Naito Tatsuhiko, Hirata Kosei, Jang Beomjin, Lakhani Chirag M, Buonfiglioli Alice, Lee Wan-Ping, Valladares Otto, Wang Li-San, Okada Yukinori, Won Hong-Hee, Papapetrou Eirini P, Marro Samuele G, Knowles David A, Raj Towfique
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
medRxiv. 2025 Jun 4:2025.05.29.25328544. doi: 10.1101/2025.05.29.25328544.
Mosaic chromosomal alterations (mCAs) in blood, a form of clonal hematopoiesis, have been linked to various diseases, but their role in Alzheimer's disease (AD) remains unclear. We analyzed blood whole-genome sequencing (WGS) data from 24,049 individuals in the Alzheimer's Disease Sequencing Project and found that autosomal mCAs were significantly associated with increased AD risk (odds ratio = 1.27; = 1.3 × 10). This association varied by ancestry, mCA subtype, APOE ε4 allele status, and chromosomal location. Using matched blood WGS and brain single-nucleus RNA-seq data, we identified microglia-annotated cells in the brain carrying the same mCAs found in blood. These findings suggest that blood mCAs may contribute to AD pathogenesis, potentially through infiltration into the brain and influencing local immune response.
血液中的嵌合染色体改变（mCAs）是一种克隆性造血形式，已与多种疾病相关联，但其在阿尔茨海默病（AD）中的作用仍不清楚。我们分析了阿尔茨海默病测序项目中24049名个体的血液全基因组测序（WGS）数据，发现常染色体mCAs与AD风险增加显著相关（优势比 = 1.27； = 1.3 × 10）。这种关联因血统、mCA亚型、APOE ε4等位基因状态和染色体位置而异。利用匹配的血液WGS和脑单核RNA测序数据，我们在大脑中鉴定出携带与血液中相同mCAs的小胶质细胞注释细胞。这些发现表明，血液mCAs可能通过渗入大脑并影响局部免疫反应，从而促进AD的发病机制。
