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.
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).
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
Further reading
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Background:
Under which conditions antibiotic combination therapy decelerates rather than accelerates resistance evolution is not well understood. We examined the effect of combining antibiotics on within-patient resistance development across various bacterial pathogens and antibiotics.
Methods:
We searched CENTRAL, EMBASE, and PubMed for (quasi)-randomised controlled trials (RCTs) published from database inception to 24 November 2022. Trials comparing antibiotic treatments with different numbers of antibiotics were included. Patients were considered to have acquired resistance if, at the follow-up culture, a resistant bacterium (as defined by the study authors) was detected that had not been present in the baseline culture. We combined results using a random effects model and performed meta-regression and stratified analyses. The trials’ risk of bias was assessed with the Cochrane tool.
Results:
42 trials were eligible and 29, including 5054 patients, qualified for statistical analysis. In most trials, resistance development was not the primary outcome and studies lacked power. The combined odds ratio for the acquisition of resistance comparing the group with the higher number of antibiotics with the comparison group was 1.23 (95% CI 0.68–2.25), with substantial between-study heterogeneity (I2=77%). We identified tentative evidence for potential beneficial or detrimental effects of antibiotic combination therapy for specific pathogens or medical conditions.
Conclusions:
The evidence for combining a higher number of antibiotics compared to fewer from RCTs is scarce and overall compatible with both benefit or harm. Trials powered to detect differences in resistance development or well-designed observational studies are required to clarify the impact of combination therapy on resistance.
Funding:
Support from the Swiss National Science Foundation (grant 310030B_176401 (SB, BS, CW), grant 32FP30-174281 (ME), grant 324730_207957 (RDK)) and from the National Institute of Allergy and Infectious Diseases (NIAID, cooperative agreement AI069924 (ME)) is gratefully acknowledged.
