Peripheral Immune Cell Shifts Associated With Alzheimer's Disease Vary in Multi-Ancestry Cohorts

Background: Alzheimer's disease (AD) is heavily influenced by immune system dysregulation, yet the role of peripheral immune processes--and how these vary across ethnicities--remains understudied. Objective: To investigate ancestry-specific immune alterations in AD by profiling peripheral immune cell proportions using high-resolution deconvolution of whole blood RNA-sequencing data, characterizing disease associated cell types, and identifying enriched biological pathways. Methods: We analyzed whole blood RNA-seq data from non-Hispanic White (NHW), African American (AA), Caribbean Hispanic (CariHISP), and Peruvian (PERU) individuals, balanced between AD cases and cognitively normal controls. Immune cell proportions were estimated using CIBERSORTx and compared using linear models (propeller R package) adjusted for age, sex, and APOE genotypes in case-control models. Cell-type-specific differential expression was performed using CARseq, and pathway enrichment analyses performed using MSigDB gene sets. Results: Baseline immune composition differed substantially across cohorts for multiple innate and adaptive cell types. In a multi-ethnic AD versus control analysis, eight cell types reached FDR significance: AD was associated with decreased proportions naive B cells, CD56dim NK cells, B cells, intermediate monocyte I, and double-negative T cells, alongside significant expansion in neutrophils and non-classical monocytes. Interaction analyses revealed heterogeneous group-specific effects, with the broadest shifts in AA and CariHISP. Pathway enrichment indicated shared heme metabolism, interferon, and oxidative phosphorylation programs across groups, with distinct emphases: broad, strong heme metabolism enrichment and the highest oxidative phosphorylation signal (in myeloid populations) in AA; MYC targets in naive B cells and eosinophils in CariHISP; dendritic cell - and T follicular helper cell - centered interferon, inflammatory, and proliferative programs in NHW; and TGF-{beta} and apoptosis signatures, unique to PERU, alongside the broadest cell-type coverage. Conclusions: Peripheral immune dysregulation in AD is characterized by depletion of lymphoid and intermediate monocyte populations with concurrent neutrophil and non-classical monocyte expansion, and these patterns vary meaningfully by ancestry. These findings underscore the need for population-informed biomarkers and therapeutic strategies in AD.