Population and single-cell analyses reveal immune cell-specific expression profiles associated with Alzheimer's disease risk.

INTRODUCTION: Dysregulation of the peripheral immune system may increase Alzheimer's disease (AD) risk, but the underlying cell type-specific mechanisms remain unclear. METHODS: We conducted Mendelian randomization and colocalization analyses of 4489 genes using single-cell expression quantitative trait locus data from unstimulated and stimulated peripheral immune cells, integrated with an AD genome-wide association study (N = 455,258). Spatial transcriptomics of brain tissue samples was used to identify brain-infiltrating immune cells. RESULTS: Thirteen genes were associated with AD risk. Expression of BIN1, CTSW, CTSH, HLA-DRB1, TSTD1, PLEKHA1, and SCIMP increased AD risk, while EPHA1-AS1, FCER1G, FIBP, KAT8, STX4, and HLA-DQA1 reduced it. These associations were peripheral immune cell type and state specific. PLEKHA1 and TSTD1 were upregulated and FIBP downregulated in natural killer and T cells in AD brain tissue. DISCUSSION: These findings link immune cell-specific gene expression to AD risk across activation states and within brain-infiltrating immune cells, highlighting potential targets for immune-based AD prevention and treatment.