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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 58:M227-M231 (2003)
© 2003 The Gerontological Society of America

Distributions of ACE and APOE Polymorphisms and Their Relations With Dementia Status in Korean Centenarians

Yoon-Ho Choi1, Ji-Hae Kim2, Doh Kwan Kim2, Jong-Won Kim3, Duk-Kyung Kim1, Mee Sook Lee4, Cheol Ho Kim5 and Sang Chul Park6

1 Department of Internal Medicine
2 Department of Psychiatry
3 Department of Clinical Pathology, Sungkyunkwan University School of Medicine, Seoul, Korea.
4 Department of Food and Nutrition, Hannam University, Daejeon, Korea.
5 Department of Internal Medicine
6 Department of Biochemistry, Aging and Apoptosis Research Center, Seoul National University College of Medicine, Seoul, Korea.


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
Background. Genetic polymorphisms of angiotensin-converting enzyme (ACE) and apolipoprotein E (APOE) have been reported to be associated with human longevity and dementia in the elderly. However, whether such putative longevity genes exert the same effects on different ethnic groups living in different environments is not well known.

Methods. We investigated the distributions of the ACE and APOE genotypes and their relations with dementia status in Korean centenarians by cross-sectional study. A total of 103 centenarians (13 men and 90 women, mean age 102.4 ± 2.6 years) were included in this study. The allele frequencies of the genes were compared with those of two control groups: 7232 apparently healthy adults (4100 men and 3132 women) of mean age 48.5 ± 9.6 years for the ACE genotyping, and 6435 adults (5008 men and 1427 women) of mean age 50.7 ± 7.9 years for the APOE genotyping. The dementia status of the centenarians was assessed by clinical psychologist using the Clinical Dementia Rating (CDR) score.

Results. The frequencies of genotypes and alleles of the ACE and APOE genes of the centenarians were not significantly different from those of the control groups. There was a lack of association between presence of the D allele on the ACE gene and dementia status. However, the frequency of the {epsilon}4 allele of the APOE gene was significantly higher in centenarians with dementia than in centenarians without definitive dementia (9.1% versus 1.5%, p <.05).

Conclusions. These results suggest that neither the ACE nor the APOE gene is significantly associated with longevity in the Korean population, but that the APOE {epsilon}4 allele is still related with dementia even at age 100 and older.

Centenarians, who have escaped major age-associated diseases and attained the extreme limit of human life, are the best subjects for the genetic study of longevity. Although twin studies have suggested that the heritability of life span would be no more than 30% (1,2), genetic factors seem to play an important role in exceptional longevity (3). When the survival of siblings of centenarians was compared with the survival of siblings of a control group who were from a similar birth cohort, the relative risk of survival to older age steadily increased with age for siblings of the centenarians (4).

Recently, significant genetic associations with human longevity have been found at the HLA [human leukocyte antigen] (5), ACE [angiotensin-converting enzyme] (6,7), APOE [apolipoprotein E] (6,8), and APOB [apolipoprotein B] loci (9). Among them, the association between ACE gene polymorphism and longevity is rather controversial. Shächter and colleagues (6) first reported that the frequency of the D allele of the ACE gene was higher in French centenarians than in the control group. However, this finding was not confirmed in a later, larger, French centenarian cohort study (10). In Asian populations, the association was only found in a certain ethnic group in China (7). Meanwhile, the D allele has been associated with increased risk for cardiovascular diseases such as myocardial infarction (11,12), left ventricular hypertrophy (13), and coronary heart disease in diabetes mellitus (14). In addition, the D allele was reported to be more frequent among Alzheimer's disease subjects than in controls (15). It seems paradoxical that such an allele with adverse effects on major diseases is also related to survival to extreme old age.

The {epsilon}4 allele of the APOE gene is known to be associated with a greater risk of Alzheimer's disease (16). And it is also related with coronary artery disease through lipoprotein metabolism and atherogenesis (17,18). Previous studies demonstrated the decrease of the {epsilon}4 allele frequency and the increase of the {epsilon}2 allele frequency in centenarians (6,8). However, most of the studies in search of the association between genetic polymorphisms and longevity have been conducted in Caucasian populations. It is not known whether the APOE polymorphisms influence longevity differently in Korean compared with Caucasian populations (6,8,19,20). Compared with Caucasian populations, Asians are reported to carry lower frequencies of the APOE {epsilon}4 allele (21,22). Given the differential environment exposures experienced by Korean centenarians, potential gene–environmental interactions would also be expected to differ from Western Caucasians.

