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APOE2 promotes longevity independent of Alzheimer’s disease

By Mitsuru Shinohara, Takahisa Kanekiyo, Masaya Tachibana, Aishe Kurti, Motoko Shinohara, Yuan Fu, Jing Zhao, Xianlin Han, Patrick M. Sullivan, William G Rebeck, John D. Fryer, Michael G. Heckman, Guojun Bu

Posted 31 Aug 2020
bioRxiv DOI: 10.1101/2020.08.31.255141

Objective Although apolipoprotein E ( APOE ) allele associates with longevity, its mechanism is not understood. The protective effects of APOE 2 and the deleterious effects of APOE4 on Alzheimer’s disease (AD) risk may confound APOE effects on longevity. Methods We 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. Results Clinically, the APOE2 allele was associated with longer lifespan, while APOE4 associated with shorter lifespan, compared to the common APOE3 allele. 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 in APOE2 carrier 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. Interpretation 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. ### Competing Interest Statement The authors have declared no competing interest.

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