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MechanismUnknown — conflicting evidence

Accumulation of amyloid-beta is the primary causal driver of Alzheimer's disease pathogenesis

Weak-link patterns

Brief §8's named failure modes, computed from this claim's own paper roles and status -- not a single weakness score. Patterns B and E aren't implemented yet (need dependency-graph machinery, docs/BASIC_ROADMAP.md Phase 11).

C: Conflicting evidence

stored status is 'unknown_conflicting'

F: Influential paper, later repeatedly contradicted

flagship 'Alzheimer's Disease: The Amyloid Cascade Hypothesis' (7507 citations) vs 4 contradicting row(s) of 11 total (needs >=3 contradicting)

Open questions

Pattern G. Human-written, never generated -- deliberately no importance or priority score (docs/BASIC_ROADMAP.md's own precedent against inventing one, matching innovation_considerations).

Is amyloid-beta accumulation the primary causal driver of Alzheimer's, or a downstream marker of the real cause -- given repeated Phase 3 trial failures directly targeting it?

Motivated by: Pattern C (conflicting evidence) and Pattern F (highly-cited original, 4 later contradicting trial results)

Evidence map

Position shows direction, circle area shows citation count. Click a paper for the reason its role was assigned.

MECHANISMCLAIMUnknown — conflicting…Original Alzheimer's Disease: The Amyloid Cascade Hypothesis 7,507 citationsHardy 19927,507 citesConceptual replication — success Lecanemab in Early Alzheimer’s Disease 5,553 citationsDyck 20225,553 citesConceptual replication — success Donanemab in Early Symptomatic Alzheimer Disease 2,777 citationsSims 20232,777 citesConceptual replication — success — RETRACTED, excluded from evidence counts RETRACTED ARTICLE: A specific amyloid-β protein assembly in the brain impairs memory 2,762 citationsLesné 20062,762 citesConceptual replication — success Amyloid β-Protein and the Genetics of Alzheimer's Disease 798 citationsSelkoe 1996798 citesConceptual replication — failure Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer's Disease 1,992 citationsSalloway 20141,992 citesConceptual replication — failure A Phase 3 Trial of Semagacestat for Treatment of Alzheimer's Disease 1,224 citationsDoody 20131,224 citesConceptual replication — failure Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease 1,065 citationsHonig 20181,065 citesConceptual replication — failure Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer’s Disease 693 citationsEgan 2018693 citesReview / meta-analysis The amyloid hypothesis of Alzheimer's disease at 25 years 6,261 citationsSelkoe 20166,261 citesReview / meta-analysis The case for rejecting the amyloid cascade hypothesis 768 citationsHerrup 2015768 citesReview / meta-analysis The amyloid cascade hypothesis: an updated critical review 285 citationsKepp 2023285 cites
SupportsDisconfirmsSynthesisCircle area ∝ citation countRetracted — not counted

Evidence dimensions

Eight independent 0–5 judgments, each with a written rationale. Deliberately never summed into one score.

Evidence strength

Enormous, high-quality and directly on point, with genuinely strong human-genetic evidence for a causal role - but the therapeutic tests that should follow from 'primary driver' mostly failed, and the two that succeeded did so modestly.

Replication (any kind)

Among the most intensively tested hypotheses in modern biomedicine, across three decades and many independent groups.

Independent replication

Strictly per the same-paradigm definition: no independent re-run of the 1992 synthesis as such. Essentially all subsequent work is different-method, which the triangulation dimension covers instead.

Methodological triangulationscored retroactively

Human genetics, transgenic animal models, biomarker imaging and multiple phase 3 RCTs all bear on the same claim - as thorough a spread of independent designs as any claim in the corpus.

Methodological quality

Trial evidence is phase 3, randomised, large and pre-registered - the highest standard in the corpus. Docked one point because a load-bearing piece of the mechanistic evidence was retracted for image manipulation, a quality fact with nowhere else to be recorded.

Predictive success

The central prediction - remove amyloid, arrest the disease - largely failed for two decades. Lecanemab and donanemab are partial vindication at best, with effects far smaller than the hypothesis implied.

Consensus

Still the field's dominant organising framework and the basis of approved therapies, but with sustained, credible, published dissent.

Alternative explanations ruled out

Tau, neuroinflammation, vascular and mitochondrial accounts are all live, and 'amyloid is a marker or downstream consequence rather than the driver' remains a well-articulated competing reading of the same data.

Scored by human.

Why this status

The derivation rule, evaluated top to bottom, first match wins. This is the rule itself — not a confidence score standing in for one.

1 retracted paper is excluded from every count below, so the rules weigh 11 of the 12 papers listed above. A retraction means the finding was withdrawn — the row stays visible, but it is not evidence.

  1. 1
    Unknown — unexplored

    11 paper rows (needs <3) and evidence_strength=3 (needs <=1); both required

  2. 2
    Unknown — conflicting evidencematched

    (a) 0 failure vs 0 success rows -> no; (b) 3 review rows — opposite-verdict test is a human judgment, not a count; (c) 4 conceptual failure vs 3 conceptual success, 1 original -> fires (balanced)

  3. 3
    Unknown — underdeterminednot reached

    alternative_explanations=2 (needs <=1) AND evidence_strength=3 (needs >=3)

  4. 4
    Establishednot reached

    independent_replication=1 (>=4), evidence_strength=3 (>=4), consensus=3 (>=4)

  5. 5
    Strong, domain-limitednot reached

    evidence_strength=3 (>=4) AND independent_replication=1 (>=3), plus a written scope limit (human judgment)

  6. 6
    Active consensus, incompletenot reached

    consensus=3 (>=4) AND (methodological_quality=4 <=3 OR alternative_explanations=2 <=2)

  7. 7
    Plausible, under active investigationnot reached

    independent_replication=1 (needs ==2) AND evidence_strength=3 (needs 2-3), plus recent activity (human judgment)

  8. 8
    Speculativenot reached

    7/11 rows are empirical (needs 0) AND evidence_strength=3 (needs <=1)

  9. 9
    Preliminarymatchednot reached

    11 non-theoretical row(s) exist AND independent_replication=1 (needs <=1)

Recorded rationale

v4 rule 2 - clause (c1) fires on a balanced 4-vs-4 split of conceptual replications (four phase 3 anti-amyloid trials confirming vs four failing), and clause (b) fires on reviews reaching opposite verdicts (Selkoe & Hardy 2016 vs Herrup 2015 and Kepp 2023). Naive citation-only guess was 'established'; divergence material. Pilot 4 (biomedicine; prior familiarity disclosed HIGH). NOTE: one conceptual_replication_success row (Lesne 2006, W2075481535) is formally RETRACTED and is nonetheless counted as supporting evidence - the rubric has no retraction provision. See Pilot 4 log Finding 1 and the proposed v5 correction. Excluding it leaves the status unchanged here (3 vs 4 is still within 1), but a worked counterexample in the log shows cases where it would flip.