Abstract 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.
Lindbohm et al. (Sun,) studied this question.
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