Peripheral blood immune cell phenotypes and Alzheimer's disease: A mediation Mendelian randomization study

Background Alzheimer's disease (AD) is a debilitating neurodegenerative disorder. Although peripheral immune cells have been implicated in the pathology of AD, the causal relationship between peripheral blood immune cells and AD remains to be fully elucidated. Objective To examine the association between peripheral blood immune cell phenotypes and AD, mediated by peripheral blood metabolite, a two-step Mendelian randomization (MR) analysis was performed. Methods Summary statistics were obtained from the two largest independent cohorts. We explored bidirectional univariable MR analysis to explore causal associations and assessed the mediated proportion of peripheral blood metabolite phenotypes. Results The proportion of IgD + CD38- B cells (Bm1) were found to increase the risk of AD in both the FinnGen database (p = 0.033) and the UK Biobank (p = 0.034). Conversely, hematopoietic stem cells were associated with a decreased risk of AD in the FinnGen database (p = 0.045) and the UK Biobank (p = 0.017). Mediation analysis revealed indirect effects of the proportion of Bm1 on AD through cysteine levels (beta = 5 x 10(-3)), Acetylcarnitine (C2) to propionylcarnitine (C3) ratio (beta = 4.5 x 10(-3)), and Gamma-glutamyl-alpha-lysine levels (beta = 2.6 x 10(-3)), with mediated proportion of 19.4%, 16.9% and 9.6% of the total effect, respectively. Additionally, hematopoietic stem cells influenced AD through Glycolithocholate sulfate levels (beta = 1.5 x 10(-3)), with a mediated proportion of 3.5%. Conclusions Our findings demonstrate that two peripheral blood immune cell phenotypes impact the risk of AD. These immune cells may influence AD through various peripheral blood metabolite, identifying potential intervention targets for individuals at risk.