APOE Genotype Differentially Modulates Plasma Lipids in Healthy Older Individuals, with Relevance to Brain Health

Apolipoprotein E (APOE) genotype is an established genetic risk factor for sporadic Alzheimer's disease (AD) but the extent to which APOE genotype influences the plasma lipidome is unknown, even though lipids are potential diagnostic or prognostic biomarkers for AD. We quantified plasma lipids using untargeted liquid chromatography coupled mass spectrometry in a total of 152 non-demented participants aged 65-100 years carrying at least one epsilon 2 or epsilon 4 allele (epsilon 2/epsilon 2 or epsilon 2/epsilon 3, n = 38: epsilon 4/epsilon 3 or epsilon 4/epsilon 4, n = 38), who were roughly matched to an epsilon 3/epsilon 3 control by age, sex, and lipid-lowering medication (n = 76). Low density lipoprotein cholesterol levels were genotype dependent (epsilon 4/epsilon 4>epsilon 4/epsilon 3>epsilon 3/epsilon 3>epsilon 2/epsilon 3>epsilon 2/epsilon 2). The greatest variation in lipids was related to the epsilon 2 isoform, where various lysophosphatidylcholines and all phosphatidylethanolamine (PE) subclasses were elevated relative to epsilon 3/epsilon 3 and epsilon 4 carriers. APOE epsilon 4 carriers had reduced phosphatidylinositol relative to epsilon 3/epsilon 3 and epsilon 2 carriers. Logistic regression revealed that epsilon 2 carriers were at least 4 times higher odds of being in the highest tertile of PE lipid level relative to epsilon 3/epsilon 3. The elevation in PE and other phospholipids in epsilon 2 carriers may indicate the protective effect of epsilon 2 is linked to these phospholipids. Additionally, high baseline PE in cognitively normal participants predicted protection against cognitive decline six years later. Our data suggest substantial modulation of plasma lipids by APOE genotype and therefore indicates possible lipid targets and pathomechanisms involved in AD risk.