Mosaic chromosomal alterations in blood are associated with an increased risk of Alzheimer’s disease

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; P = 1.3 × 10 ⁻⁵ ). 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.