Laboratory of Neuroimaging of Aging (LANVIE), University of Geneva, Geneva, Switzerland.
Memory Clinic, Geneva University Hospitals, Geneva, Switzerland.
Nat Rev Neurosci. 2022 Jan;23(1):53-66. doi: 10.1038/s41583-021-00533-w. Epub 2021 Nov 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.
当前对阿尔茨海默病（AD）的概念化是由淀粉样蛋白假说驱动的，该假说认为，一系列确定性事件会导致淀粉样蛋白沉积，然后导致tau 蛋白沉积、神经退行性变和进行性认知障碍。该模型适用于常染色体显性 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针对淀粉样蛋白的药物的挑战，需要重新考虑淀粉样蛋白假说。在这里，我们提出了一种 AD 的概率模型，其中 AD 的三种变体（常染色体显性 AD、载脂蛋白 Eε4 相关散发性 AD 和载脂蛋白 Eε4 非相关散发性 AD）的特征是外显率降低，淀粉样蛋白病理生理级联的权重降低，以及随机因素（环境暴露和低风险基因）的权重增加。所有这些变体共同解释了 AD 患者观察到的神经病理学和临床变异性的很大一部分。该模型在研究中的实施可能会导致更好地理解疾病的病理生理学，对当前临床分类法进行修订，并加速开发预防和治疗 AD 的策略。