Although the genetic polymorphism of the APOE has been associated with Alzheimer's disease and cognitive function in elderly people, very few studies have been performed in subjects aged 100 and older. In a study of 47 Japanese centenarians, no significant difference was found in the frequency of the {epsilon}4 allele between Alzheimer's disease and nondemented centenarians (22).

The purpose of this study was to investigate the distributions of the ACE and APOE gene polymorphisms in Korean centenarians and to evaluate the association of these genes with dementia in such extreme old age.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Subjects
A total of 103 centenarians (13 men and 90 women) were included in this study. They ranged in age from 100 to 115 years. The mean age ± standard deviation (SD) was 102.4 ± 2.6 years. The Korean Centenarian Study was begun in December 1999. Persons born in 1900 or earlier were identified from the national registry of centenarians of the Ministry of Health and Welfare. Fifty-eight centenarians were living in the Seoul metropolitan area and 11, 22, and 12 centenarians were recruited from Kyungsang, Chunra, and Cheju provinces, respectively. Our medical team obtained consent from each subject or close relatives and visited their homes. The ACE and APOE genotype of the control group was drawn from the data of individuals who visited the Health Promotion Center at Samsung Medical Center for periodic health examination. The control population for the ACE genotyping was 7232 apparently healthy adults, of mean age 48.5 ± 9.6 years and ranged from age 20 to 85 years. There were 4100 men (mean age 48.6 ± 9.6 years, range 23–81 years) and 3132 women (mean age 48.3 ± 9.7 years, range 20–85 years). The control population for the APOE genotyping was 6435 apparently healthy adults, of mean age 50.7 ± 7.9 years and age range from 30 to 79 years. There were 5008 men (mean age 50.6 ± 7.9 years, age range 30–79 years) and 1427 women (mean age 51.1 ± 8.1 years, age range 30–78 years).

Methods
Centenarian subjects underwent medical examination, which consisted of an interview, physical and mental examinations, and laboratory tests. General physical examination was performed by a doctor specializing in geriatric medicine, and cognitive function was assessed by a clinical psychologist. Fasting venous blood was obtained from each subject and collected into tubes containing ethylenediaminetetraacetic acid [EDTA]. Genomic DNA was extracted from peripheral white blood cells using a Wizard Genomic DNA Purification kit (Promega, Madison, WI). The APOE genotyping was done with an INNO-LiPA Apo E Kit (Innogenetics N.V., Belgium) following the manufacturer's instruction. The ACE gene polymorphism was identified as previously described (23) by polymerase chain reaction (PCR) assay with primers flanking the polymorphic region. PCR products of the two alleles of 490 and 190 bp were separated on 1.5% agarose gel and visualized by ethidium bromide staining. The number of alleles was estimated by a gene-counting method.

Dementia status was appropriately assessed in 89 centenarians (men 11, women 78) with the following Clinical Dementia Rating (CDR) scores (24): 0, no dementia; 0.5, 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 0.5 was considered to indicate the absence of definitive dementia, while a score of 1, 2, or 3, the presence of dementia (25).

To compare the difference in frequency between the groups, the chi-square test was performed. A p value of less than.05 was considered to indicate a significant difference. All results are expressed as mean ± SD. Statistical analysis was carried out using SAS (Statistical Application System, Version 6.10; SAS, Inc., Cary, NC).


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
The frequencies of the genotypes and alleles of the ACE and APOE genes in Korean centenarians and control groups are compared in Tables 1 and 2. The genotype distributions were in Hardy-Weinberg equilibrium. There was no significant difference between the two groups in the overall distribution of the genotypes and alleles for the ACE gene. The frequencies of the {epsilon}2 allele of the APOE gene in the centenarians and the control group were 6.3% and 6.4%, respectively. The frequencies of the {epsilon}4 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 {epsilon}4 allele slightly decreased after the eighth decade and tended to be lower in the centenarians. The {epsilon}2 allele apparently did not indicate any age-dependent change in their proportion.


