An integrative single-cell genetic analysis prioritizes immune cell-specific genes and drug repurposing hypotheses in Alzheimer’s disease

Immune dysregulation is increasingly recognized as a critical contributor to Alzheimer’s disease (AD), but the specific immune cell contexts and regulatory genes underlying genetic susceptibility remain incompletely understood. Here, we integrated immune cell-specific cis-expression quantitative trait loci (cis-eQTL) from the OneK1K resource with AD genome-wide association study data using two-sample Mendelian randomization (MR), Bayesian colocalization, and independent DICE replication. Exploratory peripheral blood single-cell RNA sequencing (scRNA-seq) was further applied to characterize cell-type expression patterns of prioritized genes. We identified naïve/central memory T-cell subsets and monocyte-related populations as major immune contexts enriched for AD-associated genetic regulatory signals and prioritized several immune cell-specific candidate genes, including KANSL1-AS1, CTSH, FCER1G, EPHA1-AS1, CRHR1, and JAZF1. Independent datasets supported the reproducibility of multiple prioritized signals. Integration with drug-signature resources, blood–brain barrier (BBB) permeability prediction, molecular docking, and phenome-wide association analyses generated exploratory compound–gene repurposing hypotheses while assessing potential genetic safety concerns. Collectively, this study provides an immune cell-resolved genetic framework for interpreting AD susceptibility and identifies candidate targets and therapeutic hypotheses that require further experimental validation.