© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Metabolic Cardiovascular Syndrome and Risk of Dementia in Japanese-American Elderly Men
The Honolulu-Asia Aging Study
From the Department of Chronic Diseases Epidemiology (S.K.), National Institute of Public Health and the Environment, Bilthoven, the Netherlands; Epidemiology, Demography and Biometry Program (D.F., R.J.H., L.J.L.), National Institute on Aging, National Institutes of Health, Bethesda, Md; Division of Clinical Epidemiology (L.W., J.D.C., H.P., G.W.R.), John A. Burns School of Medicine, University of Hawaii at Manoa, Manoa, Hawaii; Epidemiology and Biometry Program (C.M.B.), National Heart, Lung, and Blood Institute, Jackson, Miss; and the Department of Veterans Affairs (G.W.R.), Honolulu, Hawaii.
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Abstract |
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Abstract—Cardiovascular risk factors often cluster into a metabolic syndrome that may increase the risk of dementia. The objective of the present study was to assess the long-term association between clustered metabolic cardiovascular risk factors measured at middle age and the risk of dementia in old age. This prospective cohort study of cardiovascular disease was started in 1965 and was extended to a study of dementia in 1991. The subjects were Japanese-American men with an average age of 52.7±4.7 (mean±SD) years at baseline. Dementia was diagnosed in 215 men, according to international criteria, and was based on a clinical examination, neuropsychological testing, and an informant interview. The z scores were calculated for 7 risk factors (random postload glucose, diastolic and systolic blood pressures, body mass index, subscapular skinfold thickness, random triglycerides, and total cholesterol). The relative risk (RR [95% CI]) of dementia (subtypes) per 1 SD increase in the sum of the z scores was assessed after adjustment for age, education, occupation, alcohol consumption, cigarette smoking, and years of childhood lived in Japan. The z-score sum was higher in demented subjects than in nondemented subjects, indicating a higher risk factor burden (0.74 versus -0.06, respectively; P=0.008). Per SD increase in the z-score sum, the risk of dementia was increased by 5% (RR 1.05, 95% CI 1.02 to 1.09). The z-score sum was specifically associated with vascular dementia (RR 1.11, 95% CI 1.05 to 1.18) but not with Alzheimer’s disease (RR 1.00, 95% CI 0.94 to 1.05). Clustering of metabolic cardiovascular risk factors increases the risk of dementia (mainly, dementia of vascular origin).
Key Words: Alzheimer’s disease • dementia • elderly • epidemiology • insulin resistance syndrome
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Introduction |
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Researchers have long noted a clustering of cardiovascular risk factors, termed syndrome X or the metabolic cardiovascular syndrome.1 2 3 4 5 Factors commonly included in this syndrome are hypertension, obesity, dyslipidemia, and glucose intolerance.1 2 3 4 5 Development of these risk factors is thought to reflect a common underlying pathology. The syndrome leads to an increased risk of diabetes and cardiovascular disease.1 2 3 4 5 Both these clinical conditions have been linked to an increased risk of vascular dementia (VaD)6 7 and Alzheimer’s disease (AD),7 8 the 2 most common subtypes of dementia in the elderly. Therefore, the metabolic cardiovascular syndrome may be a subclinical condition that also increases the risk of dementia.
The clinical states of AD and VaD are characterized by hypometabolic features, such as low blood pressure, body mass index (BMI), and glucose levels. Therefore, to investigate the association of these risk factors with dementia, they should be measured long before the clinical onset of dementia. Most studies investigating the relation of metabolic cardiovascular risk factors to AD have been cross-sectional.9 10 11 12 13 14 15 16 Most prospective studies on the association of individual metabolic risk factors with the risk of AD have been based on a relatively short follow-up time.17 18 Furthermore, most studies on the risk factors for VaD focus on clinical stroke and hypertension.6 To our knowledge, there are no studies on the relationship between the clustering of metabolic risk factors and the risk of dementia with a long follow-up.
