Special Article
Dementia is one of the most important public health problems. Because of rapid increasing of old age in the world, need for prevention strategies and caring of dementia should be solved. Epidemiological studies can provide the basic data for making health policy, developing the prevention strategies. Epidemiological studies can be classified into the descriptive studies for studying the prevalence and incidence of a disease and the analytic studies for identifying risk factors of a disease. This review summarized the recent achievements in the epidemiology of dementia performed in the world and our country. The prevalence and incidence of dementia increased double by every 5 years of age over the age of 65 years in general. However, whether the prevalence rate of dementia exponentially increases in the oldest old age is uncertain.
The prevalence rates of dementia were generally lower in developing countries, but the exact mechanisms of these findings were not well understood. Although Alzheimer's disease is the most common etiology of dementia in most countries, some studies, especially from Japan, reported that vascular dementia is more common. However, recent studies suggested that the prevalence of vascular dementia decrease and Alzheimer's disease is more prevalent. Age and some genetic factors were consistently reported as the risk fac tors of dementia. In contrast, the association between most non-genetic risk factors and dementia were still controversial. The epidemiological studies for dementia should overcome some methodological difficulties such as diagnostic threshold for dementia and the diagnostic criteria of vascular dementia.
Correspondence: Dong Young Lee, MD, PhD, Department of Psychiatry & Behavioral Science, Seoul National University Hospital, 28 Yongon-dong, Chongno-gu, Seoul 110-744, Korea
Tel: +82-2-2072-2205, Fax: +82-2-744-7241, E-mail: selfpsy@plaza.snu.ac.kr
Dementia is one of the most important causes of disability in the elderly. With the rapidly growing numbers of elderly people, the numbers of dementia patients are also increasing at a very high speed in most countries. As a result, the management of dementia patients is now becoming one of the most important public health problems1,2. Epidemiological studies could give the fundamentals for the development of the government policy and the strategies for the prevention of dementia.
Although the epidemiological studies on dementia and its specific type were started in 1960s in western countries, more sophisticated and refined epidemiological studies have been carried out since 1980s3. Till now, a number of epidemiological surveys were performed around the world. The results of the epidemiological studies can be classified into two categories: one is the descriptive study in which the prevalence and incidence of a disease can be estimated and the other is the analytic study in which the risk factors of a disease can be identified4. This review follows this kind of classification. First, the prevalence and incidence studies on dementia and its subtype will be discussed. The recent epidemiological studies on dementia in Korea will be also reviewed briefly. Second, the recent findings on the risk factors of dementia and its subtype will be summarized. Most epidemiological studies have focused on dementia and Alzheimer's disease (AD). Much fewer studies focused on vascular dementia (VD), especially for identifying risk factors. Studies on rarer form of dementia, which are is frontotemoral dementia (FTD) and dementia with Lewy body (DLB), are few little. Thus, the major portion of this review will be devoted to overall dementia and AD.
Descriptive Epidemiology
Prevalence (Worldwide)
Dementia
Because there are so many studies on the prevalence of dementia in the world, it is very difficult to summarize the results of each study. Fortunately, several meta-analyses have been carriedout on pooled data from a number of comparable studies, which make it easier to summarize the literatures.
Jorm et al5. pooled 22 studies from throughout the world and reported that prevalence of dementia increased double by every 5 years of age. Hofman et al6. pooled 12 European studies performed from 1980 to 1990 and reported the very similar result to Jorm et al. Lobo et al7. pooled 11 European studies performed during 1990s and reported that the prevalence rate of dementia is 6.4%. Table 1 summarizes the age-specific prevalence rate of dementia reported from the mentioned studies. The prevalence of dementia is very low in the subjects under the age of 65 years (0.5-1.0%) and increases with age. Although Ritchie and Kildea8 reported that the prevalence rate of dementia do not increase exponentially, this observation might be influenced by survival effect and need adequate numbers of the very old.
