Dementia status was assessed with clinical dementia rating (CDR) scores: 0, no dementia; .5, dementia suspected; 1, mild dementia; 2, moderate dementia; and 3, severe dementia. Subjects were divided into two groups according to their dementia status. A CDR score of 0 or .5 indicated the absence of definitive dementia, while a score of 1, 2, or 3 indicated the presence of dementia.

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.

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 allele frequencies of the ACE and APOE genes were compared between centenarians without definitive 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 polymorphism 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 homogeneous group with the same genetic and environmental factors. Although we could not find a significant association 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 power, remains. Further studiesCompared 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 frequency of the e4 allele in Alzheimer's disease subjects decreases with age. Onset of 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 lifespan, 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 population 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 significantly higher in demented centenarians than in non-demented centenarians. This finding suggests that the e4 allele has an effect on dementia status even among centenarians.