Abstract Body

The current conceptualization of Alzheimer disease (AD) is driven by the amyloid hypothesis, a deterministic chain of events leading from amyloid 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. We propose a probabilistic model of AD, in which amyloid is still a key player, but the pathogenic weight of amyloid and stochastic factors is inversely proportional to the penetrance of genetic factors. The model identifies three variants of AD: autosomal-dominant AD, APOE ɛ4-related sporadic AD and APOE ɛ4-unrelated sporadic AD. 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 this disease.