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. 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)

Frank J Wolters  1 , Qiong Yang  2 , Mary L Biggs  3   4 , Johanna Jakobsdottir  5 , Shuo Li  2 , Daniel S Evans  6 , Joshua C Bis  3 , Tamara B Harris  7 , Ramachandran S Vasan  8 , Nuno R Zilhao  9 , Mohsen Ghanbari  1 , M Arfan Ikram  1 , Lenore Launer  7 , Bruce M Psaty  3   10   11 , Gregory J Tranah  6 , Alexander M Kulminski  12 , Vilmundur Gudnason  5   9 , Sudha Seshadri  13 ; E2-CHARGE investigators
Affiliations

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

Frank J Wolters et al. PLoS One. .

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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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.

Figures

Fig 1
Fig 1. Association of APOE-ε2 and APOE-ε4 carrier status with mortality per cohort, and meta-analysis.
Fig 2
Fig 2. Meta-analysed effect estimates of the associations between APOE genotypes and mortality.
Fig 3
Fig 3. Mean differences in lipid fractions of APOE-ε2 (orange) and APOE-ε4 (light blue) compared to homozygous ε3 carriers, per cohort and meta-analysis.
Fig 4
Fig 4. Meta-analysed effect estimates of the associations between separate APOE genotypes and lipid fractions.
See this image and copyright information in PMC

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