Increased effect of the ApoE gene on survival at advanced age in healthy and long-lived Danes: two nationwide cohort studies.

Studies of Nordic twins suggest an increased genetic influence on mortality with age. Contrary to this, the heterogeneity hypothesis predicts that the mortality of individuals carrying a 'frail' or 'risky' genotype in a population will approach that of noncarriers with age because of selection pressure. The ApoE ε4 allele is associated with an increased mortality risk, and its effect has been suggested to decrease with age. Here, we investigated the effect of ApoE ε4 allele on survival in a sample of the healthiest and long-lived Danes. The study population comprised Danes born in 1905 and a replicate sample of the 1895 cohort. For the 1905 cohort, a total of 350 carriers and 1256 noncarriers of the ApoE ε4 allele were followed from 1998 until death or end of follow-up. Cox regression models were used for the analysis. Of the 1606 persons with known ApoE ε4 status in 1998, 1546 had died at the end of the 10-year follow-up. Carriers of the ApoE ε4 allele had an increased mortality compared to noncarriers, and the influence of ApoE status on mortality increased in the age interval 92-103. For the covariates sex and independency status, the difference in relative risk of death between groups decreased with advancing age. Our findings of increasing influence of ApoE ε4 allele on mortality with age do not support previous findings of decreased influence ApoE ε4 allele on mortality with age, and alternative models such as the multifactorial threshold models should be considered for understanding the genetic effects on mortality at advanced age.