Causal relationship between circulating immune cells and the risk of Alzheimer's disease: A Mendelian randomization study

Abstract

Background: Increasing evidence has shown a link between immune cells and Alzheimer's disease (AD). Comprehensive two-sample Mendelian randomization (MR) analysis was performed to determine the causal association between 731 immune cell signatures and AD in this study.

Methods: We extracted genetic variants of 731 immune cell traits and AD from the publicly available GWAS dataset. The immune features included median fluorescence intensity (MFI), relative cellular (RC), absolute cellular (AC) and morphological parameters (MP). The inverse variance weighted (IVW) method was the main MR analysis method, and sensitivity analyses were used to validate the robustness, heterogeneity and horizontal pleiotropy of the results.

Results: After FDR adjustment, seven immune phenotypes were found to be associated significantly with AD risk: HLA DR on CD33^-HLA DR⁺ (OR = 0.938, P_FDR = 0.001), Secreting Treg %CD4 (OR = 0.972, P_FDR = 0.021), HLA DR⁺T cell AC (OR = 0.928, P_FDR = 0.041), Activated & resting Treg % CD4 Treg (OR = 1.031, P_FDR = 0.002), CD33 on CD33dim HLA DR⁺CD11b⁺ (OR = 1.025, P_FDR = 0.025), CD33 on CD14⁺monocyte (OR = 1.026, P_FDR = 0.027) and CD33 on CD66b⁺⁺myeloid cell (OR = 1.027, P_FDR = 0.036).

Conclusions: These findings demonstrated seven immune phenotypes were significantly associated with AD risk. This may provide researchers with a new perspective in exploring the biological mechanisms of AD and may lead to the exploration of earlier treatment.

Keywords: Alzheimer's disease; CD33; Causal association; Immune cells; Mendelian randomization.