The geographical variation of the prevalence of dementia was also reported. The prevalence rates of dementia in North America and Europe were quite similar. In contrast, some studies performed in developing countries reported lower prevalence rate than those of western countries. For example, Li et al9. and Liu et al10. reported very low prevalence rates of dementia (1.8% and 2.0%, respectively) in China. Recently, such a lower prevalence rate of dementia in developing countries was confirmed by inter-continental studies, which might overcome some methodological differences. In the IndoUS study, the prevalence of rural community in India is only 1.1%11. In the Indianapolis-Ibadan project, the prevalence rate of dementia in Ibadan was 2.3%, which was much lower than that of Indianapolis (8.3%)12. This geographical difference might come from several factors. First, different culture and environment including rather simple activities of daily living, low-tech environment, under-reported functional impairment by family members might influence the results10,13. Second, short life span and high mortality in developing countries might also influence the low prevalence of dementia. Third, true racial difference might exist. For example, APOE
ε4 allele, which is known as a genetic risk factor for AD in Caucasians and Asians, is not associated with a higher risk of dementia in Africans14.
The prevalence rate of AD increases with age. Lobo et al7. pooled the data from European country and reported the age-specific prevalence rate of 0.6 to 0.7% at the ages fo 60-69 years, 1.5 to 2.3 at 70-74, 1.8 to 4.3 at 75-79, 6.3 to 8.4 at the age of 80-84 years, 8.8 to 14.2 at 85-89 and 17.6 to 23.6 at 90 and the more. The prevalence of AD was higher in women than in men. The prevalence of VD also increases with age. In the same study, the prevalence of VD was 1.6% in the age of 60 years and the more. The age-specific prevalence is reported as 0.5 to 0.1% at the age of 60-69 years, 0.8 to 0.6 at 70-74 years, 1.9 to 0.9 at 75- 79, 2.4 to 2.3 at 80-84, 2.4 to 3.5 at 85-89 and 3.6-5.8 at 90 and the more.
The ratio between AD and VD was similar in most studies of US, Europe and Africa. AD is the most common etiology of dementia and accounts for 50-70% of total dementia cases. Second most common etiology is VD and account for 20-30% of total dementia15. However, two studies from Italy16 and Sweden17 in Europe and several studies from Japan reported higher prevalence rates of VD than those of AD18,19,20. These results might be explained by the following two factors. One is related with diagnostic criteria. Many early studies in Japan classified AD and VD by the
Hachinski Ischemic Score (HIS)21 only. HIS might overestimate the prevalence of dementia22. In consistent with this explanation, in two studies on Japanese immigrants, which used the
Diagnostic and Statistical Manual for Mental Disorders, the third edition, revised (DSM-III-R)23 and the criteria of the California Alzheimer's Disease Diagnostic and Treatment Centers (ADDTC)24 for diagnosing VD, AD was more prevalent than VD 25,26. On the contrary, a recent study by Ikeda et al. (2001) reported that VD was more prevalent than AD by using the Diagnostic and Statistical
Manual for Mental Disorders, the fourth edition (DSM-IV) criteria 27 for VD diagnosis. More researches should be conducted for this issue. The other explanation is related with the prevalence of stroke. In the Hisayama study28, VD/AD ratio shift 1.8: 1 to 1.1: 1 from 1984 to 1992. This result was closely matched an overall decline in stroke incidence.
Mixed of AD and VD (MXD) is a problematic entity. Many epidemiological studies on dementia did not classify mixed dementia as an independent diagnostic entity. Only a few studies classified MXD as independent entity in their studies. The reported prevalence rate of MXD is ranged from 0.2 to 4.6%29. Frontotemoral dementia (FTD) is less common than the other types of dementia. Two groups have attempted to find the prevalence of FTD. Ratnaavalli et al30. reported 15 cases/100,000 persons in the 45-64 year range of age. For this range, the ratio between FTD/AD was 1.6/1.
Rosso et al31. reported 3.6 cases/100,000 persons in the age of 50-59 years, 9.4 at 60-69, and 3.8 at 70-79. Prevalence studies on the dementia with Lewy body (DLB) were conducted mostly in pathological studies and estimated prevalence was ranged from 15 to 35% of all dementia subjects. The clinical prevalence of DLB was 5.0%, comprising 22% of all dementia subjects in the age of 75 years and the more32 or 0.1-0.6% in the age of 65 years and more years of age33,34.
