APOE2 is associated with longevity independent of Alzheimer's disease
- National Center for Geriatrics and Gerontology, Japan
- Mayo Clinic, United States
- University of Texas Health Science Center at San Antonio, United States
- Durham Veterans Health Administration Medical Center's Geriatric Research, United States
- Georgetown University Medical Center, United States
Abstract
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 database as well as animal models. Notably, APOE2 was associated with preserved physical 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.
Data availability
All source data files of animal experiments (Figure 2, Figure 4, Supplementary File 1d, and Supplementary File 1f) are included in the manuscript and supporting files. The clinical data are available from NACC (https://www.alz.washington.edu/WEB/researcher_home.html) upon request: distributing any data to a third party, who is not a collaborator or co-authors, is strictly prohibited by NACC.
Article and author information
Author details
Funding
National Institute on Aging (RF1AG057181)
- Guojun Bu
Naito Foundation
- Mitsuru Shinohara
BrightFocus Foundation
- Mitsuru Shinohara
National Center for Geriatrics and Gerontology
- Mitsuru Shinohara
Hori Sciences and Arts Foundation
- Mitsuru Shinohara
National Institute on Aging (R37AG027924)
- Guojun Bu
National Institute on Aging (R01AG046205)
- Guojun Bu
National Institute on Aging (RF1AG051504)
- Guojun Bu
National Institute on Aging (P01NS074969)
- Guojun Bu
National Institute on Aging (P30AG062677)
- Guojun Bu
Cure Alzheimer's Fund
- Guojun Bu
National Institute on Aging (R21AG052423)
- Takahisa Kanekiyo
Japan Heart Foundation
- Mitsuru Shinohara
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Rudolph E Tanzi, Harvard University, United States
Ethics
Animal experimentation: All cohorts examined in this study were generated from homozygous breeding pairs, group housed without enrichment structures in a specific pathogen-free environment in ventilated cages and used in experiments according to the standards established by the Mayo Clinic Institutional Animal Care and Use Committee (IACUC, Protocol# A58312).
Version history
- Received: August 17, 2020
- Accepted: October 13, 2020
- Accepted Manuscript published: October 19, 2020 (version 1)
- Version of Record published: October 26, 2020 (version 2)
Copyright
© 2020, Shinohara et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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APOE2 is associated with longevity independent of Alzheimer's disease
eLife 9:e62199.
https://doi.org/10.7554/eLife.62199
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