The probabilistic model of Alzheimer disease: the amyloid hypothesis revised

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Abstract
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, [size=10.2573pt]APOE ε4-related sporadic AD and [size=10.2573pt]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