APOE2promotes longevity independent of Alzheimer’s disease

Abstract

AbstractObjectiveAlthough apolipoprotein E (APOE) allele associates with longevity, its mechanism is not understood. The protective effects ofAPOE2 and the deleterious effects ofAPOE4on Alzheimer’s disease (AD) risk may confoundAPOEeffects on longevity.MethodsWe analyzed a large number of subjects from the National Alzheimer’s Coordinating Center (NACC), and animal models expressing human apoE isoforms in the absence of AD.ResultsClinically, theAPOE2allele was associated with longer lifespan, whileAPOE4associated with shorter lifespan, compared to the commonAPOE3allele. This effect was also seen irrespective of clinical AD status, and in subjects with little amyloid pathology or after adjustment for AD-related pathologies. In animal studies, apoE2-TR mice also exhibited longer lifespan, while apoE4 showed some trends of shorter lifespan. Notably, old apoE2-TR mice kept activity measured by open field assay, associated with longer lifespan. Evidence of preserved activity inAPOE2carrier was also obtained in clinical records. In animal studies, higher levels of apoE2 in brain and plasma were correlated with activity. Moreover, lower levels of total cholesterol in the brain and higher levels of high-density lipoprotein cholesterol and triglycerides in the plasma of apoE2-TR mice were associated with apoE levels and more activity.InterpretationAPOE2can contribute to longevity independent of AD. Preserved activity would be an early-observable feature of apoE2-mediated longevity, where higher levels of apoE2 and its-associated lipid metabolism might be involved.