Genetic architecture of Alzheimer’s disease is enriched in peripheral immune and metabolic programs

ABSTRACT Alzheimer’s disease (AD) is defined by progressive neurodegeneration, yet a substantial fraction of its genetic risk maps to non-neuronal processes. While brain microglia are recognized contributors to AD pathogenesis, the extent to which AD genetic risk operates through peripheral tissues remains unclear. Here, we systematically partitioned AD polygenic risk across 166 tissue-level annotations and 4.4 million cells spanning 28 peripheral tissues and 100 brain regions. AD genetic risk was consistently enriched in peripheral immune, barrier, and metabolic tissues, not explained by brain or microglial transcriptional programs. The strongest signals localized to circulating and tissue-resident myeloid cells, hepatocytes, cardiac muscle cells, and intestinal epithelial populations. Immune-cell enrichment was independent of the APOE locus, whereas a substantial proportion of metabolic enrichment was attributable to APOE -region genes. Colocalization and Mendelian randomization analyses implicated peripheral regulatory mechanisms and highlighted predominantly protective immune-gene effects. These findings extend current models of AD genetics beyond brain-resident mechanisms.