Prevalence (Korea)
Dementia
There have been at least seven population based studies performed on the dementia epidemiology, which were published at peer review journals in Korea since 1990. Table 2 and 3 summarized the methodology and results. Three studies were conducted in urban areas35,36,37 and other three studies were in rural areas38,39,40. Only one study was done for both rural and urban area41. All the studies included the people with the age over 65 years, and used DSM-III-R or DSM-IV criteria for the diagnosis of dementia. Overall prevalence rate of dementia ranged from 6.8 to 13.0% of the elderly community population, comparable to the results from the studies conducted in western countries35,36,37,38,39,40,41. Dementia was more in female than in male in all studies. The prevalence rate of dementia more increased with age in female than in male in all studies (Table 3).
Subtypes of dementia
In Korea, the prevalence rate of AD is higher than that of VD in all studies. The prevalence of AD is 4.2 to 5.3% and that of VD is 2.0-4.8%. AD accounts for 39.8 to 65.4% of total dementia cases, and VD accounts for 12.0-37.5% (Table 4). The AD/VD ratio was the highest in Park et al.'s study38 and the lowest in Kim et al.'s study35. The discrepancy of AD/VD ratio among the studies might come from methodological difference, such as the diagnostic criteria for VD, the classification method of MXD, and the use of neuroimaging. Specific high prevalence of alcoholic dementia (1%) was reported in one earlier study37, while the finding was not replicated in later studies.
Incidence (Worldwide)
There have been relatively small numbers of study on the incidence of dementia, comparing with the studies on the prevalence. Based on existing data, overall dementia occurs at the rate of approximately 1% per year in persons with the age of 60 years and the more.
The incidence of dementia increases with age. However, the increasing pattern of incidence is not so clear. Jorm et al42. reported that the incidence rate for dementia increase exponentially with age up to the age of 90 years like prevalence. In contrast, in subsequent meta-analysis43 Gao et al. reported that the incidence rate of dementia does not exponentially increase but just show slowly increasing pattern44. Disease-specific studies show highly consistent results with a general trend for a higher incidence of AD in women and a higher incidence of VD in men. However, Fratiglioni et al. pooled data from eight European studies which had used the same diagnostic criteria and found that there was little sex difference up to the age of 80 years44. In Rochester study, incidence rate of FTD was 2.2% for the age of 40-49 years, 3.3 for 50-59, 8.9 for 60-69. The ratio of FTD/AD was 1: 5.25 under the age of 7045.
Geographical variations should be noted. In general, the lowered incidence rates were reported in European studies than in North American studies, probably due to some methodological differences15. Although incidence data from other continent including Asia and Africa very limited, the recent Indo-US study13 and Indianapolis-Ibadan study46 reported significantly lower rate of incidence for overall dementia and AD.
The secular trend in the incidence of dementia should be mentioned. In Rochester study, the annual incidence rate of dementia declined from 11 cases /100,000 in 1960-64 years to 9.6/100,000 in 1965-69 and 5.7/100,000 in 1970-7448. This decline might be associated with the decline of stroke incidence.
Incidence (Korea)
Incidence study for dementia is rare in Korea. Recently, Kim et al. (2002) reported the results of the follow up studies in Yonchon. They followed up 596 nondemented elderly for 42 months and reported that the incidence rate of dementia was 1.9%48.
Analytic Epidemiology: Risk Factors
Sociodemographic factors
Age and sex
Old age is one of the most consistently reported risk factors of dementia. However, dementia itself is not a consequence of aging8. Some pathological features of AD can be found in the brain of a normal elderly individual who died without a history of AD, in spite of AD is qualitatively distinguishable to normal aging49.
In most studies, AD is more prevalent in female than in male44,50,51 although not in all studies52,53. The higher incidence of AD in female may be explained by 1) the higher survival rate in women 2) the multiple exposures of risk factors of AD (ex. head trauma, smoking) in men 3) the lower estrogen level in old women. As for VD, men have been thought to be riskier, but the issue remains controversial3.
Education
The relationship between education and dementia is one of the most controversial issues in the epidemiology of dementia. Stern et al54. reported that the relative risk of AD increased two-fold among the people with less than eight years of education comparing with those with eight or more years of education. However, other studies reported that education is not a risk factor of AD55,56,57. The interaction between gender and education was suggested. The EURODEM analysis revealed that low education increased the risk of AD in women, but not in men58. Education might be an indirect risk factor. For example, lower educated people might more frequently exposure to toxic drugs or nutritional deficiency. Education is related to intelligence. Some studies reported that higher premorbid intelligence is associated with low risk of developing dementia59,60.
