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.

目前阿尔茨海默病 (AD) 的概念化是由淀粉样蛋白假说驱动的，其中确定性的事件链从淀粉样蛋白沉积，然后是 tau 沉积导致神经变性和进行性认知障碍。该模型适合常染色体显性遗传 AD，但不太适用于散发性 AD。由于有关 AD 复杂生物学的新信息以及开发淀粉样蛋白靶向药物的挑战，需要重新考虑淀粉样蛋白假说。在这里，我们提出了 AD 的概率模型，其中 AD 的三种变体（常染色体显性遗传 AD、APOE ε4 相关散发性 AD 和APOEε4 无关的散发性 AD）具有降低外显率和降低淀粉样蛋白病理生理级联权重以及增加随机因素（环境暴露和低风险基因）权重的特征。这些变异共同解释了在 AD 患者中观察到的神经病理学和临床变异的很大一部分。在研究中实施该模型可能会导致更好地了解疾病病理生理学、修订当前的临床分类法并加速制定预防和治疗 AD 的策略。