Genetics, biomarker ordering and treatment trials support an upstream amyloid contribution in defined settings. Benefit after plaque removal varies across trials, and a universal amyloid-to-tau-to-neurodegeneration chain remains a separate question.
This dated addendum adds selected evidence and tests that could resolve the remaining questions. It does not regrade the archived review.
Each question identifies a limit in the checked evidence. A missing search result alone does not establish a gap in the entire field.
Competing explanation: Late symptomatic benefit may reflect contribution after initiation, while tau or other injury becomes self-sustaining.
Discriminating test: Long-duration prevention randomization in biomarker-defined presymptomatic groups; prespecify clinical onset, clearance, tau trajectory and adverse events.
Competing explanation: Amyloid and tau biomarkers can move together without tau carrying the treatment effect.
Discriminating test: Repeated tau PET and neurodegeneration measures within randomization; specify mediator timing, missingness and sensitivity to mediator–outcome confounding.
Competing explanation: Differences may arise from drug kinetics, target species, dose, disease stage or incomplete clearance.
Discriminating test: Harmonized analyses and prospectively matched trials with target engagement, baseline tau and equivalent outcome schedules; avoid cross-trial causal attribution.
Competing explanation: Protective host factors may block downstream tau pathology despite high amyloid.
Discriminating test: Genotype-stratified longitudinal cohorts and mechanistic follow-up with independent protective cases; retain disease subtype boundaries.
Electronic publication dates are used where recorded, with issue years shown separately. This is a selected chronology, not a claim of scientific priority or independent replication for every entry.
APP missense variation segregated with familial Alzheimer disease.
What it cannot establish: A specific inherited route does not establish the initiating cause of all sporadic disease.
APP duplication was identified in families with early-onset disease and cerebral amyloid angiopathy.
What it cannot establish: The duplicated locus and inherited exposure differ from ordinary sporadic disease.
Reducing tau prevented deficits despite persistently high amyloid.
What it cannot establish: A model-specific downstream dependency does not establish the human mediation chain.
Biomarker abnormalities were ordered relative to expected inherited-disease onset.
What it cannot establish: The authors called for longitudinal confirmation; chronology is not a causal perturbation.
APP A673T was associated with protection and reduced amyloidogenic peptide formation in vitro.
What it cannot establish: Rare lifelong genetic exposure is not equivalent to late-life plaque removal.
An APOE3 Christchurch homozygote had delayed impairment despite extensive amyloid.
What it cannot establish: A single case bounds simple sufficiency but cannot estimate prevalence.
Lecanemab modestly slowed decline over 18 months, with adverse events.
What it cannot establish: Treatment contribution does not establish disease initiation or complete tau mediation.
Donanemab slowed progression in the prespecified symptomatic trial populations.
What it cannot establish: Selected amyloid/tau-positive participants and treatment harms bound generalization.
Gantenerumab reduced plaques without significant benefit on either trial’s primary clinical endpoint.
What it cannot establish: Incomplete clearance and exposure duration limit a universal negative interpretation; two trials are one report.
Amyloid-related biomarkers diverged before other markers and cognitive decline.
What it cannot establish: Observed ordering does not isolate a necessary cause.
Long exposure suggested possible delay, while short or partial removal lacked significant clinical effects.
What it cannot establish: External controls and extension selection prevent treating this as a fresh randomized prevention result.
Case-specific Consensus records assisted gap discovery, chronology and targeted paper questions. Shared template wording about an amyloid-specific Deep follow-up is not evidence of a Deep run for this topic; the dated source records establish the actual use and access limits. Primary identifiers, selected abstract passages, correction notices and available primary-body passages were cross-checked. Generated absence cells, duplicate milestones and unsupported access claims were rejected.
Results P25/P28: both trial-specific primary CDR-SB tests were nonsignificant; only a minority attained amyloid-negative status. Pooled/exploratory results are not replacements for the primary tests.
This focused addendum does not establish 50–70 complete primary Methods/Results examinations per review. Baseline reading receipts and scores retain their original scope.
Selected full-text checks: 1; abstract checks: 10; metadata-only anchors: 0. Complete-paper examinations credited in this update: 0.
New enrichment: HSEF v5.3 causal distinctions. Archived scorecard schema: 5.4; retained as recorded.
The first Pro timeline duplicated four reports into ten entries. It was replaced after a Deep follow-up and primary-record checks. Retracted Lesné 2006 is excluded from positive evidence.
PMID 1671712 · DOI 10.1038/349704a0
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
PMID 16369530 · DOI 10.1038/ng1718
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
PMID 17478722 · DOI 10.1126/science.1141736
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
PMID 22801501 · DOI 10.1038/nature11283
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
PMID 22784036 · DOI 10.1056/NEJMoa1202753
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
Linked notices: Correction (identifier unavailable in this record)
Linked notice presence was checked in the primary record; its scientific impact was not verified in this update.
PMID 31686034 · DOI 10.1038/s41591-019-0611-3
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
PMID 36449413 · DOI 10.1056/NEJMoa2212948
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
PMID 37459141 · DOI 10.1001/jama.2023.13239
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
PMID 37966285 · DOI 10.1056/NEJMoa2304430
Selected full-text passages checked. Results P25/P28: both trial-specific primary CDR-SB tests were nonsignificant; only a minority attained amyloid-negative status. Pooled/exploratory results are not replacements for the primary tests.
PMID 38381674 · DOI 10.1056/NEJMoa2310168
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
PMID 40120616 · DOI 10.1016/S1474-4422(25)00024-9
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
Linked notices: Correction 40651485
Linked notice presence was checked in the primary record; its scientific impact was not verified in this update.
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