Department of Neuroscience, Mayo Clinic, Jacksonville, United States; Department of Aging Neurobiology, National Center for Geriatrics and Gerontology, Aichi, Japan
Takahisa Kanekiyo
Department of Neuroscience, Mayo Clinic, Jacksonville, United States; Neuroscience Graduate Program, Mayo Clinic, Jacksonville, United States
Masaya Tachibana
Department of Neuroscience, Mayo Clinic, Jacksonville, United States; United Graduate School of Child Development, Osaka University, Osaka, Japan
Aishe Kurti
Department of Neuroscience, Mayo Clinic, Jacksonville, United States
Motoko Shinohara
Department of Neuroscience, Mayo Clinic, Jacksonville, United States
Yuan Fu
Department of Neuroscience, Mayo Clinic, Jacksonville, United States
Jing Zhao
Department of Neuroscience, Mayo Clinic, Jacksonville, United States
Xianlin Han
Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, United States
Patrick M Sullivan
Duke University School of Medicine, Durham Veterans Health Administration Medical Center's Geriatric Research, Education and Clinical Center, Durham, United States
G William Rebeck
Department of Neuroscience, Georgetown University Medical Center, Washington, United States
Department of Neuroscience, Mayo Clinic, Jacksonville, United States; Neuroscience Graduate Program, Mayo Clinic, Jacksonville, United States
Michael G Heckman
Department of Neuroscience, Mayo Clinic, Jacksonville, United States; Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, United States
Guojun Bu
Department of Neuroscience, Mayo Clinic, Jacksonville, United States; Neuroscience Graduate Program, Mayo Clinic, Jacksonville, United States
Although the ε2 allele of apolipoprotein E (APOE2) benefits longevity, its mechanism is not understood. The protective effects of the APOE2 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.
