Immune cells play a mediating role in the relationship between the gut microbiota and dementia: A Mendelian randomization study

Introduction The gut microbiota modulates dementia pathogenesis through immune interactions. Using Mendelian randomization, we investigate immune mediated mechanisms linking microbial dysbiosis to four dementia subtypes (Alzheimer's disease, Frontotemporal dementia, Vascular dementia, Parkinson's disease dementia . Our study tests whether gut microbiome effects on dementia are transmitted via immunoregulatory pathways. Methods Genome wide association studies data included gut microbiota, 731 immune traits, and dementia cohorts (Alzheimer's disease, Frontotemporal dementia, Vascular dementia, Parkinson's disease dementia). Two step Mendelian randomization with Inverse Variance Weighted analyses assessed mediation effects, controlled by F-statistics >10 and Steiger filtering. Sensitivity analyses addressed pleiotropy . Results A total of 37 gut microbiome species demonstrated potential causal effects relationships with four types of dementia, and 137 immune cell subsets exhibited potential causal effects associations with these four dementia subtypes. In the Two step Mendelian randomization analysis, CD45RA + CD28− CD8+ T cells, CD19 on IgD− CD38dim B cells, and BAFF-R on CD20− B cells were shown to exert mediating effects between class/order/family.Deltaproteobacteria and Alzheimer's disease. CD4+ CD8+ T cells were found to exert a mediating effect between genus.Roseburia and Parkinson's disease dementia . CD20− CD38− B cells, CD19 on CD20− B cells, and IgD on unswitched memory B cells were found to exert a mediating effect between class/order/family.Coriobacteriales,genus.Lactococcus and Vascular dementia. Conclusion This Mendelian randomization study revealed that certain immune cells serve as mediators in the pathway by which the gut microbiome contributes to the onset of dementia.