Causal relationships between immune cells, Blood Metabolites, and Alzheimer's disease: a two-step, two-sample Mendelian randomization study

Background Peripheral immune cells may accelerate the progression of Alzheimer's disease (AD), and blood metabolites provide potential biomarkers for AD, but it remains to be explored whether the effect of the immune cells is mediated by blood metabolites. The study aims to explore the pathogenic role of immune cells in AD and explore whether this role is mediated by blood metabolites using Mendelian randomization analysis. Methods This study employed a two-sample, two-way MR design to investigate the causal relationships between immune cells, blood metabolites, and AD. Data sources included genome-wide association studies (GWAS) datasets for AD, immune cell traits, and blood metabolites. Instrumental variables (IVs) were screened according to strict criteria and Mendelian randomization analyses were performed using various statistical methods. Results MR analyses determined the protective effects of 7 immune cell traits on AD and 10 traits that increase the risk of developing AD. In addition, 17 blood metabolite indicators were suggestively associated with AD. Of note, X-13723 and Androstenediol (3beta,17beta) monosulfate (2) acetate respectively exert neuroprotective effects in the myeloid inhibitory cell-AD and CD33 + monocyte-AD pathways, while X-25828 has the unique bidirectional regulatory characteristics of immune cell subsets. Conclusion The study highlights the interplay relationship between immune cells, blood metabolites, and AD, shedding light on potential mechanisms underlying AD pathogenesis. Further research is needed to explore additional mediators and validate these findings in diverse populations. The study's findings contribute to the understanding of AD etiology and offer new avenues for clinical interventions.