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

P>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 epsilon 4 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 epsilon 4 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 epsilon 4 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 epsilon 4 status in 1998, 1546 had died at the end of the 10-year follow-up. Carriers of the ApoE epsilon 4 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 epsilon 4 allele on mortality with age do not support previous findings of decreased influence ApoE epsilon 4 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.