Coverage Fraction

An epistemic guardrail for the corpus. The three-phase architecture makes claims about "Alzheimer's disease." That phrase carries two incompatible meanings — a biologically defined entity and a clinical syndrome — and the architecture describes only the first. This note records the difference and the price.

The statement the corpus should make, and until July 2026 never did: the architecture describes Alzheimer's disease biologically defined — amyloid-positive, tau-positive, of typical topography — which is between 3 and 22 per cent of dementia, most plausibly 10 to 15 per cent.

Why there is a range and not a number

"Pure AD" is not a fixed biological quantity. It falls monotonically as more pathologies are scored, which means the figures below are not competing measurements of one thing — they are one disease seen through panels of different width.

The filters must not be multiplied. They are not independent — co-pathology and atypical topography covary, since limbic-predominant cases carry the most LATE-NC and hippocampal-sparing cases the least — and they come from cohorts of different mean age, which matters enormously: Boyle's cohort has a mean age at death of 89.7, where co-pathology is near-obligate; Murray's hippocampal-sparing group has a mean age at death of 73.

What a small fraction does and does not mean

It does not invalidate the architecture. A framework may legitimately describe a minority and still be important — the minority may be the mechanistically clearest case, the one in which the process runs uncontaminated. Pure AD is rare in the way that uncomplicated anything is rare in the ninth decade.

The problem was never the size of the fraction. It was that the corpus had never stated it, and had therefore never distinguished claims that hold for the pure case from claims about the disease as encountered.

The entry problem: ignition is near-universal

The sharpest consequence sits underneath the whole subtype literature. Abnormal tau is essentially universal in adult humans: of 2,332 unselected brains aged 1–100, only 10 (0.4 per cent) were free of it (Braak 2011). Primary age-related tauopathy — tau in the brainstem and medial temporal distribution without significant amyloid — was found in 719 of 1,589 (45.2 per cent) of a forensic series aged ≥ 40 (Yoshida 2024), and Crary's original description holds that PART "generally does not progress to the isocortical Braak stages" (Crary 2014).

The dementia rate in PART is 1.4 per cent, against 54.1 per cent in AD cases in the same series (Yoshida 2024). Remaining lifetime dementia risk at 65 is 10.9 per cent for men, 19 per cent for women (Seshadri 1997).

Phase I, as written, therefore describes near-universal human ageing rather than the event that starts the disease. It should be stated as the substrate on which the disease is built. The corpus has no exit criterion distinguishing an ignition that progresses from one that does not — this is its largest open question, and it is worth noting that the difference between PART and AD in the series above is amyloid. The corpus's own steelman of amyloid primacy, The Case for the Cascade, states the candidate answer — amyloid as the permissive trigger licensing tau's escape from the medial temporal lobe — and the two documents have not been read against each other. See Plaque Origin What is Established.

The exit problem: traversal is not sufficient

Completing the pathological arc does not reliably produce the syndrome. Phase III produces the substrate of dementia; whether it produces the syndrome is set by resilience factors the architecture does not model. See Phase Measurability for the parallel instrument problem.

The remainder are routes, not attrition

The cases the funnel discards are not absent — they have dementia, and they went somewhere. Read as forks rather than filters, they resolve into describable alternative routes: limbic-predominant and hippocampal-sparing topographies, LATE-NC, Lewy co-pathology, vascular contribution. The corpus's coverage of this literature is currently zero — the terms co-pathology, LATE-NC and hippocampal-sparing appear nowhere in the research directory outside the stress-test documents. That gap is logged and open.

Primary sources

• Boyle PA, Yu L, Wilson RS, et al. (2018). Person-specific contribution of neuropathologies to cognitive loss in old age. Ann Neurol 83(1):74–83. PMID 29244218
• Boyle PA, Yu L, Leurgans SE, et al. (2019). Attributable risk of Alzheimer's dementia attributed to age-related neuropathologies. Ann Neurol 85(1):114–124. PMID 30421454
• Schneider JA, Arvanitakis Z, Bang W, Bennett DA (2007). Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology 69(24):2197–2204. PMID 17568013
• Kapasi A, DeCarli C, Schneider JA (2017). Impact of multiple pathologies on the threshold for clinically overt dementia. Acta Neuropathol 134(2):171–186. PMID 28488154
• Murray ME, Graff-Radford NR, Ross OA, et al. (2011). Neuropathologically defined subtypes of Alzheimer's disease with distinct clinical characteristics. Lancet Neurol 10(9):785–796. PMID 21802369
• Vogel JW, Young AL, Oxtoby NP, et al. (2021). Four distinct trajectories of tau deposition identified in Alzheimer's disease. Nat Med 27(5):871–881. PMID 33927414
• Braak H, Thal DR, Ghebremedhin E, Del Tredici K (2011). Stages of the pathologic process in Alzheimer disease: age categories 1–100 years. J Neuropathol Exp Neurol 70(11):960–969. PMID 22002422
• Yoshida K, Hata Y, Ichimata S, et al. (2024). Prevalence and clinicopathological characteristics of primary age-related tauopathy. Acta Neuropathol Commun 12:104. PMID 38938196
• Crary JF, Trojanowski JQ, Schneider JA, et al. (2014). Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol 128(6):755–766. PMID 25348064
• Humphrey WM, Wang H, Keene CD, et al. (2021). PART and the spectrum of tau pathology. J Neuropathol Exp Neurol 80(1):41–49. PMID 33147361
• Seshadri S, Wolf PA, Beiser A, et al. (1997). Lifetime risk of dementia and Alzheimer's disease. Neurology 49(6):1498–1504. PMID 9409336

Converges on

Phase Measurability · Plaque Origin What is Established · Staged anatomical progression · Tau Propagation