Variation in the apolipoprotein E gene (APOE) has been reported to be associated with longevity in humans. The authors assessed the allelic distribution of APOE isoforms epsilon 2, epsilon 3, and epsilon 4 among 10,623 participants from 15 case-control and cohort studies of age-related macular degeneration (AMD) in populations of European ancestry (study dates ranged from 1990 to 2009). The authors included only the 10,623 control subjects from these studies who were classified as having no evidence of AMD, since variation within the APOE gene has previously been associated with AMD. In an analysis stratified by study center, gender, and smoking status, there was a decreasing frequency of the APOE epsilon 4 isoform with increasing age (chi(2) for trend 14.9 (1 df); P = 0.0001), with a concomitant increase in the epsilon 3 isoform (chi(2) for trend 11.3 (1 df); P = 0.001). The association with age was strongest in epsilon 4 homozygotes; the frequency of epsilon 4 homozygosity decreased from 2.7% for participants aged 60 years or less to 0.8% for those over age 85 years, while the proportion of participants with the epsilon 3/epsilon 4 genotype decreased from 26.8% to 17.5% across the same age range. Gender had no significant effect on the isoform frequencies. This study provides strong support for an association of the APOE gene with human longevity.