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

Abstract

Abstract Background Although 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. Methods Statistical 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. Results Genetically 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. Conclusions The findings underscore the pivotal role of CSF metabolomics in elucidating the lipid-mediated pathogenesis of LOAD, highlighting potential diagnostic and preventative biomarkers.

Keywords

• Lipids
• Cerebrospinal fluid metabolites
• Late-Onset Alzheimer’s Disease
• Mediator
• Mendelian randomization