Note: CI 5 confidence interval.

1 years to 104 years) more than doubled the frequency of « the 2—a statistically significant result roughly consistent with model 1.

« Carriers of the 2 allele were not more frequent in men (5/28, 18%) than in women (19/151, 13%; x2 5 0.5, df 5 1, 5 p .45). The low numbers of the cells of the male popula- tion (see Table 1) prevented further analyses.

The percentages of each genotype are shown in Table 1. The sample was composed primarily of women. In the raw « data, the frequency of the 2/3 genotype increased with age from 9% to 25% (Mantel-Haenszel x2 test for linear associ- 5 5 5 « ation 5.9, df 1, p .02), although 3/3 became less frequent (x2 5 4.3, df 5 1, p 5 .04). There were no subjects « who carried the 2/4 genotype. For counts of at least 5, per- centages across age groups were comparable for men and women.

D ISCUSSION

We found that the frequency of the « 2 allele of APOE shows a marked increase after age 100, supporting the view that the allele is related to longevity.

Although an increase of the frequency of the « 2 allele with age has been previously reported in other elderly popu- lations (4,12–16), data on the frequency of « 2 carriers within the group of centenarians have never been reported. Mathe- matical simulations of the changes in the genetic composi- tion of large populations have shown that, starting from around age 100, longevity genes have an increased likeli- hood of being selected (17). Thus, the finding of a rise in fre- quency of the « 2 allele with age in Finnish centenarians strengthens the idea that the allele is related to longevity.

Odds ratios from the two logistic models were computed for women (shown in Table 2). In model 1, women aged « 102 to 103 years were 2.6 times more likely to carry the 2 allele compared with those aged 100 to 101 years. Those aged 104 years and older were 4.4 times more likely to carry « the 2 allele compared with those aged 100 to 101 years. The 95% CI for this odds ratio did not include 1, indicating statistical significance. Model 2 estimates that each age in- crement (100–101 years to 102–103 years, and 102–103

The selection of the 2 allele with age has been previ- ously shown in a relatively younger Swedish cohort (75–98 years). Corder and colleagues (12) found an increased fre- « quency of 2/3 individuals with older age, and this associa- tion was more marked in men (12%, 14%, and 17% in those 1 aged 75–79, 80–84, and 85 years, respectively) than « women (13%, 11%, and 15%, respectively). Moreover, 2/3 « individuals had two- and fourfold lower mortality than 3/3 « « and 3/4 individuals (12), and 3/4 individuals had lower survival rates following ischemic stroke (26). These data are in agreement with other observations on the attrition of the « 4 allele with age (4,13–15) and with our own of low preva- « lence (17%) of 4 carriers in the Finnish centenarians. This figure is about half that expected on the basis of studies in large population samples that have shown the prevalence of « 4 carriers in young and adult Finns is 35% to 40% (27,28).

Table 1. Genotypic Frequencies of Apolipoprotein E in a Population of 179 Centenarians (the Finnish Centenarians

No. 100–101 Years No. 102–103 Years No. 1041 Years Men (n 5 17) (n 5 9) (n 5 2) «1/3 1 (6%) — — «2/2 — — — «2/3 2 (12%) 3 (33%) — «3/3 13 (77%) 5 (56%) 2 (100%) «3/4 1 (6%) 1 (11%) — «4/4 — — — Women (n 5 100) (n 5 33) (n 5 18) «1/3 — — — «2/2 — 1 (3%) — «2/3 8 (8%) 5 (15%) 5 (28%) «3/3 75 (75%) 19 (58%) 10 (56%) «3/4 17 (17%) 7 (21%) 3 (17%) «4/4 — 1 (3%) — All (n 5 117) (n 5 42) (n 5 20) «1/3 1 (1%) — — «2/2 — 1 (2%) — «2/3 10 (9%) 8 (19%) 5 (25%) «3/3 88 (75%) 24 (57%) 12 (60%) «3/4 18 (15%) 8 (19%) 3 (15%) «4/4 — 1 (2%) —

One other study of Japanese centenarians failed to detect any frequency increase of the « 2 allele. Asada and col- « leagues (16) found that the frequency of carriers of the 2 allele was not significantly different from that of younger 5 controls (9% vs 7%); however, their sample was small (N 33). We believe that the few epidemiological studies on this issue can be accounted for by the considerable practical dif- ficulties met by the collection of sizable and representative samples of centenarians. The proportion of centenarians is very small, even in developed countries: only 1 in 10,000

Note: Percentages may not add to 100 because of rounding.

6. Saunders AM, Strittmatter WJ, Schmechel D, et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic

adults reach age 100, and, of these, less than 1 in 100 reaches age 110. Therefore, studies must draw subjects from large geographical areas, often nationwide. Moreover, centenarians are often in poor physical and mental condi- tion, and the refusal rate can be as high as 30% (29). It should be noted that, although the Finnish Centenarians Study overcomes some of these methodological problems, its numbers are insufficient to assess some phenomena, such as age-related effects in men.

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