Deciphering the peripheral immune landscape of Alzheimer’s disease through integrated multi-omics research and cohort validation

Objective: This study investigated molecular drivers of AD-associated peripheral immune dysregulation to identify pathogenic genes and therapeutic targets for precision diagnosis and intervention. Methods: A large-scale GWAS meta-analysis (n = 894,710) was performed, followed by two-sample Mendelian randomization (MR) using multi-tissue cis-eQTL data to identify putative causal genes. Immune response differential genes (IRDGs) were defined from AD peripheral blood transcriptomes and the MSigDB database. A three-step summary-data-based MR framework integrating blood cis-eQTLs and cis-mQTLs was applied to prioritize causal genes and epigenetic regulatory elements. Findings were validated through colocalization analysis, PBMC scRNA-seq and blood-tissue TWAS. Multi-dimensional clinical validation was performed in the ADNI cohort encompassing gene expression, CSF biomarkers, cognitive measures, immune cell profiles, survival analysis, and plasma proteomics, with cross-cohort transcriptomic replication in AddNeuroMed. Results: ¹²). Conclusion: Integrating GWAS, multi-omics Mendelian randomization, single-cell transcriptomics, transcriptome-wide association study, and clinical cohort validation, this study identified peripheral immune causal genes for AD whose blood transcriptomic and epigenetic signatures track with CSF pathology, cognitive decline, and disease progression, supporting their translational potential for early diagnosis and therapeutic development.