Genetic factors
Down syndrome
Most of patients with Down syndrome who live up to the age of 40 years develop the pathological changes of AD61. The family history of Down syndrome increases the risk of AD two to three-fold62. Nevertheless, the prevalence of dementia in Down syndrome is much less than 100%, even at the age of 5063. This phenomenon is not well explained.
Family history
The individuals who have the first degree relatives with AD have an increased risk of AD two to four-fold and the risk might be even higher when two or more degree relatives were affected64. In general, family history is a strong risk factor in the early onset AD rather than in late onset AD.
Mutation and polymorphism
The mutations in the APP gene on chromosome 21, in the presenilin 1 on chromosome 14, and the presenilin 2 on chromosome 1 were found in the families with autosomal dominant hereditary AD65. The individuals with apolipoprotein (APOE)
ε4 allele, which is located on chromosome 19, have an increased risk of AD by three to five-folds not only in western countries but also in Asian countries66,67. The genetic risk factors of VD have been rarely studied despite of the existence of hereditary forms of amyloid angiopathy and CADASIL68.
Medical history
Vascular risk factors
In general, vascular risk factors are significantly associated not only with VD but also with AD. Hypertension, which is the most important risk factor for cerebrovascular disease (CVD), was reported as an important risk factor for cognitive decline and VD69. Recent studies suggested that hypertension also play a role in the development of AD. In the Honolulu- Asia aging study, men with untreated hypertension in midlife had an increased risk for both VD and AD70. The indicators of the atherosclerosis in carotid and peripheral arteries were significantly associated with AD.
The results from Rotterdam study indicated that severe atherosclerosis could increase the risk ratio three times as comparing with those without atherosclerosis. In this study, subjects with having severe atherosclerosis and at least one APOE
ε4 allele had nearly twenty-fold increased risk for AD71. Cholesterol might play a role in developing AD and VD. Recent epidemiological studies reported that statin can reduce the risk of AD and overall dementia approximately 30%72,73. Homocysteine, a well known risk factor for cardiovascular and cerebrovascular disease, is a thiol-containing amino acid and produced during one-carbon metabolism74. During homocysteine metabolism, various cofactors including vitamin B12, B6 and folate are needed. Many studies reported that homocysteine not only increased the risk of VD74,75,76,77 but also AD74,76,78,79,80,81.
Depression
Relationship between depression and AD is much more complex. Depression may be a risk factor82 or a symptom of dementia83,84. Recent meta-analysis, Jorm et al85. suggested that the history of depression approximately double the risk of AD and overall dementia.
Endocrine disease
Most studies found that the presence of diabetes mellitus almost doubled the risk not only for overall dementia but also for AD86,87,88. Hypothyroidism might increase the risk of dementia89,90, but its explanatory mechanism and reversibility were still unclear.
Head trauma
Previous retrospective studies reported that a prior traumatic head injury can increase the risk of AD91,92,93. The association of head injury with AD might be explained by the fact that head injury can induce up-regulation of APP and neuronal loss94. However, selective recall bias might influence the results. Many prospective studies51,95,96,97,98 failed to find any association between AD and head injury except the study of Schofield et al.99.
Drug use
Estrogen may impact on brain functions and protect against AD. Some studies reported that Estrogen Replacement Therapy (ERT) might reduce the risk of AD by around 30%100,101. However, these results should be cautiously interpreted. The recent results from the Women's Health Initiative study,102 which is an epidemiological study on a large scale sponsored by the National Institute of Health of the United States, showed that ERT could not improve cognitive function in post-menopausal women and even increase the risk for dementia and mild cognitive impairment. The study also indicated that ERT increase the risk of breast cancer, ovarian cancer, colorectal cancer, and ischemic stroke.
The inflammatory response cbrings to the degeneration in AD. Recent longitudinal studies for association of NSAID and AD reported inconsistent results103,104,105,106. Stewart et al.103 supported the hypothesis that NSAID has a protective effect against AD, while Fourrier et al.104 and Henderson et al.105 did not. In the recent Rotterdam study, in which 6989 subjects the age of 55 years or the more were followed up approximately for 7 years, the relative risk of AD in those who use NSAIDS for more than two years was significantly reduced to 0.2. In contrast, the risk of VD was not reduced106.
