APOE epsilon 2 resilience for Alzheimer's disease is mediated by plasma lipid species: Analysis of three independent cohort studies

Introduction: The apolipoprotein E (APOE) genotype is the strongest genetic risk factor for late-onset Alzheimer's disease. However, its effect on lipid metabolic pathways, and their mediating effect on disease risk, is poorly understood. Methods: We performed lipidomic analysis on three independent cohorts (the Australian Imaging, Biomarkers and Lifestyle [AIBL] flagship study, n = 1087; the Alzheimer's Disease Neuroimaging Initiative [ADNI] 1 study, n = 819; and the Busselton Health Study [BHS], n = 4384), and we defined associations between APOE epsilon 2 and epsilon 4 and 569 plasma/serum lipid species. Mediation analysis defined the proportion of the treatment effect of the APOE genotype mediated by plasma/serum lipid species. Results: A total of 237 and 104 lipid species were associated with APOE epsilon 2 and epsilon 4, respectively. Of these 68 (epsilon 2) and 24 (epsilon 4) were associated with prevalent Alzheimer's disease. Individual lipid species or lipidomic models of APOE genotypes mediated up to 30% and 10% of APOE epsilon 2 and epsilon 4 treatment effect, respectively. Discussion: Plasma lipid species mediate the treatment effect of APOE genotypes on Alzheimer's disease and as such represent a potential therapeutic target.