The probabilistic model of Alzheimer disease: the amyloid hypothesis revised

Giovanni B. Frisoni*, Daniele Altomare, Dietmar Rudolf Thal, Federica Ribaldi, Rik van der Kant, Rik Ossenkoppele, Kaj Blennow, Jeffrey Cummings, Cornelia van Duijn, Peter M. Nilsson, Pierre-Yves Dietrich, Philip Scheltens, Bruno Dubois

*Corresponding author for this work

Research output: Contribution to journalReview articleAcademicpeer-review


The current conceptualization of Alzheimer disease (AD) is driven by the amyloid hypothesis, in which a deterministic chain of events leads from amyloid deposition and then tau deposition to neurodegeneration and progressive cognitive impairment. This model fits autosomal dominant AD but is less applicable to sporadic AD. Owing to emerging information regarding the complex biology of AD and the challenges of developing amyloid-targeting drugs, the amyloid hypothesis needs to be reconsidered. Here we propose a probabilistic model of AD in which three variants of AD (autosomal dominant AD, APOE ε4-related sporadic AD and APOE ε4-unrelated sporadic AD) feature decreasing penetrance and decreasing weight of the amyloid pathophysiological cascade, and increasing weight of stochastic factors (environmental exposures and lower-risk genes). Together, these variants account for a large share of the neuropathological and clinical variability observed in people with AD. The implementation of this model in research might lead to a better understanding of disease pathophysiology, a revision of the current clinical taxonomy and accelerated development of strategies to prevent and treat AD.
Original languageEnglish
Pages (from-to)53-66
Number of pages14
JournalNature Reviews Neuroscience
Issue number1
Early online date2021
Publication statusPublished - Jan 2022

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