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PLoS One. 2019 Jul 29;14(7):e0219668. doi: 10.1371/journal.pone.0219668. eCollection 2019.

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

Author information

Department of Epidemiology, Erasmus Medical Centre, Rotterdam, the Netherlands.
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
Department of Biostatistics, University of Washington, Seattle, Washington, United States of America.
Faculty of Medicine, University of Iceland, Reykavik, Iceland.
California Pacific Medical Center Research Institute, San Francisco, California, United States of America.
Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Bethesda, Maryland, United States of America.
Sections of Preventive Medicine and Epidemiology, and Cardiology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
Icelandic Heart Association, Kopavogur, Iceland.
Departments of Epidemiology and Health Services, University of Washington, Seattle, Washington, United States of America.
Kaiser Permanente Washington Health Research Institute, Seattle, Washington, United States of America.
Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, North Carolina, United States of America.
Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America.



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.


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.


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.


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.

Conflict of interest statement

Dr. Psaty serves on the DSMB for a clinical trial funded by Zoll LifeCor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. This does not alter our adherence to PLOS ONE policies on sharing data and materials. None of the other authors report any conflict of interest.

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