Plasma lipid subspecies and Alzheimer’s disease: genetic evidence for risk and protection

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder with lipid metabolism implicated in its pathogenesis. The potentially causal relationship between specific lipid subtypes and AD remains unclear due to confounding factors. This study employs Mendelian randomization (MR) to investigate the genetic associations between plasma lipid subtypes and AD risk. METHODS: A MR method was employed utilizing genetic instruments derived from a genome-wide association study (GWAS) involving 7174 Finnish participants who were assessed for 179 lipid species. Summary statistics for AD were sourced from the European Alzheimer & Dementia Biobank, which included 39 106 cases and 46 828 controls. Primary estimates were calculated through inverse-variance weighted (IVW) regression, and sensitivity analyses were performed to confirm reliability. RESULTS: MR analysis identified phosphatidylinositol (PI) (16:0_20:4), phosphatidylcholine (PC) (16:0_22:4) and sterol ester (SE) (27:1/15:0) as risk factors for AD. Conversely, PI (16:0_18:1), PI (18:0_18:1), PI (18:1_18:1) and several triacylglycerol (TAG) subtypes were protective. Sensitivity analyses confirmed the robustness of these associations. CONCLUSION: This study provides genetic evidence supporting a potential causal association between lipid metabolism and AD, identifying specific PI, PC, SE and TAG subtypes as risk or protective factors. These findings offer insights into AD pathogenesis and highlight potential lipid-based therapeutic targets.