Integrative multi-omics analysis identifies AIF1 as an immune-associated factor linked to monocyte-centered inflammatory networks in Alzheimer's disease.
Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder in which immune dysregulation has emerged as an important component of disease pathogenesis; however, the contribution of circulating proteins and their cellular context remains incompletely understood. Here, we performed an integrative multi-omics analysis combining Mendelian randomization (MR), bulk transcriptomics, single-cell RNA sequencing, and peripheral blood validation to systematically identify plasma proteins associated with AD. Proteome-wide MR analysis identified multiple circulating proteins associated with AD risk. Integration with transcriptomic data identified AIF1 (allograft inflammatory factor 1) as a shared candidate supported by both genetic prioritization and differential expression analysis. Although bulk transcriptomic data showed reduced AIF1 expression in AD, single-cell analysis revealed distinct cell type-specific expression patterns, with predominant enrichment in monocytes and other innate immune populations. PBMC-based qPCR further confirmed an overall reduction in AIF1 expression in AD. Further analyses suggested that AIF1-associated immune alterations were linked to changes in inflammatory signaling pathways, including STAT, IRF, and NF-κB-related activity, as well as differences in intercellular communication involving MIF, GALECTIN, ANNEXIN, and CypA-related signaling. Peripheral immune cell composition analysis indicated differences between AD and control samples, characterized by relative changes in innate immune cell proportions. Collectively, these findings identify AIF1 as an immune-associated factor linked to genetic and transcriptional alterations in AD and suggest its association with monocyte-related immune states and altered immune signaling patterns. This study provides a multi-layered framework for investigating peripheral immune involvement in AD and highlights potential directions for understanding immune-related alterations and biomarker discovery.