Β rule, yet do not establish physical transfer. Bassoon and Arc are endogenous manipulations in engineered tau backgrounds; their controls strengthen specific model claims without proving the full propagation mediator. The assembled evidence is assessed together without re-capping independent convergence.

Gamma hard-rule audit: Forced seeds alone do not establish endogenous propagation necessity. Overexpressed source tau does not by itself identify natural human precursor-product transfer. Fluid or PET movement is not clinical neuroprotection. Convergent lines were assessed together; the unresolved mediator remains selective propagation, not the absence of an all-purpose RCT.

SC3 cap: “Exogenous seeding models alone” Wild-type recipients, mouse-specific antibody and tau-null/species-specific comparisons strengthen physiological host-tau conversion after imposed seeds. These establish important bounded capabilities. The registered transferred endogenous pathway remains reliant on forced initiation; host recruitment alone does not prove natural disease necessity.

SC1 field-valid definition: “
- Endogenous genetic deletion, suppression, or degron depletion of the proposed mediator in vivo
- Selective pathway inhibition that changes onset/progression while preserving broader viability
- Vagotomy-type natural experiment, only if confounding is rigorously controlled AND effect is disease-initiation relevant rather than merely associated” Positive full-scope result: no. Longitudinal PET predicts later accumulation along connected systems, supported by anatomical and perturbational models. This is temporal proof beyond static association, but physical propagation is inferred and disease-pattern exceptions remain. The causal explanation of human network progression is Γ.

SC2 field-valid definition: “
- Endogenous genetic deletion, suppression, or degron depletion of the proposed mediator in vivo
- Selective pathway inhibition that changes onset/progression while preserving broader viability
- Vagotomy-type natural experiment, only if confounding is rigorously controlled AND effect is disease-initiation relevant rather than merely associated” Positive full-scope result: no. Donor-restricted models, receptor perturbations and activity experiments establish transport capability. Spontaneous PS19 patterns lack injected seeds but retain widespread mutant tau expression. Direct endogenous lineage transfer under natural disease conditions has not been separated from recipient expression and selective vulnerability.

SC3 field-valid definition: “
- Endogenous genetic deletion, suppression, or degron depletion of the proposed mediator in vivo
- Selective pathway inhibition that changes onset/progression while preserving broader viability
- Vagotomy-type natural experiment, only if confounding is rigorously controlled AND effect is disease-initiation relevant rather than merely associated” Positive full-scope result: no. Wild-type recipients, mouse-specific antibody and tau-null/species-specific comparisons strengthen physiological host-tau conversion after imposed seeds. These establish important bounded capabilities. The registered transferred endogenous pathway remains reliant on forced initiation; host recruitment alone does not prove natural disease necessity.

SC4 field-valid definition: “
- Endogenous genetic deletion, suppression, or degron depletion of the proposed mediator in vivo
- Selective pathway inhibition that changes onset/progression while preserving broader viability
- Vagotomy-type natural experiment, only if confounding is rigorously controlled AND effect is disease-initiation relevant rather than merely associated” Positive full-scope result: no. Bassoon, exosome-pathway, antibody and source-suppression contrasts affect pathology or function, but also source tau, synaptic physiology, ceramides, clearance or inflammation. Arc loss reduces transmission with early toxicity increased; clinical antibody failures and a mixed LAURIET result constrain progression mediation without proving all tau biology irrelevant.

### Upward threshold ladder

SC1 Δ: “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. Donor-specific native tau tracking combined with prespecified longitudinal prediction and a selective intervention would identify the explanation of the spatial trajectory.

SC2 Δ: “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. Trace a pathogenic donor species at physiological expression in spontaneous disease, showing transfer to genetically distinguished recipients without forced seeds and with matched transfer-loss/rescue controls.

SC3 Δ: “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. Demonstrate physiological recipient precursor-product conversion after native donor release, suppress recipient conversion without disrupting tau transport/viability, then restore it with matched rescue.

SC4 Δ: “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. Selectively block the implicated transfer/conversion step after onset, preserve source tau and recipient baseline physiology, and alter blinded function and neuron-survival trajectories; mechanistically matched rescue must reinstate both propagation and injury.

Upper ladder: Human anti-tau clinical trials, MAPT-linked biology and natural variant-related protection were considered. MAPT disease causality and APOE protection do not identify propagation as their mediator. Biomarker-only ASO effects and negative/mixed extracellular-antibody outcomes cannot cross the clinical propagation gate. Orthogonal endogenous selective inhibition with clinical or neuronal-survival benefit could support higher levels without requiring one impossible experiment.

Independence: Different controls exclude different errors, but receptor, seeded and mutant-line experiments share a forced-pathology failure mode. MAPTRx/PET reports and semorinemab biomarker reanalyses are grouped by original trial. Human imaging datasets overlap. These are not 66 independent demonstrations of propagation-mediated neuron loss.

Recipient-origin controls [66, 15, 61]: Reduce donor staining versus host conversion ambiguity, while retaining imposed initiation.

Source-limited and transport perturbations [45, 1, 5, 3]: Reduce pure spatial-covariance explanations in laboratory models; tau expression, trafficking and physiology remain shared confounds.

Human temporal and kinetic measures [24, 51, 60]: Exclude a solely static terminal association, but neither imaging nor kinetics identifies molecular lineage.

Randomized clinical strategies [36, 38, 34, 40]: Randomization narrows treatment-confounding; epitope engagement is not universal seed blockade, and clinical results are negative or mixed.

### Falsification and pitfalls

Reduced transmission does not uniformly improve toxicity. PMID42372723 Arc loss nearly removes transfer yet increases intracellular tau and modest early toxicity in its mutant model. Additional downgrade: False.

Simple transfer equals templating equals injury conflation fails. PMID26538322 reports host-null transfer and a separate host-null neuroprotection experiment; these are distinct models. Additional downgrade: False.

Fluid engagement does not ensure clinical trajectory change. PASSPORT, TANGO and tilavonemab have clinical nulls; LAURIET has isolated cognitive benefit but no coprimary functional/PET/atrophy benefit. Additional downgrade: False.

Network covariance mistaken for directly observed transfer. Human PET and reconstructed staging.

Spontaneous pathology mistaken for physiological tau expression. PS19 age-series models retain pan-neuronal mutant human tau.

Local replication misread as excluding all cell transfer. Meisl Results explicitly include local transfer in replication.

All antibody trials described as uniformly null. LAURIET cognitive success retained with negative overall trial interpretation.

Endogenously formed reporter aggregates mistaken for native unseeded disease. K18 seeded reporter assays.

Retrospective score target or blinded claim. Historical Γ tau/neuro scores were visible in a memory quick pass; explicitly unblinded fresh appraisal.

