OBJECTIVE: Numerous studies have demonstrated that dysregulated lipid metabolism contributes to the pathological progression of Alzheimer's disease (AD); however, the causal relationship and underlying mechanisms between peripheral plasma lipidome and AD remain incompletely elucidated.
METHODS: We conducted a two-sample Mendelian randomization (MR) analysis using summary statistics from genome-wide association studies (GWAS). Data included 179 lipid species,731 immune cell phenotypes, 473 gut microbiotas, 91 inflammatory proteins, 1,400 plasma metabolites, and AD cases. Inverse-variance weighted (IVW) regression served as the primary MR method, supplemented by sensitivity analyses to ensure robustness. Mediation analysis was conducted to explore potential mediating effects of immune cells, inflammatory proteins, gut microbiota, and plasma metabolites, with multiple sensitivity analyses ensuring result robustness.
RESULTS: Significant causal relationships were identified between 7 lipid species, 14 immune cell phenotypes, 23 gut microbiota (1order, 1 phylum, 1unclassified, 9 species, and 11 genera), 2 inflammatory proteins, and 25 plasma metabolites (20 metabolites and 5 ratios) with AD. Mediation analysis demonstrated partial mediation effects of three immune cell phenotypes, four gut microbiota taxa, one inflammatory protein and six plasma metabolites on the relationship between plasma lipidome and AD.
CONCLUSION: Our findings support a causal relationship between plasma lipidome, immune cells, inflammatory proteins, gut microbiota, plasma metabolites and AD. The identified biomarkers and mediating pathways provide mechanistic insights into AD pathogenesis and may inform future preventive and therapeutic strategies.
