The role of cerebrospinal fluid metabolites in mediating the impact of lipids on Late-Onset Alzheimer’s Disease: a two-step mendelian randomization analysis

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BackgroundAlthough research has indicated correlations between lipids, cerebrospinal fluid (CSF) metabolites, and Late-Onset Alzheimer’s Disease (LOAD), the specific causal relationships among these elements, as well as the roles and mechanisms of the cerebrospinal fluid metabolites, remain unclear.MethodsStatistical datasets derived from Genome-Wide Association Studies (GWAS) were utilized to assess the bidirectional causal relationships between lipids and LOAD. Subsequently, genetic variants associated with CSF metabolites and established lipids underwent a two-step Mendelian randomization (MR) analysis to explore potential mediators and analyze mediation effects. Sensitivity analyses were employed to assess the robustness of the detection systems.ResultsGenetically predicted cholesterol (IVW OR = 0.989; 95% CI 0.982–0.996) was found to reduce the risk of LOAD, whereas Phosphatidylcholine (PC) (18:1_0:0) (IVW OR = 1.015; 95% CI 1.005–1.025) posed a risk factor. The potential mediator, CSF metabolite N-acetylneuraminate (NeuAC), was identified with a mediation proportion of 21.02% (3.25%, 45.50%). No pleiotropy or heterogeneity was detected across MR analyses.ConclusionsThe findings underscore the pivotal role of CSF metabolomics in elucidating the lipid-mediated pathogenesis of LOAD, highlighting potential diagnostic and preventative biomarkers.