### Adversarial steelman: above, then below

The strongest Δ case combines native Bassoon/Arc perturbations, source-restricted donor tracing, wild-type host conversion and clinical fluid engagement. This is a serious mechanistic case. Yet the selective natural spread-to-neuron-loss mediator is still unisolated: Bassoon affects intrinsic seeds/synapses, Arc toxicity moves in the opposite direction and clinical occupancy does not prove seed blockade.

The strongest Β case treats everything as anatomical association and artificial seed capability. It misses actual donor transfer, recipient substrate controls, temporal human progression and function-changing perturbations. Γ is justified even though the conjunctive disease-driving necessity has not crossed Δ.

Reject Δ for the broad conjunction on missing selective endogenous mediation; reject Β for the assembled temporal and mechanistic case. Defined conversion capabilities remain meaningful rather than being dismissed as artifacts.

### Final score, causal direction and M/S/D

The preregistered weakest-link conjunction returns Γ. Longitudinal human network progression, recipient-host conversion experiments and causal modifiers make the claim more than association alone. None of the assembled lines selectively establishes that spontaneous templated neuronal propagation is necessary for the neuronal-loss trajectory across tauopathies. Defined laboratory capability is credited, while selective propagation mediation is the remaining gate.

The mechanism exceeds co-occurrence in laboratory transfer/conversion systems. Human initiation plus prevention and rate limitation is not established; necessity across progression is unresolved. Conditional amplification of established pathology is the best-supported role. Reactive release and local transfer may participate causally without being the initiating event, and the conditional role does not assert universal human mediation.

Momentum: Mechanistic only. Recent Arc loss, physiological recipient-origin controls, neuronal proteostasis screens and bepranemab safety/occupancy interrogate relevant boundaries. No verified pending clinical efficacy result is asserted.

Stability: Stable. The packet verifies completed reports, not a presently pending result expected to move the registered level.

Divergence: Contested; no single implied-level arithmetic. These dimensions do not change level or confidence.

## PROPOSED DECISIVE EXPERIMENTS

In spontaneous tauopathy with physiological donor and recipient tau, induce a selective transfer/conversion block after pathology onset and provide mechanistically matched rescue, with source tau burden and neuronal physiology held comparable.

Readout: Direct recipient lineage conversion, regional spread, blinded neuron counts and cognitive/functional trajectory. Controls: Donor and recipient allele tags, source load, synaptic/lysosomal viability, transfer-independent intracellular toxicity and sham rescue. Supporting: Selective interruption reduces new recipient conversion and subsequent neuronal loss, and matched rescue restores both. Falsifying: Verified selective interruption leaves neuronal-loss progression unchanged or worsens it while matched intrinsic-toxicity control explains the trajectory.

## RESEARCH TIMELINE

| Year | Milestone | Primary source | Interpretation |
|---|---|---|---|
| 2007 | Early synapse loss and microgliosis before tangles | [PMID17270732](https://pubmed.ncbi.nlm.nih.gov/17270732/) | Temporal pathology dissociation. |
| 2009 | Induced host filament assembly | [PMID19503072](https://pubmed.ncbi.nlm.nih.gov/19503072/) | Templating capability after imposed entry. |
| 2012 | Entorhinal-restricted donor tau in connected neurons | [PMID22365544](https://pubmed.ncbi.nlm.nih.gov/22365544/) | Source-tracing model with expression caveats. |
| 2013 | Source suppression prevents neuronal loss | [PMID23946388](https://pubmed.ncbi.nlm.nih.gov/23946388/) | Also removes intrinsic source toxicity. |
| 2014 | Strain-like serial templating | [PMID24857020](https://pubmed.ncbi.nlm.nih.gov/24857020/) | Reporter/inoculation capability. |
| 2015 | Microglial/exosome perturbation reduces model spread | [PMID26436904](https://pubmed.ncbi.nlm.nih.gov/26436904/) | Broad clearance and trafficking effects. |
| 2015 | Host tau separates transfer from toxicity | [PMID26538322](https://pubmed.ncbi.nlm.nih.gov/26538322/) | Distinct experimental models. |
| 2016 | Activity changes release and pathology | [PMID27322420](https://pubmed.ncbi.nlm.nih.gov/27322420/) | Activity affects several mechanisms. |
| 2018 | Presynaptic tau binding perturbation | [PMID29398363](https://pubmed.ncbi.nlm.nih.gov/29398363/) | Intrinsic synaptic mechanism. |
| 2019 | Central versus N-terminal antibody contrast | [PMID31038156](https://pubmed.ncbi.nlm.nih.gov/31038156/) | Secondary model propagation strengthened. |
| 2020 | LRP1 uptake and model spread | [PMID32296178](https://pubmed.ncbi.nlm.nih.gov/32296178/) | Transport step. |
| 2020 | Nontransgenic host conversion after seeds | [PMID33005889](https://pubmed.ncbi.nlm.nih.gov/33005889/) | Physiological substrate, imposed initiation. |
| 2021 | Local amplification controls late human kinetics | [PMID34714685](https://pubmed.ncbi.nlm.nih.gov/34714685/) | Includes local cell-to-cell transfer. |
| 2021 | PASSPORT clinical null despite fluid engagement | [PMID34385707](https://pubmed.ncbi.nlm.nih.gov/34385707/) | Strategy/compartment boundary. |
| 2022 | Bassoon seed/function/atrophy rescue | [PMID36344699](https://pubmed.ncbi.nlm.nih.gov/36344699/) | Presynaptic and seed-stability effects. |
| 2023 | MAPTRx phase1b fluid tau lowering | [PMID37095250](https://pubmed.ncbi.nlm.nih.gov/37095250/) | Safety/biomarkers, not proven efficacy. |
| 2023 | LAURIET mixed cognitive/functional outcome | [PMID37643887](https://pubmed.ncbi.nlm.nih.gov/37643887/) | Overall trial negative, cognitive signal retained. |
| 2023 | TANGO clinical null despite fluid engagement | [PMID38012285](https://pubmed.ncbi.nlm.nih.gov/38012285/) | No PET dose response. |
| 2024 | Mouse-specific antibody restricts host recruitment | [PMID39500576](https://pubmed.ncbi.nlm.nih.gov/39500576/) | Imposed-seed context. |
| 2025 | Spontaneous PS19 connectome progression | [PMID40886860](https://pubmed.ncbi.nlm.nih.gov/40886860/) | Still widespread mutant tau expression. |
| 2026 | Arc loss separates transfer reduction from early toxicity | [PMID42372723](https://pubmed.ncbi.nlm.nih.gov/42372723/) | No automatic spread-suppression benefit. |

## KNOWLEDGE GAPS

Identify the transmitted species, route and physiological recipient conversion separately; seed-positive assays need not report a pathogenic species.

Distinguish local cell transfer, intracellular replication and interregional migration across preclinical and late stages.

