Genomic partitioning of Alzheimer's disease in humans reveals non-CNS etiology

Abstract

Alzheimer's disease (AD) is marked by hallmark neuropathological changes in the brain. However, its upstream genetic determinants, beyond the central nervous system (CNS), remain largely unexplored. To that extent, we integrated human genomic data with cross-tissue and single-cell analyses across up to 40 peripheral tissues and 100 brain regions. We observed limited genetic enrichment in the CNS, with brain-resident microglia emerging as the sole enriched cell type. Instead, AD risk loci were predominantly enriched in peripheral immune compartments and immune-enriched barrier tissues, such as the lung and the digestive tract, and particularly within myeloid-lineage cells. Leveraging gene expression profiles from peripheral immune cells, we recreated an age-related susceptibility curve for AD, identifying ages 55-60 as a critical window for immune activation linked to AD risk. Our findings position the peripheral immune system as a central contributor of disease susceptibility, opening new directions for early intervention beyond the brain.