Abstract P193: Lipidomics of APOE Genotype Among Older Black Men Revealed ε2 Carriers Were More Different and ε4 Carriers Were Less Different When Compared to ε3 Homozygous

Abstract

Introduction: The ability of apolipoprotein E (APOE) to regulate lipid metabolism in the brain and periphery is impacted by APOE genotype. The ε4 and ε2 variants are associated with higher and lower risks of Alzheimer’s disease, respectively, than ε3 homozygous. The ε4 variant is also associated with a higher cardiovascular disease risk. Differences in lipoprotein affinity by APOE genotype can cause altered profiles of plasma lipids and lipoproteins. APOE ε4 carriers have higher levels of triglycerides and total cholesterol, whereas ε2 carriers have higher levels of triglycerides, but lower levels of total cholesterol. A detailed description of specific lipid molecular species that differ by APOE genotype may indicate therapeutic targets to mitigate the associated higher disease risk. We used lipidomics to identify metabolites and metabolic pathways that differ by APOE genotype among 278 black men ages 70-81 from the Health, Aging, and Body Composition study. Hypothesis: Multiple cholesterols and triglycerides will differ by APOE genotype. Methods: Using liquid chromatography-mass spectrometry, 222 lipids/lipid-like metabolites were detected in overnight-fasting plasma. APOE genotype was categorized as ε4 carriers (ε3ε4 and ε4ε4), ε2 carriers (ε2ε3 and ε2ε2), or ε3 homozygous. We excluded ε2ε4 carriers (n=14). We identified metabolites associated with APOE genotype using linear regression, adjusting for age and study site. To account for multiple comparisons, we used a Benjamini-Hochberg correction with 30% false discovery rate. We applied a Lipid Pathway Enrichment Analysis. Results: LDL cholesterol was lower among ε2 carriers vs. remaining participants. There was no difference in HDL cholesterol or triglycerides by APOE genotype. Twenty-three lipids/lipid-like molecules differed by APOE genotype (p<0.05); 12 were significantly lower and eight were significantly higher among ε2 carriers vs. ε3 homozygous and ε4 carriers, two metabolites were higher among ε2 vs. ε4 carriers, and one metabolite was lower among ε4 carriers vs. ε3 homozygous. Top pathways identified were fat digestion/absorption (p=0.005) and cholesterol metabolism (p=0.005). Five lipids/lipid-like molecules remained significant after accounting for multiple comparisons: C16:1 monoacylglycerols, C18:2 cholesteryl esters (CE), C20:3 CE, C16:0 CE, and C54:10 triacylglycerol. BMI or waist circumference did not alter associations. Conclusion: The ε2 carriers had lower levels of all seven cholesteryl esters and higher levels of all, but one of the seven triacylglycerols associated with APOE genotype. Almost all metabolites that differed significantly by APOE genotype were due to differences in ε2 carriers, whereas ε3 homozygous and ε4 carriers were more similar. The observed differences in lipid species provides a better metabolic characterization of APOE genotype in this cohort of older black men.