Test whether blocking transfer shifts toxic material back into donor cells, as the Arc contrast suggests, rather than assuming that all spread suppression protects.

Resolve clinical epitope/compartment occupancy and whether a trial truly neutralized relevant seeds; CSF free tau is incomplete engagement evidence.

Replicate subtype-specific causal mediation across AD, PSP and other tauopathies without treating forced inoculation as natural origin.

Separate glial protective clearance from glial EV-mediated amplification in amyloid and nonamyloid settings.

## METHODS AND CONSENSUS CONTRIBUTION

Consensus was used through the signed-in browser for discovery, counterevidence, research-gap and timeline suggestions, and attempted checks of specific indexed full-text passages. Returned Methods/Results passages were reconciled with original-paper passages where available; failed retrievals, source substitutions and unverified aspects are recorded in the case reconciliation. Successful passage checks are distinguished from provider summaries. Provider screening counts, citation counts and meters were not used as primary counts or HSEF scores. This source log records access depth; it does not claim complete-paper or supplement review. The monthly API allowance was conserved: zero Consensus API calls in this batch.

## REVIEWER NOTES

66 primary reports with seven selected original-body examinations. All complete abstracts and linked-status metadata examined; no complete-paper or supplement audit. Six identified correction records retrieved; the MAPTRx publisher correction changes affiliation. Other correction details remain unexamined. UpdateOf entries link preceding preprints rather than separate replications. Historical tau/neuro Γ letters were inadvertently visible in a memory quick pass; no blinded derivation is claimed. Consensus: two Pro queries, zero Deep, zero API.

Search leads, reviews, protocols and correction notices do not pad the primary count. Downloaded XML does not earn examination credit. Linked notices remain attached; unexamined correction details limit inference. This is a coordinator source/claim consistency assessment, not independent blinded calibration.

## ADVERSARIAL REVIEW AND APPROVAL

**Authoring model:** Sol 6.1. **Adversarial reviewer:** Claude Opus 5.5 (Anthropic). **Date:** 2026-10-06.

**Scope of checks.** Reference PMIDs verified 66/66 against PubMed records (title, first author, journal, year); no retractions or expressions of concern found. Load-bearing claims spot-checked against PubMed abstracts and the local `examinations/` and `full-text/` passages: 18. Scoring logic checked against `framework/hsef-hypothesis-review-v5/SKILL.md`, `references/hsef-framework.md` and `references/evidence-rubrics/01-neurodegeneration.md`: cap precedence, the declared weakest-link aggregation, the Β/Γ/Δ boundary, the Δ field-valid-perturbation definition, subclaim-level/rationale coherence, and internal consistency with the scorecard, COMPLETION.json and the batch OVERVIEW row. Timeline years checked against the cited records: 21/21 match.

**Findings.**

| ID | Severity | Location | Original → corrected | Evidence |
|---|---|---|---|---|
| — | — | — | No corrections required | All checks below resolved in favour of the original text |

**Rejected findings (checked, no change).**

1. *Timeline attribution of PASSPORT.* Checked that the 2021 "PASSPORT clinical null" row points to the gosuranemab PSP phase 2 and not to the tilavonemab PSP trial listed nearby. PMID34385707 is the gosuranemab PSP trial; the tilavonemab PSP trial (PMID33609476) and tilavonemab AD trial (PMID36730056) are cited separately in the same sentence. No change.
2. *LAURIET characterisation.* The review credits an ADAS-Cog11 benefit while calling the trial negative and reporting no tau-PET and no atrophy difference. The report states a 42.2% reduction in ADAS-Cog11 decline (−2.89 points, p = 0.0008), no ADCS-ADL coprimary effect, and no between-arm difference in rates of cerebral atrophy or tau-PET accumulation. No change.
3. *TANGO "no PET dose response".* The report states that no dose–responses were observed for changes in tau-PET SUVR. No change.
4. *Meisl kinetics framing.* The review states that the original Results fold local cell-to-cell transfer into the replication term. The paper states that effects of local cell-to-cell transfer are subsumed into an effective local replication term, and that local replication dominates from Braak stage III onward. No change.
5. *Bassoon claims.* The review states that Bassoon downregulation preserves total human tau and that the separate transfer arm carries source GFP controls. The paper reports that Bsn downregulation did not influence total human tau levels in PS19 brains while seeding activity fell sharply, and that the AAV spreading model discriminates GFP-positive transduced neurons from neurons positive for human tau only. No change.
6. *Arc direction of effect.* The review states that Arc loss nearly removes transmission while increasing intracellular tau and early toxicity. The record reports increased intracellular tau accumulation and a modest early increase in toxicity with transmission almost absent. No change.
7. *BIIB080 / MAPTRx separation.* The review treats PMID37902726 and PMID37095250 as one 46-participant phase 1b trial plus extension, credits dose-dependent CSF tau lowering and PET reduction in small imaging subsets (n = 13 and n = 12), and declines to call this efficacy. Confirmed against both records; the greater ventricular-volume change in active arms is also correctly reported. No change.
8. *Bepranemab PSP figures.* "25-person" and "about 80 percent reduction in mean free CSF tau" match the record (25 enrolled; 80.41% reduction). No change.
9. *Cards 2, 9, 55, 53, 7, 12, 65 and the APOE4 "after onset" claim.* Each checked against its abstract; the receptor split (HSPG for aggregates, LRP1 for monomer), permeabilisation irrespective of tau seeds in a small fraction of cells, enhanced seeding after TREM2 loss or microglial ablation, the 18 cell-isolated strains, serial inoculation through three mouse generations, contact- and nanotube-dependent transfer, and tamoxifen administration after the onset of tau pathology are all stated as the sources state them. No change.
10. *Scoring logic.* The Γ cap hard rule invoked for SC3 ("Exogenous seeding models alone") is quoted as written; the Δ threshold text and field-valid-perturbation list are quoted verbatim; the declared weakest-link rule over SC1–SC4 (all Γ) returns Γ, which matches the headline, the scorecard, COMPLETION.json and the batch OVERVIEW row. The rival at Ε does not raise the nominal level, and the review says so. No change.
11. *Reference rendering.* No instance of the collective-first-author rendering bug (leading comma, dropped author) was found in REFERENCES.
12. *Citation-year convention.* Print/e-pub year differences of ±1 were treated as acceptable per the review protocol and were not recorded as errors.

**Residual limitations.** Verification is bounded attribution against abstracts and seven partial bodies; no complete-paper or supplement audit was performed by either the author or this reviewer. Six linked correction records remain only partly examined, as the review itself states. The validator's standing `v5.claim_form` warning (entry form recorded as `phenomenon`) is retained: the restatement in "Registered claim and scope" does grade the causal proposition rather than the topic, so the warning is informational and no level change follows.

**Approval:** Following adversarial review and the corrections listed above, the revised document is approved. — Claude Opus 5.5 (Anthropic), 2026-10-06.

