APOE2 is associated with longevity independent of Alzheimer’s disease
Open accessAbstract
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.
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APOE2 greatly increases the risk of type III hyperlipidemia when present in two copies in some cases.
“APOE2 is protective against late-onset AD (hereafter referred to as AD) and benefits longevity, but greatly increases the risk of type III hyperlipidemia when present in two copies in some cases.14–16”
From ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis (2025) · cites this paper as [16]
The Introduction says APOE2 is protective against late-onset Alzheimer’s disease and is associated with longevity. The Discussion says only a small percentage of humans with two APOE2 copies develop hyperlipidemia, but it does not establish a greatly increased risk or identify those human cases specifically as type III hyperlipidemia. No page numbers are provided in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredAPOE2 is protective against late-onset Alzheimer's Disease.
“APOE2 is protective against late-onset AD (hereafter referred to as AD) and benefits longevity, but greatly increases the risk of type III hyperlipidemia when present in two copies in some cases.14–16”
From ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis (2025) · cites this paper as [16]
APOE2 benefits longevity.
“APOE2 is protective against late-onset AD (hereafter referred to as AD) and benefits longevity, but greatly increases the risk of type III hyperlipidemia when present in two copies in some cases.14–16”
From ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis (2025) · cites this paper as [16]
The associations between APOE and survival seem to be independent of baseline serum LDL cholesterol, cardiovascular risk and even Alzheimer disease diagnosis or the burden of Alzheimer disease neuropathology.
“Of note, contrary to expectation, these associations seem to be independent of baseline serum LDL cholesterol93, cardiovascular risk93,94 and even AD diagnosis or the burden of AD neuropathology94.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [94]
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- Authors
- Shinohara, M., Kanekiyo, T., Tachibana, M., Kurti, A., Shinohara, M., Fu, Y., Zhao, J., Han, X., Sullivan, P. M., Rebeck, G. W., Fryer, J. D., Heckman, M. G., & Bu, G.
- Affiliations
- Mayo Clinic (US)
- The University of Texas at San Antonio Health Science Center (US)
- Duke University (US)
- Georgetown University Medical Center (US)
- Corresponding author
- Shinohara, Mitsuru
- Bu, Guojun
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2020-10-19
- Volume
- 9
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC7588231
- OpenAlex
- W3092943378
- Cited by
- 82
- References
- 44
- Citations by year
- 2026: 11 · 2025: 18 · 2024: 15 · 2023: 13 · 2022: 12 · 2021: 12 · 2020: 1
- FWCI
- 3.22
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- National Institute on Aging (RF1AG057181, R37AG027924, R01AG046205, RF1AG051504, P01NS074969, P30AG062677, R21AG052423)
- Cure Alzheimer's Fund
- Japan Heart Foundation
- Naito Foundation
- BrightFocus Foundation
- National Center for Geriatrics and Gerontology
- Hori Sciences and Arts Foundation
- NACC Junior Investigator Award
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- APOE2, apolipoprotein E, longevity, lifespan, Alzheimer's disease, aging, physical activity, APOE isoforms, cholesterol, triglycerides, lipid metabolism, amyloid, tau protein
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Humans, Longevity, Lipid Metabolism, Mice, Apolipoprotein E2
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