*Mean 6 standard deviation p value ,.001 from t test.

were in Hardy-Weinberg equilibrium. There was no sig- nificant difference between the two groups in the overall distribution of the genotypes and alleles for the ACE gene. The frequencies of the e2 allele of the APOE gene in the centenarians and the control group were 6.3% and 6.4%, respectively. The frequencies of the e4 allele were 6.8% and 9.2%, respectively, which were not significantly different. Figure 1 presents the distribution of three alleles of the APOE gene according to the decade of subject age from the combined population of the control group and centenarians. Although it was not statistically significant, the frequency of the e4 allele slightly decreased after the eighth decade and tended to be lower in the centenarians. The e2 allele apparently did not indicate any age-dependent change in their proportion.

dementia status was not determined by standardized Diagnostic and Statistical Manual of Mental Disorders (DSM-III) or National Institute of Neurological Disorders and Stroke (NINDS) criteria, but only by CDR scores. CDR, an instrument to assess the severity of dementia symptoms, is not an especially sensitive measure of cognitive function, particularly in very old and functionally dependent persons. However, there are few reports on the results of cognitive function tests in centenarians, so standardized protocols or normative data are not available for this specific group. As conventional cognitive assessment is often complicated by sensory impairment and medical illness (26), a simple CDR score might be useful in this setting to evaluate the dementia status in frail centenarians.

Although French and Chinese centenarian studies have presented an association between the ACE gene and longevity, the association has not been found in our Korean centenarians. The distribution of ACE genotypes in Korean people is different from that in the Western population (12,27), but similar to that in the Chinese and Japanese (7,28). Thus the discrepancy could not be explained merely by the difference of the allele proportions between ethnic groups.

The prevalence of dementia in centenarian subjects was 61.8% (55/89) by CDR criteria (a CDR score of 1, 2, or 3 indicating the presence of dementia). Table 3 shows the number and dementia status of the subjects according to the CDR score. The allele frequencies of the ACE and APOE genes were compared between centenarians without de- finitive dementia and those with dementia (Tables 4 and 5). The frequency of the D allele of the ACE gene in the centenarians with dementia was not significantly different from that in the centenarians without definitive dementia (37.3 % versus 45.6 %, p . .05). The frequency of the e4 allele of APOE was significantly higher in centenarians with dementia than in those without definitive dementia (9.1% versus 1.5%, p , .05). However, it is a potential limitation of the analysis that this comparison was based on a single centenarian subject with APOE e4 and without definitive dementia.

Farrer and colleagues (15) reported that the D allele was more frequent among Alzheimer’s disease subjects aged 66 to 70 than in controls. However, in a Japanese study, the frequency of II genotypes of ACE was 1.4 times higher in Alzheimer’s disease subjects than in controls, while that of DD genotypes was only 0.4 times as high (29). In our study, there was no significant association between ACE poly- morphism and dementia status in Korean centenarians. It seems that the ACE gene confers such weak effects on the cardiovascular system, cognitive function, or longevity that they are easily offset by other factors. Therefore, the genetic effects of ACE seem to be revealed only in a very homo- geneous group with the same genetic and environmental factors. Although we could not find a significant associa- tion between ACE polymorphism and the dementia status of centenarians, the possibility of a type II error, i.e., the existing association was not found because of insufficient

D ISCUSSION

This is the first report on Korean centenarians with regard to genetic polymorphisms and dementia. The subjects were recruited nationwide from various urban and rural areas. As expected in such a survey on the very old, there is a potential for selection bias, as healthier subjects are more likely to participate in the study. Another limitation may be that

Table 5. Comparison of Apolipoprotein E Genotypes and Alleles in Centenarians According to Dementia Status

Table 4. Comparison of Angiotensin-Converting Enzyme Genotypes and Alleles in Centenarians According to Dementia Status

Centenarians Without Centenarians Definitive Dementia With Dementia (n 5 34) (n 5 55) Number (frequency) Number (frequency) Genotype E2/2 E2/3 4 (11.8%) 5 (9.1%) E3/3 29 (85.3%) 40 (72.7%) E4/2 1 (1.8%) E4/3 1 (2.9%) 9 (16.4%) E4/4 p value .207 Allele e2 4 (5.9%) 6 (5.5%) e3 63 (92.7%) 94 (85.5%) e4 1 (1.5%) 10 (9.1%) p value .122 (e21e3) 67 (98.5%) 100 (90.9%) e4 1 (1.5%) 10 (9.1%) p value .040 Fisher’s .035 (one-sided)

Centenarians Without Centenarians With Definitive Dementia Dementia (n 5 34) (n 5 55) Number (frequency) Number (frequency) Genotype DD 7 (20.6%) 7 (12.7%) ID 17 (50.0%) 27 (49.1%) II 10 (29.4%) 21 (38.2%) p value .524 Allele D 31 (45.6%) 41 (37.3%) I 37 (54.4%) 69 (62.7%) p value .272

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