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49. Samelson AJ, Ariqat N, McKetney J et al. CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis. Cell. 2026. [PMID 41610849](https://pubmed.ncbi.nlm.nih.gov/41610849/). DOI: 10.1016/j.cell.2025.12.038. Access: abstract_metadata. Study: PMID41610849.

50. Stopschinski BE, Del Tredici K, Estill-Terpack SJ et al. Anatomic survey of seeding in Alzheimer's disease brains reveals unexpected patterns. Acta neuropathologica communications. 2021. [PMID 34635189](https://pubmed.ncbi.nlm.nih.gov/34635189/). DOI: 10.1186/s40478-021-01255-x. Access: abstract_metadata. Study: PMID34635189.

51. Franzmeier N, Dewenter A, Frontzkowski L et al. Patient-centered connectivity-based prediction of tau pathology spread in Alzheimer's disease. Science advances. 2020. [PMID 33246962](https://pubmed.ncbi.nlm.nih.gov/33246962/). DOI: 10.1126/sciadv.abd1327. Access: abstract_metadata. Study: PMID33246962.

52. Yang F, Chowdhury SR, Jacobs HIL et al. Longitudinal predictive modeling of tau progression along the structural connectome. NeuroImage. 2021. [PMID 33957234](https://pubmed.ncbi.nlm.nih.gov/33957234/). DOI: 10.1016/j.neuroimage.2021.118126. Access: abstract_metadata. Study: PMID33957234.

53. Clayton K, Delpech JC, Herron S et al. Plaque associated microglia hyper-secrete extracellular vesicles and accelerate tau propagation in a humanized APP mouse model. Molecular neurodegeneration. 2021. [PMID 33752701](https://pubmed.ncbi.nlm.nih.gov/33752701/). DOI: 10.1186/s13024-021-00440-9. Access: abstract_metadata. Study: PMID33752701.

54. Martinez P, Patel H, You Y et al. Bassoon contributes to tau-seed propagation and neurotoxicity. Nature neuroscience. 2022. [PMID 36344699](https://pubmed.ncbi.nlm.nih.gov/36344699/). DOI: 10.1038/s41593-022-01191-6. Access: full_text_partial. Study: PMID36344699.

55. Gratuze M, Chen Y, Parhizkar S et al. Activated microglia mitigate Aβ-associated tau seeding and spreading. The Journal of experimental medicine. 2021. [PMID 34100905](https://pubmed.ncbi.nlm.nih.gov/34100905/). DOI: 10.1084/jem.20210542. Access: abstract_metadata. Study: PMID34100905.

56. Rauch JN, Chen JJ, Sorum AW et al. Tau Internalization is Regulated by 6-O Sulfation on Heparan Sulfate Proteoglycans (HSPGs). Scientific reports. 2018. [PMID 29686391](https://pubmed.ncbi.nlm.nih.gov/29686391/). DOI: 10.1038/s41598-018-24904-z. Access: abstract_metadata. Study: PMID29686391.

57. Mirbaha H, Holmes BB, Sanders DW et al. Tau Trimers Are the Minimal Propagation Unit Spontaneously Internalized to Seed Intracellular Aggregation. The Journal of biological chemistry. 2015. [PMID 25887395](https://pubmed.ncbi.nlm.nih.gov/25887395/). DOI: 10.1074/jbc.M115.652693. Access: abstract_metadata. Study: PMID25887395.

58. Funk KE, Mirbaha H, Jiang H et al. Distinct Therapeutic Mechanisms of Tau Antibodies: Promoting Microglial Clearance Versus Blocking Neuronal Uptake. The Journal of biological chemistry. 2015. [PMID 26126828](https://pubmed.ncbi.nlm.nih.gov/26126828/). DOI: 10.1074/jbc.M115.657924. Access: abstract_metadata. Study: PMID26126828.

59. Ramirez DMO, Whitesell JD, Bhagwat N et al. Spontaneous pathology in PS19 tauopathy mice progresses via brain networks. Neurobiology of disease. 2025. [PMID 40886860](https://pubmed.ncbi.nlm.nih.gov/40886860/). DOI: 10.1016/j.nbd.2025.107072. Access: abstract_metadata. Study: PMID40886860.

60. Meisl G, Hidari E, Allinson K et al. In vivo rate-determining steps of tau seed accumulation in Alzheimer's disease. Science advances. 2021. [PMID 34714685](https://pubmed.ncbi.nlm.nih.gov/34714685/). DOI: 10.1126/sciadv.abh1448. Access: full_text_partial. Study: PMID34714685.

61. 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. [PMID 39284839](https://pubmed.ncbi.nlm.nih.gov/39284839/). DOI: 10.1038/s41598-024-72232-2. Access: abstract_metadata. Study: PMID39284839.

62. Penny LK, Arastoo M, Lofthouse R et al. Timing matters: early administration of a high-affinity antibody targeting the tau repeat domain prevents aggregation in a mouse tauopathy model. Alzheimer's research & therapy. 2026. [PMID 41691301](https://pubmed.ncbi.nlm.nih.gov/41691301/). DOI: 10.1186/s13195-026-01985-x. Access: abstract_metadata. Study: PMID41691301.

63. Liu L, Drouet V, Wu JW et al. Trans-synaptic spread of tau pathology in vivo. PloS one. 2012. [PMID 22312444](https://pubmed.ncbi.nlm.nih.gov/22312444/). DOI: 10.1371/journal.pone.0031302. Access: abstract_metadata. Study: PMID22312444.

64. Albert M, Mairet-Coello G, Danis C et al. Prevention of tau seeding and propagation by immunotherapy with a central tau epitope antibody. Brain : a journal of neurology. 2019. [PMID 31038156](https://pubmed.ncbi.nlm.nih.gov/31038156/). DOI: 10.1093/brain/awz100. Access: abstract_metadata. Study: PMID31038156.

65. Chastagner P, Loria F, Vargas JY et al. Fate and propagation of endogenously formed Tau aggregates in neuronal cells. EMBO molecular medicine. 2020. [PMID 33179866](https://pubmed.ncbi.nlm.nih.gov/33179866/). DOI: 10.15252/emmm.202012025. Access: abstract_metadata. Study: PMID33179866.

66. 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. [PMID 33005889](https://pubmed.ncbi.nlm.nih.gov/33005889/). DOI: 10.1093/braincomms/fcaa091. Access: abstract_metadata. Study: PMID33005889.

## Source-specific evidence cards

### [1] Depletion of microglia and inhibition of exosome synthesis halt tau propagation.

**Shows:** Microglial depletion and exosome-synthesis inhibition reduced tau propagation in an AAV entorhinal-to-dentate model and changed dentate excitability.

**Does not show:** AAV expression and broad microglial/exosome effects do not isolate spontaneous tau templating as the mediator of neuron death.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC4.