The Honolulu-Asia Aging Study (HAAS) gave us the opportunity to examine the long-term association between the metabolic cardiovascular syndrome at middle age and the risk of dementia in late age. The HAAS is based on a cohort of Japanese-American men followed since 1965. Previously, we reported that AD and VaD were associated with high blood pressure19 and that VaD was associated with diabetes, 1-hour postprandial glucose levels, and coronary heart disease.20 21
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Methods |
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The cohort was started as the Honolulu Heart Program (1965 to 1971) on cardiovascular disease22 and was followed up as a part of the HAAS (1991 to present) involving the diseases of old age.23 The original cohort included 8006 Japanese-American men who were born between 1900 and 1919 and were living on the island of Oahu, Hawaii, in 1965. Metabolic cardiovascular risk factors were assessed at baseline when the men were aged 45 to 68 years. Screening for dementia took place in 1991 to 1993, when the men ranged in age from 71 to 93 years. Of the 4678 men who were still alive at that time, 3734 (80%) participated in the dementia case-finding effort. The study was approved by an institutional review committee, and informed consent was obtained from the study participants.
Definition of Variables
Cardiovascular metabolic risk
factors were measured at baseline (1965) and included the following:
BMI (in kilograms per square meter), subscapular skinfold thickness (in
millimeters), diastolic and systolic blood pressure
(in millimeters of mercury), random postload glucose (in milligrams per
deciliter), random triglycerides (in milligrams per
deciliter), and total cholesterol (in milligrams per
deciliter).24 BMI was calculated as weight (in kilograms),
measured with subjects in light clothing and without shoes, divided by
height (in meters) squared. Subscapular skinfold thickness, an estimate
of central obesity, was measured to the nearest millimeter with Lange
calipers. Systolic and diastolic blood pressures
were measured with a standard sphygmomanometer and a standard cuff on
the left arm of a seated subject. The mean of 3 measurements was used
in the analysis. Blood was collected with the patient in a
nonfasting state 1 hour after a 50-g glucose load and was frozen at
-20°C for shipment to the Public Health Service, Heart Disease
Control Program Laboratory, San Francisco, Calif. Serum total
cholesterol, triglycerides, and serum glucose
levels were measured by using Auto-Analyzer
methods.25 The nonfasting 1-hour post–50-g load glucose
test reflects glucose tolerance status26 and is comparable
to levels observed after the now standard 2-hour post–75-g load
test.27
Confounding variables that were taken into account included age,
years of education, occupation, alcohol consumption, cigarette smoking,
years of childhood lived in Japan, and antihypertensive medication. We
also examined whether the apolipoprotein 
4 allele and smoking
modified the association. ApoE is a marker of genetic susceptibility
and may modify the association between atherosclerosis
and dementia.8 Self-reported alcohol consumption was
categorized into <1 drink per week, <1 drink per day, <2 drinks per
day, and 
2 drinks per day. Cigarette smoking from examination I to
III was coded as never smokers at both exams, former smokers at both
exams, quitters at examination III, and those who continued to smoke at
both exams. Apolipoprotein genotyping was performed at the Joseph
and Kathleen Bryan Alzheimer’s Disease Research
Center28 with restriction isotyping by use of a polymerase
chain reaction protocol described by Hixson and Vernier.29
Subjects who were either heterozygous or homozygous for the 4
allele were grouped together; those without an 4 allele
(apoE33, apoE23, and apoE22) served as the reference group. Subjects
with apoE24 (n=32) were excluded from these analyses, because
this is a combination of potentially protective (2) and adverse
(4) alleles.
Variables thought to mediate the association between metabolic cardiovascular risk factors and dementia were stroke, coronary heart disease, subclinical atherosclerosis, and diabetes.6 7 8 A history of stroke was ascertained by continuous surveillance of hospital discharge records, death certificates, local obituary notices, and Medical Examiner’s cases on the island of Oahu.30 A history of coronary heart disease was ascertained on the basis of the surveillance data, as well as ECG and questionnaire data collected at all 4 examinations. The ankle to brachial index measured at the fourth examination was used as a proxy for subclinical atherosclerosis.31 32 The brachial blood pressure was measured twice at the right arm, and the ankle blood pressure was measured twice at the right and the left sides with patients in the supine position by use of a Doppler stethoscope attached to a standard sphygmomanometer. The mean of the 2 measurements was taken, and the lowest value of the ankle to brachial index was taken when the right and left side differed. Thereafter, the ankle to brachial index was categorized into quartiles. A diagnosis of diabetes was based on a subject’s report of a physician’s diagnosis of diabetes, the use of oral diabetic medication or insulin, or, at examination IV, on the basis of a glucose tolerance test.
