APOE2 is associated with longevity independent of Alzheimer’s disease

Abstract

Although the ε2 allele of apolipoprotein E (APOE2) benefits longevity, its mechanism is not understood. The protective effects of theAPOE2 on Alzheimer’s disease (AD) risk, particularly through their effects on amyloid or tau accumulation, may confoundAPOE2effects on longevity. Herein, we showed that the association betweenAPOE2and longer lifespan persisted irrespective of AD status, including its neuropathology, by analyzing clinical datasets as well as animal models. Notably,APOE2was associated with preserved activity during aging, which also associated with lifespan. In animal models, distinct apoE isoform levels, whereAPOE2has the highest, were correlated with activity levels, while some forms of cholesterol and triglycerides were associated with apoE and activity levels. These results indicate thatAPOE2can contribute to longevity independent of AD. Preserved activity would be an early-observable feature ofAPOE2-mediated longevity, where higher levels of apoE2 and its-associated lipid metabolism might be involved.