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