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, 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