<i>APOE2</i> is associated with longevity independent of Alzheimer's disease.

Abstract

Although the ε2 allele of apolipoprotein E (<i>APOE2</i>) benefits longevity, its mechanism is not understood. The protective effects of the <i>APOE</i>2 on Alzheimer's disease (AD) risk, particularly through their effects on amyloid or tau accumulation, may confound <i>APOE2</i> effects on longevity. Herein, we showed that the association between <i>APOE2</i> and longer lifespan persisted irrespective of AD status, including its neuropathology, by analyzing clinical datasets as well as animal models. Notably, <i>APOE2</i> was associated with preserved activity during aging, which also associated with lifespan. In animal models, distinct apoE isoform levels, where <i>APOE2</i> has the highest, were correlated with activity levels, while some forms of cholesterol and triglycerides were associated with apoE and activity levels. These results indicate that <i>APOE2</i> can contribute to longevity independent of AD. Preserved activity would be an early-observable feature of <i>APOE2</i>-mediated longevity, where higher levels of apoE2 and its-associated lipid metabolism might be involved.