APOE2 is associated with longevity independent of Alzheimer's disease

  1. Mitsuru Shinohara  Is a corresponding author
  2. Takahisa Kanekiyo
  3. Masaya Tachibana
  4. Aishe Kurti
  5. Motoko Shinohara
  6. Yuan Fu
  7. Jing Zhao
  8. Xianlin Han
  9. Patrick M Sullivan
  10. G William Rebeck
  11. John D Fryer
  12. Michael G Heckman
  13. Guojun Bu  Is a corresponding author
  1. National Center for Geriatrics and Gerontology, Japan
  2. Mayo Clinic, United States
  3. University of Texas Health Science Center at San Antonio, United States
  4. Durham Veterans Health Administration Medical Center's Geriatric Research, United States
  5. 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

  1. Mitsuru Shinohara

    Aging Neurobiology, National Center for Geriatrics and Gerontology, Obu, Japan
    For correspondence
    shinohara@ncgg.go.jp
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3045-7338
  2. Takahisa Kanekiyo

    Neuroscience, Mayo Clinic, Jacksonville, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Masaya Tachibana

    Neuroscience, Mayo Clinic, Jackosonville, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Aishe Kurti

    Neuroscience, Mayo Clinic, Jacksonville, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Motoko Shinohara

    Neuroscience, Mayo Clinic, Jacksonville, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Yuan Fu

    Neuroscience, Mayo Clinic, Jacksonville, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Jing Zhao

    Neuroscience, Mayo Clinic, Jacksonville, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Xianlin Han

    Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Patrick M Sullivan

    Duke University School of Medicine, Durham Veterans Health Administration Medical Center's Geriatric Research, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. G William Rebeck

    Neuroscience, Georgetown University Medical Center, Washington, DC, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. John D Fryer

    Neuroscience, Mayo Clinic, Jacksonville, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3390-2994
  12. Michael G Heckman

    Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Guojun Bu

    Neuroscience, Mayo Clinic, Jacksonville, United States
    For correspondence
    bu.guojun@mayo.edu
    Competing interests
    The authors declare that no competing interests exist.

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

  1. 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

  1. Received: August 17, 2020
  2. Accepted: October 13, 2020
  3. Accepted Manuscript published: October 19, 2020 (version 1)
  4. 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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  1. Mitsuru Shinohara
  2. Takahisa Kanekiyo
  3. Masaya Tachibana
  4. Aishe Kurti
  5. Motoko Shinohara
  6. Yuan Fu
  7. Jing Zhao
  8. Xianlin Han
  9. Patrick M Sullivan
  10. G William Rebeck
  11. John D Fryer
  12. Michael G Heckman
  13. Guojun Bu
(2020)
APOE2 is associated with longevity independent of Alzheimer's disease
eLife 9:e62199.
https://doi.org/10.7554/eLife.62199

Share this article

https://doi.org/10.7554/eLife.62199

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