### [2] Distinct regulation of Tau Monomer and aggregate uptake and intracellular accumulation in human neurons.

**Shows:** Human neuron assays distinguished aggregate uptake through HSPG-related mechanisms from largely LRP1-dependent monomer accumulation.

**Does not show:** Recombinant protein exposure and uptake assays do not demonstrate recipient conversion or endogenous human disease progression; the abstract's leading-cause framing exceeds its experiment.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

### [3] Arc mediates intercellular tau transmission via extracellular vesicles.

**Shows:** Arc knockout nearly abolished intercellular transmission in mutant-tau mice while reducing EV tau and increasing intracellular accumulation with modest early toxicity.

**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.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. UpdateOf: PMID39484489. Subclaims: SC2, SC4.

### [4] Synaptic oligomeric tau in Alzheimer's disease - A potential culprit in the spread of tau pathology through the brain.

**Shows:** Postmortem subdiffraction microscopy detected oligomeric tau in human pre- and postsynaptic terminals, including regions with little fibrillar deposition.

**Does not show:** Static terminal colocalization does not trace transfer direction, recipient templating or an early causal sequence in living people.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2.

### [5] LRP1 is a master regulator of tau uptake and spread.

**Shows:** LRP1 knockdown reduced tau uptake in human-derived cells and reduced neuronal tau spread in a mouse model.

**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.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

### [6] Trem2 deletion enhances tau dispersion and pathology through microglia exosomes.

**Shows:** Trem2 deletion enhanced AAV-P301L tau dispersion, EV seeding activity, synaptic dysfunction and memory deficits; exosome inhibition reduced release in culture.

**Does not show:** Microglial clearance and broader immune effects confound selective transfer mediation; pathological human tau expression is imposed, and Trem2 can protect in this context.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC4.

### [7] Tau Prion Strains Dictate Patterns of Cell Pathology, Progression Rate, and Regional Vulnerability In Vivo.

**Shows:** Eighteen cell-isolated tau strains induced distinct regional and cellular pathology and different network propagation rates in inoculated PS19 mice.

**Does not show:** This demonstrates strain capability in a P301S recipient rather than natural human strain origin or propagation-driven neuronal loss.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

### [8] Proteopathic tau seeding predicts tauopathy in vivo.

**Shows:** A FRET biosensor detected tau seeding in P301S mice before histological tau pathology and discriminated AD tissue from comparison samples.

**Does not show:** Temporal assay sensitivity and mutant-model correlation do not establish seed necessity, direct transfer or neuronal toxicity.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3.

### [9] Exosomes induce endolysosomal permeabilization as a gateway by which exosomal tau seeds escape into the cytosol.

**Shows:** Endolysosomal permeabilization allowed EV-associated tau seeds to reach biosensor-cell cytosol; RAB7 manipulation changed aggregation.

**Does not show:** Permeabilization also occurred with tau-free EVs, only a minority of cells aggregated, and RAB7/lysosomal perturbations affect general trafficking.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

### [10] Alzheimer's disease brain-derived extracellular vesicles spread tau pathology in interneurons.

**Shows:** Human AD EV inoculation in aged wild-type mice induced endogenous tau misfolding with preferential GABAergic pathology and reduced inhibitory synaptic transmission.

**Does not show:** Forced brain EV delivery bypasses normal release and dose; dysfunction and marker reductions are not an audited neuron-death mediation assay. A linked correction requires qualification.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. ErratumIn: PMID33437996. Subclaims: SC2, SC3, SC4.

### [11] Neuronal activity enhances tau propagation and tau pathology in vivo.

**Shows:** Donor physiological tau transferred through medium; optogenetic and chemogenetic stimulation increased release and in-vivo tau pathology.

**Does not show:** Activity also changes intrinsic vulnerability and proteostasis; increased pathology is not proof that transfer-mediated recipient conversion causes degeneration.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC4.

### [12] Distinct tau prion strains propagate in cells and mice and define different tauopathies.

**Shows:** Cell-derived tau conformations retained strain-like characteristics across three inoculated transgenic-mouse generations and patient-derived biosensor isolates differed by tauopathy.

**Does not show:** Repeat-domain reporters and imposed serial inoculation establish templating capability, not natural human intercellular disease causation or infectivity equivalence to PrP.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

### [13] Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in an Alzheimer's disease mouse model.

**Shows:** Brain-penetrant nSMase2 inhibition normalized ceramides and reduced PS19 tau pathology, neuronal-layer thinning and glial changes; it separately reduced AAV-mutant contralateral tau transfer.

**Does not show:** The survival/pathology and transfer experiments use separate systems; ceramide and EV changes have broader effects, so propagation is not the uniquely demonstrated neuroprotective mediator. Original Results show reduced total human tau and loss of the pThr181 difference after total-tau normalization. Layer density/thickness and synaptophysin improve, but no audited total-neuron stereology or behavioral rescue is credited here. The AAV arm normalizes contralateral signal to ipsilateral signal.

**Access/status:** Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph5, 2:Results:paragraph7, 2:Results:paragraph9, 2:Results:paragraph14. No complete-paper or supplement audit claimed. UpdateOf: PMID37502930. Subclaims: SC2, SC4.

### [14] Removing endogenous tau does not prevent tau propagation yet reduces its neurotoxicity.

**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.

**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.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3, SC4.

### [15] Targeting Endogenous Tau in Seeded Tauopathy Models Inhibits Tau Spread.

**Shows:** A mouse-tau-specific antibody reduced human AD-tau-seeded pathology in female wild-type mice despite not binding the human inoculum.

**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.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

### [16] Dendrimer-Conjugated nSMase2 Inhibitor Reduces Tau Propagation in Mice.

**Shows:** Dendrimer-conjugated nSMase2 inhibitor improved exposure and reduced contralateral tau pathology after unilateral mutant-human-tau AAV expression.

**Does not show:** EV suppression and trafficking are broader than a tau-only mediator; this is an engineered transfer model without a reported clinical or neuronal-loss endpoint.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

### [17] Tau seeding activity begins in the transentorhinal/entorhinal regions and anticipates phospho-tau pathology in Alzheimer's disease and PART.

**Shows:** Biosensor testing across 247 fixed human brains found early seeding in transentorhinal/entorhinal cortex and activity ahead of phospho-tau staining, including in later cortical regions.

**Does not show:** Cross-sectional reconstructed timing and an amplification assay do not trace physical transfer; locus-coeruleus phospho-tau does not imply its seeds initiate the whole sequence.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3.

### [18] Tau monomer encodes strains.

**Shows:** Seed-competent monomer ensembles encoded reproducible cell strains and distinct PS19-inoculated pathology, with AD and CBD isolates differing.

