Mortality differences by APOE genotype estimated from demographic synthesis

The 4 allele of apolipoprotein E (APOE) is associated with increased risk of two major causes of death in low-mortality populations: ischemic heart disease and Alzheimer's disease. It is less common among centenarians than at younger ages. Therefore, it is likely that it is associated with excess risk of death. This article extends demographic models that estimate relative mortality risks from changes in gene frequencies with age. The resulting demographic synthesis combines gene frequencies with data on mortality by genotype from cohort studies. The model was applied to data from Denmark, Finland, France, Italy, Sweden, and the United States. Near age 50, the 3/4 genotype is associated with a risk of death of 1.34 times that of the 3/3 (95% CI 1.18-1.67). The relative risk for 4/4 is the square of the relative risk for 3/4, 1.81. The 2/3 genotype is protective with a relative risk of 0.84 (0.68-0.93) near age 50. These relative risks move toward 1.0 at the oldest ages and APOE genotype is associated with little variation in mortality over age 100. There are no significant differences in the relative risks by sex. There is little evidence of differences within Europe in the effects of APOE. This approach can be generalized to combine data on genetic risk factors for disease from a wide variety of study designs and sample characteristics.