Reitz Christiane, Rogaeva Ekaterina, Beecham Gary W
Taub Institute for Research on Alzheimer's Disease and the Aging Brain (C.R.), Gertrude H. Sergievsky Center (C.R.), Department of Neurology (C.R.), and Department of Epidemiology (C.R.), College of Physicians and Surgeons, Columbia University, New York, NY; Tanz Centre for Research in Neurodegenerative Disease (E.R.), University of Toronto, ON, Canada; and The John P. Hussman Institute for Human Genomics (G.W.B.), University of Miami, FL.
Neurol Genet. 2020 Oct 6;6(5):e512. doi: 10.1212/NXG.0000000000000512. eCollection 2020 Oct.
There is mounting evidence that only a small fraction of early-onset Alzheimer disease cases (onset <65 years) are explained by known mutations. Even multiplex families with early onset often also have late-onset cases, suggesting that the commonly applied categorization of Alzheimer disease into early- and late-onset forms may not reflect distinct underlying etiology. Nevertheless, this categorization continues to govern today's research and the design of clinical trials. The aim of this review is to evaluate this categorization by providing a comprehensive, critical review of reported clinical, neuropathologic, and genomic characteristics of both onset-based subtypes and explore potential overlap between both categories. The article will lay out the need to comprehensively assess the phenotypic, neuropathologic, and molecular variability in Alzheimer disease and identify factors explaining the observed significant variation in onset age in persons with and without known mutations. The article will critically review ongoing large-scale genomic efforts in Alzheimer disease research (e.g., Alzheimer Disease Sequencing Project, Dominantly Inherited Alzheimer Network, Alzheimer Disease Neuroimaging Initiative) and their shortcomings to disentangle the delineation of unexplained nonmendelian early-onset from late-onset and mendelian forms of Alzheimer disease. In addition, it will outline specific approaches including epigenetic research through which a comprehensive characterization of this delineation can be achieved.
越来越多的证据表明，早发性阿尔茨海默病病例（发病年龄<65岁）中只有一小部分可由已知突变解释。即使是早发性的多重家庭也常常有晚发性病例，这表明将阿尔茨海默病普遍分为早发和晚发形式的分类可能无法反映不同的潜在病因。然而，这种分类仍然主导着当今的研究和临床试验设计。本综述的目的是通过对基于发病年龄的亚型所报道的临床、神经病理学和基因组特征进行全面、批判性的综述，并探讨这两类之间的潜在重叠，来评估这种分类。本文将阐述全面评估阿尔茨海默病表型、神经病理学和分子变异性的必要性，并确定解释有或没有已知突变的个体中观察到的发病年龄显著差异的因素。本文将批判性地回顾阿尔茨海默病研究中正在进行的大规模基因组工作（如阿尔茨海默病测序项目、显性遗传性阿尔茨海默病网络、阿尔茨海默病神经影像学倡议）及其在区分未解释的非孟德尔早发性与晚发性及孟德尔形式的阿尔茨海默病方面的不足。此外，本文还将概述包括表观遗传学研究在内的具体方法，通过这些方法可以实现对这种区分的全面表征。
