Bradley Joseph, Pottier Cyril, da Fonseca Eder Lucio, Kurup Jiji Thulaseedhara, Western Daniel, Wang Ciyang, Neupane Achal, Ray Nicholas R, Jean-Francois Melissa, Ali Muhammad, Timsina Jigyasha, Bergmann Kristy, Budde John, Martin Eden R, Pericak-Vance Margaret A, Cuccaro Michael, Naj Adam C, Kunkle Brian W, Schellenberg Gerard D, Fernandez Victoria, Haines Jonathan, Morris John C, Holtzman David M, Perrin Richard J, Reitz Christiane, Beecham Gary W, Cruchaga Carlos
NeuroGenomics and Informatics, Washington University School of Medicine, St. Louis, Missouri, USA.
Department of Psychiatry, Washington University in St. Louis, St Louis, Missouri, USA.
Alzheimers Dement. 2025 Jun;21(6):e70377. doi: 10.1002/alz.70377.
Most genetic studies for Alzheimer's disease (AD) have been focused on late-onset AD (LOAD). There are no large genetic studies on early-onset AD (EOAD).
We performed a multi-ancestry (non-Hispanic European, African, and East Asian) genome-wide association study (GWAS) including a total of 7,349 cases and 17,887 control. Cases with age at onset younger than 70 years were included. Sensitivity analysis including cases with onset <65 was performed. Only controls older than 70 were included to decrease the risk of developing LOAD.
We identified eight novel significant loci: six in the ancestry-specific analyses and two in the trans-ancestry analysis. By integrating gene-based analysis, expression quantitative trait loci (eQTL), protein quantitative trait loci (pQTL), and functional annotations, we nominate eight novel genes that are involved in microglia activation, glutamate production, and signaling pathways.
EOAD, although sharing genes with LOAD, harbors unique genes and pathways that could be used to create better prediction models or target identification.
We performed the largest and first multi-ethnic genetic screening for early-onset Alzheimer's disease (AD). We identified eight novel significant loci: six in the ancestry-specific analyses and two in the trans-ancestry analysis. The novel genes are implicated microglia activation, glutamate production, and signaling pathways. EOAD, although sharing many genes with LOAD, harbors unique genes and pathways that could be used to create better prediction models or target identification for this type of AD.
大多数针对阿尔茨海默病（AD）的基因研究都集中在晚发型AD（LOAD）上。目前尚无关于早发型AD（EOAD）的大规模基因研究。
我们进行了一项多血统（非西班牙裔欧洲人、非洲人和东亚人）全基因组关联研究（GWAS），共纳入7349例病例和17887例对照。纳入发病年龄小于70岁的病例。进行了敏感性分析，包括发病年龄<65岁的病例。仅纳入70岁以上的对照以降低患LOAD的风险。
我们鉴定出8个新的显著基因座：6个在特定血统分析中，2个在跨血统分析中。通过整合基于基因的分析、表达数量性状基因座（eQTL）、蛋白质数量性状基因座（pQTL）和功能注释，我们提名了8个参与小胶质细胞激活、谷氨酸生成和信号通路的新基因。
EOAD虽然与LOAD共享一些基因，但具有独特的基因和通路，可用于创建更好的预测模型或进行靶点识别。
我们对早发型阿尔茨海默病（AD）进行了规模最大的首次多民族基因筛查。我们鉴定出8个新的显著基因座：6个在特定血统分析中，2个在跨血统分析中。这些新基因与小胶质细胞激活、谷氨酸生成和信号通路有关。EOAD虽然与LOAD共享许多基因，但具有独特的基因和通路，可用于为这种类型的AD创建更好的预测模型或进行靶点识别。
