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The impact of APOE genotype on survival: Results of 38,537 participants from six population-based cohorts (E2-CHARGE)

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Wolters, Frank J., Yang, Qiong, Biggs, Mary L., Jakobsdottir, Johanna, Li, Shuo, Evans, Daniel S., Bis, Joshua C., Harris, Tamara B. +11 more·2019·PLOS ONE
DOI 10.1371/journal.pone.0219668PMC PMC6663005
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Abstract

BACKGROUND: Apolipoprotein E is a glycoprotein best known as a mediator and regulator of lipid transport and uptake. The APOE-ε4 allele has long been associated with increased risks of Alzheimer's disease and mortality, but the effect of the less prevalent APOE-ε2 allele on diseases in the elderly and survival remains elusive. METHODS: We aggregated data of 38,537 individuals of European ancestry (mean age 65.5 years; 55.6% women) from six population-based cohort studies (Rotterdam Study, AGES-Reykjavik Study, Cardiovascular Health Study, Health-ABC Study, and the family-based Framingham Heart Study and Long Life Family Study) to determine the association of APOE, and in particular APOE-ε2, with survival in the population. RESULTS: During a mean follow-up of 11.7 years, 17,021 individuals died. Compared with homozygous APOE-ε3 carriers, APOE-ε2 carriers were at lower risk of death (hazard ratio,95% confidence interval: 0.94,0.90-0.99; P = 1.1*10-2), whereas APOE-ε4 carriers were at increased risk of death (HR 1.17,1.12-1.21; P = 2.8*10-16). APOE was associated with mortality risk in a dose-dependent manner, with risk estimates lowest for homozygous APOE-ε2 (HR 0.89,0.74-1.08), and highest for homozygous APOE-ε4 (HR 1.52,1.37-1.70). After censoring for dementia, effect estimates remained similar for APOE-ε2 (HR 0.95,0.90-1.01), but attenuated for APOE-ε4 (HR 1.07,1.01-1.12). Results were broadly similar across cohorts, and did not differ by age or sex. APOE genotype was associated with baseline lipid fractions (e.g. mean difference(95%CI) in LDL(mg/dL) for ε2 versus ε33: -17.1(-18.1-16.0), and ε4 versus ε33: +5.7(4.8;6.5)), but the association between APOE and mortality was unaltered after adjustment for baseline LDL or cardiovascular disease. Given the European ancestry of the study population, results may not apply to other ethnicities. CONCLUSION: Compared with APOE-ε3, APOE-ε2 is associated with prolonged survival, whereas mortality risk is increased for APOE-ε4 carriers. Further collaborative efforts are needed to unravel the role of APOE and in particular APOE-ε2 in health and disease.

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  • 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 [93]

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Cited by

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Authors
Wolters, F. J., Yang, Q., Biggs, M. L., Jakobsdottir, J., Li, S., Evans, D. S., Bis, J. C., Harris, T. B., Vasan, R. S., Zilhao, N. R., Ghanbari, M., Ikram, M. A., Launer, L., Psaty, B. M., Tranah, G. J., Kulminski, A. M., Gudnason, V., Seshadri, S., & for the E2-CHARGE investigators
Affiliations
  • Erasmus MC (NL)
  • Boston University (US)
  • University of Washington (US)
  • California Pacific Medical Center (US)
  • National Institutes of Health (US)
  • Kaiser Permanente Washington Health Research Institute (US)
  • Duke University (US)
  • University of Iceland (IS)
Corresponding author
  • Wolters, Frank J.
  • Seshadri, Sudha
ORCID
Venue
PLOS ONE
Publisher
Public Library of Science (PLoS)
Published
2019-07-29
Volume
14
Issue
7
Pages
e0219668
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0219668
PMC
PMC6663005
OpenAlex
W2965285787
Cited by
74
References
7
Citations by year
2026: 8 · 2025: 5 · 2024: 10 · 2023: 10 · 2022: 11 · 2021: 22 · 2020: 7 · 2019: 1
FWCI
9.60
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • Yale University
  • National Institutes of Health (1r01hl120393-01a1)
  • National Institute on Aging (P30AG010129, U01AG049505, R01AG031287, U01AG052409, U01AG023712, R01AG054076, U24AG051129, R01AG049607, R01AG033040, R01AG061853, R01AG033193, P01AG043352, RF1AG059421, R01AG008122, P30AG034424, U19AG023122)
  • National Heart, Lung, and Blood Institute (HL-105756, R01-HL120393, U01HL130114, U01HL120393, R01HL105756, AG033193)
  • National Institute of Neurological Disorders and Stroke (R01NS017950)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R03HD050374)
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
apolipoprotein E, APOE ε2 allele, APOE ε4, APOE genotype, mortality, survival, Alzheimer's disease, dementia, serum lipids, LDL cholesterol, older adults, genetic risk factors, dose-dependent association, European ancestry populations, Rotterdam Study, AGES-Reykjavik Study, Cardiovascular Health Study
MeSH terms
Aged, Apolipoproteins E, Female, Genotype, Heterozygote, Humans, Lipids, Male, Meta-Analysis as Topic, Cohort Studies, Survival Analysis

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