Multi-omics analysis of potential therapeutic targets for Alzheimer's disease and associated differences in immune...

Alzheimer's disease (AD) represents a progressive neurodegenerative disorder that predominantly impairs the central nervous system. This study integrated single-cell RNA sequencing (scRNA-seq) and Mendelian randomization (MR) analysis to explore AD therapeutic targets and characterize alterations in immune cell infiltration and function. We analyzed the subtypes, developmental trajectories and intercellular communication of peripheral blood T cells from AD scRNA-seq data. Cell clustering identified CD8⁺ T cells as the key immune subpopulation in AD, with two vital intercellular communication pathways (MIF-(CD74⁺CD44) and MIF-(CD74⁺CXCR4)) identified by trajectory analysis. The expression quantitative trait loci (eQTL) data retrieved from the IEU OpenGWAS database were utilized to perform MR and colocalization analysis to evaluate the association between target genes and AD. Six multiple-SNP and one single-SNP potential target genes were screened via differential expression and MR analysis. Among these, dual-specificity phosphatase 2 (DUSP2) showed a suggestive but weak association with AD, with a mild positive correlation observed in sensitivity analyses. No statistically significant shared genetic signals were detected via colocalization analysis. Additionally, significant differences in intercellular communication were observed between DUSP2+IM and DUSP2-IM cells, with distinct activity across various communication pathways. Gene expression levels in the AD group were significantly higher than in healthy individuals (P = 0.01). In conclusion, this study identified CD8⁺ T cells as crucial factors in AD pathogenesis, while DUSP2 emerged as a suggestive candidate gene requiring further validation, providing novel mechanistic insights and potential therapeutic targets for AD treatment.