APOE Alleles and Extreme Human Longevity

Abstract

We assembled a collection of 28,297 participants from seven studies of longevity and healthy aging comprising New England Centenarian, Long Life Family, Longevity Gene Population, Southern Italian Centenarian, Japanese Centenarian, the Danish Longevity, and the Health and Retirement Studies to investigate the association between the APOE alleles ε2ε3 and ε4 and extreme human longevity and age at death. By using three different genetic models and two definitions of extreme longevity based on either a threshold model or age at death, we show that ε4 is associated with a substantially decreased odds for extreme longevity, and increased risk for death that persists even beyond ages reached by less than 1% of the population. We also show that carrying the ε2ε2 or ε2ε3 genotype is associated with significantly increased odds to reach extreme longevity, with decreased risk for death compared with carrying the genotype ε3ε3 but with only a modest reduction in risk for death beyond an age reached by less than 1% of the population.

Figure 1.

Forest plots of odds ratio (OR) for extreme longevity estimated using the genotypic model. Meta_2017 denotes results from the meta-analysis published in (14). ${\chi }_n^2$ denotes Cochran’s Q test of heterogeneity with n degrees of freedom and p is the p value to test the null hypothesis of no heterogeneity across studies (a nonsignificant result for this test suggests that meta-analysis is appropriate). CI = confidence interval.

Figure 2.

Forest plots of odds ratio (OR) and hazard ratios, relative risk (RR) estimated using the additive genetic models. The analysis was restricted to carriers of the ${\epsilon }_3{\epsilon }_3$${\epsilon }_2{\epsilon }_3$ and ${\epsilon }_2{\epsilon }_2$ genotypes. The Japanese set was not included in the survival analysis of all study participants because ages of controls are unknown. ES = extreme survivors. ${\chi }_n^2$ denotes Cochran’s Q test of heterogeneity with n degrees of freedom and p is the p value to test the null hypothesis of no heterogeneity across studies. CI = confidence interval; HRS = Health and Retirement Study.

Figure 3.

Forest plots of odds ratio and hazard ratios estimated using the genotype group models. $E2={\epsilon }_2{\epsilon }_2, {\epsilon }_2{\epsilon }_3$$E3={\epsilon }_3{\epsilon }_3$ and $E4={\epsilon }_2{\epsilon }_4,{\epsilon }_3{\epsilon }_4,{\epsilon }_4{\epsilon }_4$ The Japanese set was not included in the survival analysis of all study participants because ages of controls are unknown. ES = extreme survivors. ${\chi }_n^2$ denotes Cochran’s Q test of heterogeneity with n degrees of freedom and p is the p value to test the null hypothesis of no heterogeneity across studies. CI = confidence interval; HRS = Health and Retirement Study; RR = relative risk.