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Although the ε2 allele of apolipoprotein E ( APOE2 ) benefits longevity, its mechanism is not understood. The protective effects of the  APOE 2 on Alzheimer’s disease (AD) risk, particularly through their effects on amyloid or tau accumulation, may confound  APOE2  effects on longevity. Herein, we showed that the association between  APOE2  and longer lifespan persisted irrespective of AD status, including its neuropathology, by analyzing clinical datasets as well as animal models. Notably,  APOE2  was associated with preserved activity during aging, which also associated with lifespan. In animal models, distinct apoE isoform levels, where  APOE2  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  APOE2  can 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.

APOE2 is associated with longevity independent of Alzheimer’s disease