Scientific article

The probabilistic model of Alzheimer disease: the amyloid hypothesis revised

Published inNature reviews. Neuroscience, vol. 23, no. 1, p. 53-66
Publication date2022-01
First online date2021-11-23

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.

  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Alzheimer Disease / psychology
  • Amyloid / metabolism
  • Amyloid Neuropathies / metabolism
  • Amyloid Neuropathies / pathology
  • Amyloid beta-Peptides
  • Animals
  • Humans
  • Models, Statistical
  • Tau Proteins / metabolism
Citation (ISO format)
FRISONI, Giovanni et al. The probabilistic model of Alzheimer disease: the amyloid hypothesis revised. In: Nature reviews. Neuroscience, 2022, vol. 23, n° 1, p. 53–66. doi: 10.1038/s41583-021-00533-w
Main files (1)
Article (Published version)
ISSN of the journal1471-003X

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