常染色体显性阿尔茨海默病的概况：全球分布与发病年龄。

The landscape of autosomal-dominant Alzheimer's disease: global distribution and age of onset.

作者信息

Liu Haiyan, Marsh Thomas W, Shi Xinyu, Renton Alan E, Bowling Kevin M, Ziegemeier Ellen, Wang Guoqiao, Cao Yuchen, Aristel Alisha, Li Jessie, Dickson Alexa, Perrin Richard J, Goate Alison M, Fernández Victoria, Day Gregory S, Doering Michelle, Daniels Alisha, Gordon Brian A, Benzinger Tammie L S, Hassenstab Jason, Ibanez Laura, Supnet-Bell Charlene, Xiong Chengjie, Allegri Ricardo, Berman Sarah B, Fox Nick C, Ryan Natalie, Huey Edward D, Vöglein Jonathan, Noble James M, Roh Jee Hoon, Jucker Mathias, Laske Christoph, Ikeuchi Takeshi, Sanchez-Valle Raquel, Schofield Peter R, Chrem Mendez Patricio, Chhatwal Jasmeer P, Farlow Martin, Lee Jae-Hong, Levey Allan I, Levin Johannes, Lopera Francisco, Martins Ralph, Niimi Yoshiki, Rosa-Neto Pedro, Morris John C, Bateman Randall J, Karch Celeste M, Cruchaga Carlos, McDade Eric, Llibre-Guerra Jorge J

机构信息

Department of Neurology, Washington University School of Medicine, St Louis, MO, 63110, USA.

Department of Psychiatry, Washington University School of Medicine, St Louis, MO, 63110, USA.

出版信息

Brain. 2025 Feb 4. doi: 10.1093/brain/awaf038.

DOI:10.1093/brain/awaf038

PMID:39903689

Abstract

We present a comprehensive global analysis of genetic variants associated with autosomal-dominant Alzheimer's disease (ADAD). A total of 550 variants in the APP, PSEN1, and PSEN2 genes were identified, of which 279 were classified as pathogenic or likely pathogenic based on ACMG-AMP criteria, utilizing data from the Dominantly Inherited Alzheimer Network (DIAN), literature, and public databases. Symptomatic age at onset (AAO) data was estimated for 227 of these variants, allowing detailed characterization of their frequency, pathogenicity, and AAO. Importantly, 226 variants meet eligibility criteria for inclusion in disease-modifying clinical trials. Furthermore, we demonstrate the predictive value of mean variant AAO and parental AAO in predicting symptomatic AAO, validated against converters who became symptomatic during follow-up in the DIAN Observational Study (DIAN-OBS). This dataset provides critical insights into the global landscape of ADAD and reveals the genetic and AAO heterogeneity of ADAD variants while refining variant trial eligibility criteria.

摘要

我们对与常染色体显性阿尔茨海默病（ADAD）相关的基因变异进行了全面的全球分析。在APP、PSEN1和PSEN2基因中总共鉴定出550个变异，其中279个根据美国医学遗传学与基因组学学会（ACMG）-分子病理学协会（AMP）标准被分类为致病性或可能致病性，这些分类利用了来自显性遗传阿尔茨海默病网络（DIAN）、文献和公共数据库的数据。对其中227个变异的症状性发病年龄（AAO）数据进行了估计，从而能够详细描述它们的频率、致病性和AAO。重要的是，226个变异符合纳入疾病修饰临床试验的资格标准。此外，我们证明了平均变异AAO和父母AAO在预测症状性AAO方面的预测价值，并在DIAN观察性研究（DIAN-OBS）随访期间出现症状的转化者中进行了验证。该数据集为ADAD的全球格局提供了关键见解，揭示了ADAD变异的遗传和AAO异质性，同时完善了变异试验资格标准。