power, remains. Further studies with larger sample size are needed to confirm our results.

Many studies have documented the association of APOE polymorphisms with blood lipid levels and with the risk of atherosclerosis and cardiovascular disease. It was reported that the frequency of the e4 allele of APOE decreases with advancing age (19,30) and that of the e2 allele contrarily increases in the elderly and centenarians (6,20). The elimination of the e4 allele at an earlier age and its decreased frequency in old people can be explained by the fact that the e4 allele is associated with coronary heart disease and Alzheimer’s disease (31,32). Nevertheless a significant change of allele frequency with advancing age was not confirmed in this study of a Korean population. One reason may be that Koreans have lower frequencies of e2 and e4 alleles than Western people (18,33). Another explanation might be the smaller proportion of coronary heart disease and Alzheimer’s disease as causes of mortality in Korean elderly. Whereas coronary heart disease is the leading cause of death (usually more than 20%) after middle age in Western countries, in Korea it causes only 4.5% of deaths (34), partly because of lower fat intake and a lower level of serum cholesterol. Malignancies and cerebrovascular accidents contribute more to mortality in Korea. If the e4 allele increases the risk of mortality in association with hypercho- lesterolemia and coronary heart disease, the adverse impact of the allele would be much less significant in a population with low serum cholesterol and less coronary heart disease.

still exerts an unfavorable effect on cognitive function in extremely old age. Since cognitive dysfunction is very closely related with activities of daily living, especially in the oldest old, it may be possible that the e4 allele is a risk factor for general functional decline at the final stage of human life.

In this study, although we could not define Alzheimer’s disease in our demented subjects, the majority of them is expected to be included within the category of Alzheimer’s disease. Asada and colleagues (22) found that 75.8% (25/33) of demented centenarians were diagnosed with Alzheimer’s disease. The distribution of APOE alleles in Korean late-onset Alzheimer’s disease patients (mean age of onset 73.1 6 5.8 years) was previously reported. The frequencies of the e2, e3, and e4 alleles were 2.8%, 63.5%, and 33.7%, respectively (35). Compared with the 33.7% frequency of the e4 allele in elderly Alzheimer’s disease cases, the absolute percentage of the e4 allele (9.1%) in demented centenarians is very small. This finding supports the contention of Asada and colleagues (22) that the fre- quency of the e4 allele in Alzheimer’s disease subjects de- creases with age.

onset Alzheimer’s disease, the prevalence of which increases markedly in the very old. Therefore, the influence of the e4 allele on Alzheimer’s disease might increase with advancing age. Furthermore, APOE alleles have a significant impact on the age of onset of Alzheimer’s disease. Therefore, it is plausible that for the population with a relatively short life span, the e4 allele could have a reduced chance to lead to Alzheimer’s disease and hence contribute less to this disease mortality. The average life expectancy for the Korean popu- lation was 62 in 1971, 66 in 1981, and 71 in 1991; about 5–10 years shorter than that for developed countries.

Although the overall distribution of the APOE allele in Korean centenarians was not statistically different from that in the control population, it was noticed that the frequency of the e4 allele gradually decreased after the eighth decade and tended to be lower in the centenarians. However, the e2 allele did not show any age-dependent change in its proportion (Figure 1). This finding suggests that the e4 allele may have a noticeable effect on survival disadvantage, as previously reported from Western countries. Therefore, the important determinant for longevity of Korean people may be the absence of the e4 allele rather than the presence of the e2 allele. This hypothesis is concordant with a previous report by Gerdes and colleagues (32).

We found that the frequency of the e4 allele was signi- ficantly higher in demented centenarians than in nonde- mented centenarians. This finding suggests that the e4 allele

Schunkert H, Hense H-W, Holmer SR, et al. Association between a deletion polymorphism of the angiotensin-converting enzyme gene and left ventricular hypertrophy. N Engl J Med.

;

:

–

Ruiz J, Blanche H, Cohen N, et al. Insertion/deletion polymorphism of the angiotensin-converting enzyme gene is strongly associated with coronary heart disease in non-insulin-dependent diabetes mellitus. Proc Natl Acad Sci U S A.

;

:

–

Farrer LA, Sherbatich T, Keryanov SA, et al. Association between angiotensin-converting enzyme and Alzheimer disease. Arch Neurol.

;

:

–

Corder EH, Saunder AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type

allele and risk of Alzheimer’s disease in late onset families. Science.

;

:

–

Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science.

;

:

–

Wilson PWF, Myers RH, Larson MG, Ordovas JM, Wolf PA, Schaefer EJ. Apolipoprotein E alleles, dyslipidemia and coronary heart disease: the Framingham Offspring Study. JAMA.

;

:

–

Cauley JA, Eichner JE, Kamboh MI, Ferrell RE, Kuller LH. Apo E allele frequencies in younger (age

–

) vs. older (age

–

) women. Genet Epidemiol.

;

:

–

Corder EH, Lannfelt L, Viitanen M, et al. Apolipoprotein E genotype determines survival in the oldest old (

years or older) who have good cognition. Arch Neurol.

;

:

–

Davignon J, Gregg RE, Sing CF. Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis.

;

:

–

Asada T, Yamagata Z, Kinoshita T, et al. Prevalence of dementia and distribution of Ap