**Does not show:** Monomer preparation and reporter selection do not establish spontaneous human strain formation or disease progression dependency.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

### [19] Templated misfolding of Tau by prion-like seeding along neuronal connections impairs neuronal network function and associated behavioral outcomes in Tau transgenic mice.

**Shows:** Injected synthetic tau seeds in P301S mice produced region-dependent spread, impaired synaptic plasticity and corresponding cognitive or motor dysfunction.

**Does not show:** Forced seeds plus mutant tau create a bounded sufficiency paradigm; functional deficits are not direct proof that naturally transferred seeds cause progressive human neuron death.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3, SC4.

### [20] Reversal of neurofibrillary tangles and tau-associated phenotype in the rTgTauEC model of early Alzheimer's disease.

**Shows:** Suppressing entorhinal mutant-tau transgene expression resolved inclusions and abnormal sprouting and prevented progressive neuron loss in rTgTauEC mice.

**Does not show:** Doxycycline lowers the source protein and its cell-autonomous toxicity as well as spread; it is not a propagation-selective mediation test.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC4.

### [21] Exploratory Tau Biomarker Results From a Multiple Ascending-Dose Study of BIIB080 in Alzheimer Disease: A Randomized Clinical Trial.

**Shows:** The 46-person BIIB080 phase 1b trial and extension showed dose-related fluid tau lowering and reduced PET accumulation in small imaging subsets.

**Does not show:** Safety was the original primary endpoint; open-label extension and biomarker outcomes do not establish clinical efficacy or selective propagation blockade. Same trial as MAPTRx primary report.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC4.

### [22] Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer's disease: a phase 1b, randomized, placebo-controlled trial.

**Shows:** In a randomized 46-person MAPTRx phase 1b study, intrathecal antisense lowered CSF total tau by more than half at higher doses; no treated serious adverse events were reported.

**Does not show:** The primary endpoint was safety, not clinical disease modification, and total MAPT synthesis lowering cannot identify spread mediation. A linked author correction remains attached. Original Results show no consistent clinical outcome trend and no dose-responsive injury-biomarker effect; ventricular-volume change was greater in active arms. The examined publisher correction changes an author affiliation, not efficacy results (doi:10.1038/s41591-023-02639-3).

**Access/status:** Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph13, 1:Results:paragraph18, 1:Results:paragraph20, 1:Results:paragraph22, 1:Results:paragraph23. No complete-paper or supplement audit claimed. ErratumIn: PMID37845513. Subclaims: SC4.

### [23] Safety and efficacy of tilavonemab in progressive supranuclear palsy: a phase 2, randomised, placebo-controlled trial.

**Shows:** The 378-randomized tilavonemab PSP trial met prespecified futility criteria and showed no beneficial PSPRS trajectory effect versus placebo.

**Does not show:** This tests an N-terminal extracellular antibody in symptomatic PSP, not verified removal of every intracellular or transmissible tau species; null efficacy restricts this strategy without disproving all tau mechanisms.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC4.

### [24] Connectivity as a universal predictor of tau progression in atypical Alzheimer's disease.

**Shows:** Across 320 atypical AD PET cases, 78 longitudinal cases and 93 independent autopsies, functional connectivity predicted variant-specific tau patterns and accumulation.

**Does not show:** The connectome comes from healthy controls and epicentres are inferred from baseline/accumulation; covariance cannot distinguish tau transfer from network-linked vulnerability or activity.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

### [25] Increased between-network connectivity: A risk factor for tau elevation and disease progression.

**Shows:** In 46 older participants, increased between-network connectivity predicted later tau PET elevation, cortical thinning and lower delayed recall, particularly with amyloid positivity.

**Does not show:** Small observational clustering and correlated vulnerability do not demonstrate molecular movement or recipient templating.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

### [26] Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model.

**Shows:** Synaptic loss and microgliosis preceded fibrillar tangles in P301S mice; broad FK506 immunosuppression attenuated pathology and increased lifespan.

**Does not show:** Earlier dysfunction weakens a mature-tangle-only model; broad immunosuppression and mutant expression do not identify spread mediation. A linked erratum lacks an identifier and its details remain unexamined.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. ErratumIn: PMIDnot supplied. Subclaims: SC1, SC4.

### [27] ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids.

**Shows:** Isogenic MAPT-V337M organoids developed splicing/autophagy changes before selective glutamatergic-neuron loss; PIKFYVE inhibition rescued glutamate toxicity.

**Does not show:** This establishes a familial cell-intrinsic vulnerability route in organoids, not organismal follow-through or intercellular propagation dependency.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC4.

### [28] Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia.

**Shows:** Conditional astrocytic APOE4 removal after pathology onset protected against neurodegeneration and synaptic loss in P301S mice and reduced microglial phagocytosis.

**Does not show:** A real glial causal contribution need not be mediated by tau transfer; mutant-tau and APOE context restrict generalization.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC4.

### [29] Lowering Synaptogyrin-3 expression rescues Tau-induced memory defects and synaptic loss in the presence of microglial activation.

**Shows:** Reducing Synaptogyrin-3 rescued mutant-tau synaptic plasticity, memory and synapse loss while neuroinflammation remained elevated.

**Does not show:** The contrast identifies synaptic toxicity independent of persistent glial activation; it does not directly test pathological species transfer.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC4.

### [30] Regional vulnerability and spreading of hyperphosphorylated tau in seeded mouse brain.

**Shows:** Whole-brain mapping showed injected fibrils produced a more AD-like pattern than spontaneous P301L pathology; deposits also appeared beyond direct connections and antibody treatment reduced burden.

**Does not show:** Choosing a seed to improve resemblance is not natural disease validation, and static connectivity plus antibody effects does not isolate physical transfer-driven neuronal loss.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2.

### [31] Tau Oligomer-Containing Synapse Elimination by Microglia and Astrocytes in Alzheimer Disease.

**Shows:** Among 40 autopsies, dementia cases had more tau-oligomer-tagged synapses within glia and lower synaptic density than resilient cases with similar Braak stage.

**Does not show:** Cross-sectional engulfment and matching cannot show that transfer or glial activity caused the antecedent cognitive decline; tangle-equivalent resilience challenges burden-only explanations.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC4.

### [32] Synaptogyrin-3 Mediates Presynaptic Dysfunction Induced by Tau.

**Shows:** Synaptogyrin-3 reduction in fly and mouse tauopathy restored vesicle mobility and neurotransmission by reducing pathological tau-vesicle association.

**Does not show:** This narrows a presynaptic toxicity mechanism, not templated propagation; engineered tau systems and conserved synaptic function require separate generalization.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC4.

### [33] PTEN activation contributes to neuronal and synaptic engulfment by microglia in tauopathy.

**Shows:** PTEN activation and phosphatidylserine exposure preceded neuronal-structure engulfment in rTg4510 mice; PTEN inhibition reduced microglial uptake.