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  		Table 1. Distribution of Angiotensin-converting Enzyme Genotypes and Alleles in Centenarian and Control Groups.

 

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  		Table 2. Distribution of Apolipoprotein E Genotypes and Alleles in Centenarian and Control Groups.

 


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  		Figure 1. Distribution of apolipoprotein E alleles according to age in a Korean population. The frequency of the {epsilon}4 allele gradually decreases after the eighth decade and tends to be lower in the centenarians. However, the {epsilon}2 allele does not show any age-dependent change in its proportion

 
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 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 {epsilon}4 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 {epsilon}4 and without definitive dementia.


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  		Table 3. Dementia Status According to Clinical Dementia Rating in Centenarians.

 

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

 

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

 

   Discussion
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 Abstract
 Methods
 Results
 Discussion
References
 
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 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.

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 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 {epsilon}4 allele of APOE decreases with advancing age (19,30) and that of the {epsilon}2 allele contrarily increases in the elderly and centenarians (6,20). The elimination of the {epsilon}4 allele at an earlier age and its decreased frequency in old people can be explained by the fact that the {epsilon}4 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 {epsilon}2 and {epsilon}4 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 {epsilon}4 allele increases the risk of mortality in association with hypercholesterolemia 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.

The {epsilon}4 allele is an important genetic risk factor for late-onset Alzheimer's disease, the prevalence of which increases markedly in the very old. Therefore, the influence of the {epsilon}4 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 {epsilon}4 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.

We found that the frequency of the {epsilon}4 allele was significantly higher in demented centenarians than in nondemented centenarians. This finding suggests that the {epsilon}4 allele 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 {epsilon}4 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 ± 5.8 years) was previously reported. The frequencies of the {epsilon}2, {epsilon}3, and {epsilon}4 alleles were 2.8%, 63.5%, and 33.7%, respectively (35). Compared with the 33.7% frequency of the {epsilon}4 allele in elderly Alzheimer's disease cases, the absolute percentage of the {epsilon}4 allele (9.1%) in demented centenarians is very small. This finding supports the contention of Asada and colleagues (22) that the frequency of the {epsilon}4 allele in Alzheimer's disease subjects decreases with age.

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 {epsilon}4 allele gradually decreased after the eighth decade and tended to be lower in the centenarians. However, the {epsilon}2 allele did not show any age-dependent change in its proportion (Figure 1). This finding suggests that the {epsilon}4 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 {epsilon}4 allele rather than the presence of the {epsilon}2 allele. This hypothesis is concordant with a previous report by Gerdes and colleagues (32).

In summary, the present Korean centenarian study produced rather different results about the effect of ACE and APOE polymorphisms on human longevity and dementia. It is not surprising that Asian people with different genetic and environmental backgrounds show different results from Westerners in research on multifactorial phenomena. Our data disproved the association of the D allele of the ACE gene with longevity and dementia. One possible explanation may be that the effect of the allele is sufficiently mild as to be buffered by environmental and other genetic factors. Nevertheless the limitation of the study due to small sample size needs to be overcome in future research for a definitive conclusion to be made. The genetic polymorphism of APOE was not significantly different between the centenarians and control population. However, {epsilon}4 allele frequency showed a tendency to decrease at extremely old age. It was found that the unfavorable effect of the {epsilon}4 allele on dementia status is still remarkable among centenarians.


   Acknowledgments
 
This research was supported by grants from the Ministry of Health and Welfare, the Aging and Apoptosis Research Center (RII-2002-001-01-001), the Korea Research Foundation for Health Science, and Seoul National University Interdisciplinary Research Program.

Address correspondence to Sang Chul Park, MD, PhD, Department of Biochemistry, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-ku, Seoul 110-744, South Korea. E-mail: scpark{at}snu.ac.kr

Received July 23, 2002

Accepted December 20, 2002


   References
Top
 Abstract
 Methods
 Results
 Discussion
 References
 

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