Environmental factors
Smoking
Some earlier studies reported that smoking has a protective role against the development of AD. However, recent longitudinal studies did find the association between smoking and AD108,109,110. Moreover, in Rotterdam study, people who smoked cigarettes had more than two-fold increased risk of AD110.
Alcohol
Moderate alcohol intake is not associated with AD111. In PAQUID study, protective effect of alcohol consumption on the risk of dementia was reported112. In contrast, alcohol abuse has been reported to increase the risk of dementia113. These results indicate that the alco-hol consumption and cognitive performance is associated to each other according to a J shape curve pattern. It is very similar to the relationship between alcohol con-sumption and risk of stroke which also shows a J shape curve pattern114.
Diet
Although oxidative stress is a one of the major causes of AD, the protective effect of antioxidant like Vitamin C and E is not clear. An evidence of the effect of Vitamin E comes from the study of Sano et al.115 In this study, moderately demented patients with Vitamin E had significantly longer period in which they did not reach to several bad functional end point than those with. placebo. Heavy meat-eaters had a two-fold increased risk of dementia comparing with to vegetarians116. A recent study found that total fat, and saturated fat, cholesterol increased the risk of dementia up to two-fold and high fish consumption reduced the risk of dementia117. Fat intake might increase the risk of dementia by atheroscle-rosis, thrombosis, inflammation, cell membrane function, and accumulation of beta amyloid.
Social network and activities
Never married, living alone and those without any social ties were associated with the risk of AD44,118. Low social or leisure activities were also associated with the risk of AD119,120,121,122. For example, in Bronx Aging study, Verghese et al.123 followed up 469 non-demented people older than the age of 75 years, and reported that leisure activities, reading, playing board game, playing musical instrument, dancing could reduce the risk of dementia. Their finding suggested that if someone participates in a cognitive activity one day per week, it can reduce the risk of AD and VD 7%.
Discussion
We reviewed recent findings of the epidemiological studies on dementia. While many valuable findings have been reported, some issues were still controversial. Although the prevalence of dementia increases with age, whether the occurrence of dementia will exponentially increase in oldest old age or not is still unclear. In most studies, AD is more prevalent than VD, but geographical variations also exist and the exact reasons for the variation are not fully understood yet. Many risk factors of dementia and AD were also reported. However, most of them were not conclusive and the exact relationship between the risk factors and the occurrence of dementia is still not clear.
Researchers should overcome some issues on dementia in the field survey. First, more refined case finding method for dementia in the field survey is needed. The differentiation of early stage of dementia and mild cognitive impairment or normal aging is difficult in most situ-ations. ADL impairment is difficult to evaluate in very old people who have restricted life. The presence of multiple diseases is also very common in old age, and the co-morbidity may interfere with cognitive function test3. These factors could be a the source of bias.
Second, the concepts and diagnostic criteria of VD should be refined. At least 5 diagnostic criteria including DSM-IV, ICD-10124, Neuroepidemiology Branch of the National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN)125, ADDTC and HIS were used for diagnosing VD, but they are not interchangeable126,127. The extent of using neuroimaging for diagnosing dementia also influenced the results. In Rochester study, among no clinical history of stroke, people of 26% were found to have vascular lesions sufficient to cause dementia and incidence of VD was increased more than double after the age of 85 years in with neuroimaging findings group than without neuroimaging findings group3. Whether MXD classified as VD or not was also influence the prevalence of VD.
Third, cross-cultural studies for dementia should be encouraged. Geographical variation or racial difference of the prevalence and incidence of dementia is well known. Because dementia might be caused by interaction of genetic, environmental factors, and cross cultural studies using same research method including the same case-finding method could give a powerful explanation for geographical variation. Nevertheless, cross cultural studies are still rare.
Finally, in our country, the future epidemiological studies for dementia should be performed on a large population based the sample with a longitudinal study design, in order to get an insight on the causality of various candidate risk factors for the occurrence of dementia, its specific subtypes, and the incidence data from our elderly population.
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