**Does not show:** Synaptic tagging and engulfment are rival or downstream toxicity mechanisms, and pharmacology plus mutant overexpression do not isolate templated transfer.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC4.

### [34] Tilavonemab in early Alzheimer's disease: results from a phase 2, randomized, double-blind study.

**Shows:** Tilavonemab failed to improve 96-week CDR-SB versus placebo in 453 randomized early-AD participants.

**Does not show:** This is a clinical efficacy null for a particular antibody, not a demonstration that every pathogenic tau pool was neutralized or propagation selectively blocked. Original Results confirm lower free CSF tau at higher doses, higher plasma total tau and no tau PET or NfL response. Isolated MRI differences lacked multiplicity adjustment.

**Access/status:** Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph0, 2:Results:paragraph17, 2:Results:paragraph20, 2:Results:paragraph21, 2:Results:paragraph22, 2:Results:paragraph25. No complete-paper or supplement audit claimed. none_found. Subclaims: SC4.

### [35] Safety and Efficacy of Semorinemab in Individuals With Prodromal to Mild Alzheimer Disease: A Randomized Clinical Trial.

**Shows:** TAURIEL semorinemab produced no slowing of 73-week CDR-SB progression in the 422-person modified intention-to-treat cohort.

**Does not show:** A symptomatic N-terminal antibody trial does not verify selective interruption of intracellular recipient conversion; failure restricts this clinical strategy.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC4.

### [36] Safety and efficacy of anti-tau monoclonal antibody gosuranemab in progressive supranuclear palsy: a phase 2, randomized, placebo-controlled trial.

**Shows:** PASSPORT gosuranemab showed no PSPRS or secondary clinical benefit in 486 dosed PSP patients despite a 98 percent fall in unbound N-terminal CSF tau.

**Does not show:** Strong fluid target engagement is not complete seed neutralization or proof of all pathogenic-pool blockade; a linked author correction is attached to the parent.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. ErratumIn: PMID36253611. Subclaims: SC4.

### [37] Pharmacodynamic effects of semorinemab on plasma and CSF biomarkers of Alzheimer's disease pathophysiology.

**Shows:** Semorinemab biomarker analyses from TAURIEL and LAURIET showed increased CSF YKL-40 and plasma pTau181, with GFAP stabilization in LAURIET but not TAURIEL.

**Does not show:** These are reused trial samples and mechanistic biomarker effects, not new independent efficacy trials or direct evidence of beneficial microglial mediation.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC4.

### [38] TANGO: a placebo-controlled randomized phase 2 study of efficacy and safety of the anti-tau monoclonal antibody gosuranemab in early Alzheimer's disease.

**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.

**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.

**Access/status:** 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. none_found. Subclaims: SC4.

### [39] Assessment of Efficacy and Safety of Zagotenemab: Results From PERISCOPE-ALZ, a Phase 2 Study in Early Symptomatic Alzheimer Disease.

**Shows:** PERISCOPE-ALZ zagotenemab did not slow clinical progression in 360 randomized participants; PET, MRI and NfL showed no disease-modifying response.

**Does not show:** Only 218 completed treatment and pathogenic brain engagement was not established; plasma tau increases do not prove seed neutralization. A linked correction remains qualified.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. ErratumIn: PMID40184595. Subclaims: SC4.

### [40] Randomized Phase II Study of the Safety and Efficacy of Semorinemab in Participants With Mild-to-Moderate Alzheimer Disease: Lauriet.

**Shows:** LAURIET semorinemab improved ADAS-Cog11 decline at week 49 but not the coprimary activities-of-daily-living endpoint or global secondary measures.

**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.

**Access/status:** 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. none_found. Subclaims: SC4.

### [41] Safety, tolerability and biomarker results of bepranemab in participants with progressive supranuclear palsy: a randomised, multicentre, double-blind, placebo-controlled, phase 1b trial.

**Shows:** A 25-person bepranemab PSP phase 1b trial reported acceptable safety and about 80 percent reduction in mean free CSF tau.

**Does not show:** Safety and target occupancy are not clinical disease modification; small phase 1 enrollment cannot settle whether mid-region neutralization blocks propagation-driven degeneration.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC4.

### [42] Galectin-3 aggravates microglial activation and tau transmission in tauopathy.

**Shows:** Galectin-3 deletion in THY-Tau22 mice reduced activation, tau pathology and synaptic loss and rescued memory; cell studies linked Gal3 to EV release and fibrillation.

**Does not show:** Genetic removal also changes broad immune responses; the two arms do not isolate propagation as the uniquely causal neuroprotective mediator.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC4.

### [43] ApoE3 R136S binds to Tau and blocks its propagation, suppressing neurodegeneration in mice with Alzheimer's disease.

**Shows:** ApoE3-Christchurch reduced tau uptake and fragmentation, seeded spread, inflammatory signals and cognitive defects relative to wild-type ApoE3 in amyloid and P301S models.

**Does not show:** APOE changes several uptake, inflammatory and proteolytic pathways, and PFF initiation remains imposed; a natural human variant does not isolate propagation mediation here.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC4.

### [44] Transmission and spreading of tauopathy in transgenic mouse brain.

**Shows:** Mutant-P301S brain extract induced filament assembly of wild-type human tau and regional pathology in inoculated transgenic recipients.

**Does not show:** The recipients express human tau and receive artificial intracerebral exposure; capability is not natural cell-to-cell necessity or neurodegeneration mediation.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

### [45] Propagation of tau pathology in a model of early Alzheimer's disease.

**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.

**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.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. ErratumIn: PMIDnot supplied. Subclaims: SC2, SC3, SC4.

### [46] hiPSC-neurons recapitulate the subtype-specific cell intrinsic nature of susceptibility to neurodegenerative disease-relevant aggregation.

**Shows:** Different human iPSC neuronal subtypes showed distinct susceptibility to identical tau or synuclein seeds; uptake/degradation did not explain the tau differences.

**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.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3.

### [47] Amyloid-associated hyperconnectivity drives tau spread across connected brain regions in Alzheimer's disease.

**Shows:** Two human imaging samples associated amyloid-related hyperconnectivity with later regional tau accumulation, with statistical mediation of the amyloid association.

**Does not show:** Observational mediation requires unverified no-confounding assumptions and does not trace molecular transfer; the paper's causal wording exceeds selective perturbation evidence.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

### [48] Tau seeding without tauopathy.

**Shows:** Seed-enriched material from 19 neurologically normal human brains showed parietal-cortex seeding by two amplification assays without conventional tau pathology.

**Does not show:** Control seeds differed conformationally from AD seeds; seeding positivity alone is not pathological progression, and assay amplification is not natural neuronal conversion.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3.

### [49] CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis.

**Shows:** Human-neuron CRISPR screens identified tau proteostasis dependencies including UFMylation, GPI biosynthesis and CRL5-SOCS4, with mitochondrial disruption generating altered tau fragments.

**Does not show:** Cellular aggregation control and disease correlation do not demonstrate intercellular spread or clinical neuroprotection; the linked preprint is not a second study.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. UpdateOf: PMID37398204. Subclaims: SC3, SC4.

### [50] Anatomic survey of seeding in Alzheimer's disease brains reveals unexpected patterns.

**Shows:** Twenty AD brains sampled across 25 regions showed seeding before some AT8 pathology and in unexpected sites including axons and Bergmann glia.

**Does not show:** Cross-sectional seed maps are not lineage tracing and complicate a single canonical regional sequence; the linked correction requires qualification.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. ErratumIn: PMID38835097. Subclaims: SC1, SC3.

### [51] Patient-centered connectivity-based prediction of tau pathology spread in Alzheimer's disease.

**Shows:** Patient-specific connectivity predicted longitudinal tau accumulation in two imaging samples better than fixed Braak readouts; simulated trials required smaller samples.

**Does not show:** Simulated intervention efficiency is not a conducted therapeutic test, and model fit cannot establish physical transfer or necessity.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

### [52] Longitudinal predictive modeling of tau progression along the structural connectome.

**Shows:** A structural-connectome diffusion model fit two-timepoint HABS/ADNI PET and predicted a third measurement in available participants.

**Does not show:** Source/clearance terms and graph diffusion are mathematical assumptions, not measured intracellular conversion; cohort and imaging overlap restrict independence.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

### [53] Plaque associated microglia hyper-secrete extracellular vesicles and accelerate tau propagation in a humanized APP mouse model.

**Shows:** Microglial depletion reduced AAV-tau spread in wild-type and APP-knock-in mice but increased plaques and plaque-associated dystrophic-neurite tau; tagged microglial EVs carried tau.

**Does not show:** Depletion changes clearance and injury as well as transfer, so reduced distal signal cannot be relabeled uniform protection. A linked correction remains attached.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. ErratumIn: PMID33853665. Subclaims: SC2, SC4.

### [54] Bassoon contributes to tau-seed propagation and neurotoxicity.

**Shows:** Bassoon downregulation reduced tau seed-associated pathology and spread and rescued synaptic/behavioral defects and atrophy in experimental tauopathy systems.

**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.

**Access/status:** 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. none_found. Subclaims: SC2, SC3, SC4.

### [55] Activated microglia mitigate Aβ-associated tau seeding and spreading.

**Shows:** TREM2 deficiency or microglial ablation increased amyloid-associated tau seeding/spread, and repopulated microglia did not recover the protective activation state.

**Does not show:** This shows protective microglial function in an amyloid-seeded context and contradicts universal beneficial depletion; seed burden is not equivalent to neuron-loss causality.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC4.

### [56] Tau Internalization is Regulated by 6-O Sulfation on Heparan Sulfate Proteoglycans (HSPGs).

**Shows:** CRISPRi and sulfation manipulation identified HSPG 6-O-sulfation dependence of tau uptake across cells, human-derived neurons and mouse slices.

**Does not show:** Uptake is one step; these experiments do not establish intact-animal endogenous transfer, conversion or degeneration dependency.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

### [57] Tau Trimers Are the Minimal Propagation Unit Spontaneously Internalized to Seed Intracellular Aggregation.

**Shows:** Fractionated recombinant and AD-derived tau assemblies of at least three units underwent uptake and seeded biosensor aggregation, with HSPG-sensitive entry.

**Does not show:** The minimum size depends on preparation and assay; extracellular exposure and reporter amplification do not prove a universal naturally propagating toxic species.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [58] Distinct Therapeutic Mechanisms of Tau Antibodies: Promoting Microglial Clearance Versus Blocking Neuronal Uptake.

**Shows:** Tau antibodies differed in promoting Fc-mediated microglial uptake versus blocking neuronal uptake according to epitope and aggregate preparation/size.

**Does not show:** An antibody's pathology benefit cannot be assigned automatically to transfer blockade; this is cultured-cell mechanism analysis, not new in-vivo disease causality.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

### [59] Spontaneous pathology in PS19 tauopathy mice progresses via brain networks.

**Shows:** Whole-brain age-series maps of pan-neuronal P301S PS19 mice fitted retrograde-biased connectivity models without injected seeds.

**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.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. UpdateOf: PMID37293074. Subclaims: SC1, SC2.

### [60] In vivo rate-determining steps of tau seed accumulation in Alzheimer's disease.

**Shows:** Kinetic fits across multiple human seed/tau measures suggested local replication, rather than interregional spread, limits neocortical accumulation from Braak III onward.

**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.

**Access/status:** 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. none_found. Subclaims: SC1, SC4.

### [61] The cellular prion protein does not affect tau seeding and spreading of sarkosyl-insoluble fractions from Alzheimer's disease.

**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.

**Does not show:** Forced inoculation establishes host conversion capability and excludes an obligatory PrP receptor in this setting, not natural human tau propagation necessity.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

### [62] Timing matters: early administration of a high-affinity antibody targeting the tau repeat domain prevents aggregation in a mouse tauopathy model.

**Shows:** A repeat-domain antibody reduced seed-competent/aggregated tau and injury biomarkers when started early in Line66 mice, but later treatment did not remove established aggregates below baseline.

**Does not show:** The endpoints were aggregation and fluid injury markers, without a reported functional trajectory test; epitope and timing matter but do not establish spread-mediated neuroprotection.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3, SC4.

### [63] Trans-synaptic spread of tau pathology in vivo.

**Shows:** Entorhinal-biased human-tau transgenic mice developed human tau staining and mature pathology in connected hippocampal and cortical regions with age.

**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.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2.

### [64] Prevention of tau seeding and propagation by immunotherapy with a central tau epitope antibody.

**Shows:** A central-epitope antibody neutralized human AD-extract seeding and reduced distal pathology after K18-P301L fibrils, outperforming one N-terminal comparator.

**Does not show:** Imposed seeds and transgenic substrate limit inference; reducing secondary pathology is more specific than inoculum neutralization but not proof of clinical neuronal-loss mediation.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [65] Fate and propagation of endogenously formed Tau aggregates in neuronal cells.

**Shows:** A neuronal reporter model visualized K18/AD-seeded aggregate formation and contact-dependent transfer with new deposits in neighboring cells, including nanotube-associated material.

**Does not show:** Endogenously formed refers to aggregates formed inside reporter cells after seeding, not native unseeded human disease; tau-fragment reporters and cultures restrict generalization.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [66] Dextran sulphate-induced tau assemblies cause endogenous tau aggregation and propagation in wild-type mice.

**Shows:** Dextran-sulfate-assembled full-length tau induced host mouse-tau aggregation and connected-region pathology in nontransgenic mice after intracerebral injection.

**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.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.