Dementia Assessment
Case finding for dementia followed a 3-stage procedure,
described in detail elsewhere.23 Briefly, all men were
administered the 100-point Cognitive Abilities Screening Instrument
(CASI) at phase I.33 Those with a CASI score <74
(sensitivity for dementia according to the Diagnostic
and Statistical Manual of Mental Disorders, edition 3, revised
[DSM-III-R] was 80%, and the specificity was 91%), and all men aged
85 years were invited back for phase II. In addition, a random
subsample of respondents was selected for phase II by using
cell-sampling fractions proportional to the probability of dementia.
The phase II examination included a second CASI, a neurological
examination, and tests of hearing and vision. An informant was given
the Informant Questionnaire on Cognitive Decline in the Elderly
(IQCODE) to assess changes in cognition, autonomy, and behavior over
the past 10 years.34 All individuals with
consistently low CASI scores, those with an IQCODE score of
>3.6, and a stratified random sample of the remaining phase II
participants were invited back for phase III, in which dementia was
diagnosed by a neurologist according to DSM-III-R
criteria.35 Probable and possible AD was diagnosed
according to the National Institute of Neurological and Communicative
Disorders and Stroke–Alzheimer’s Disease and Related
Disorders Association (NINCDS-ADRDA) criteria,36 and VaD
was diagnosed according to criteria proposed by the California
Alzheimer’s Disease and Treatment Centers.37
Approximately 86% of all cases had CT imaging to carefully exclude
vascular lesions contributing to the dementia in AD cases. Of the 507
subjects selected for the full 3-step procedure, 426 (84%) completed
it. Two hundred twenty-six persons received a diagnosis of
dementia.
For these analyses, subtypes of dementia were classified as follows: AD designated as the sole or principal cause and no contributing cerebrovascular disease; AD with contributing cerebrovascular disease (CVD); VaD as the sole or principal cause without any apparent AD component; and other dementias attributed to Parkinson’s disease, progressive supranuclear palsy, subdural hematoma, trauma, and vitamin B12 deficiency.
Statistical Analysis
Complete information on dementia and risk factors was available
for 3555 men, including 82 cases of AD, 73 cases of VaD, 32 cases of AD
with CVD, and 28 cases of other dementia. Baseline characteristics
between demented and nondemented subjects were compared with the
Kruskal-Wallis test for nonnormally distributed variables.
Differences between participants and nonparticipants at follow-up were
compared by adjusting for age by ANCOVA.
Because we were interested in examining the effect of risk factor
clusters, we converted all risk factors into the same unit, ie, a
z score. The z score ranks individuals according
to their place in a normal distribution of values. The z
scores ranged from 
-4 SDs to 4 SDs, with a mean of 0. A subject
with a z score of 0.5 has a blood pressure that is 0.5 SDs
higher than the mean of a normalized distribution. To normalize the
distributions, serum triglycerides and glucose levels were
logarithmically transformed before the z score was
calculated. For each individual, the sum of the z scores of
all 7 factors (ie, random postload glucose, systolic and
diastolic blood pressures, BMI, subscapular skinfold
thickness, total cholesterol, and
triglycerides) was calculated as a summary measure of
metabolic risk factor burden.38 This
z-score sum gives equal weights to all factors. The
z-score sum was shown to yield a measure of the insulin
resistance syndrome similar to one derived with a principal components
analysis.38 Principal components
analysis generates a component, ie, a new linear variable,
that explains as much of the variance of all the measured risk factors
as possible. By use of the continuous z-score sum, the
dementia risk across the complete range of risk factor levels can be
examined. The method assumes a linear relation of the risk factors to
the outcome. We checked for a nonlinear relationship between any of the
risk factors and dementia by categorizing them into quintiles and also
by adding the risk factor as a quadratic term to the model; this
revealed that the associations between the risk factors and dementia
were linear.
The age- and education-adjusted z-score sum across dementia subtypes was estimated by ANCOVA. We used multiple logistic regression to estimate the odds ratios and 95% CIs for the relation of the individual z scores and the overall z-score sum to dementia (subtypes). Under the rare disease assumption, the odds ratio can be considered an estimation of the relative risk (RR). Adjustments were made for confounders. In addition, mediating variables were included in the models. Finally, we stratified the analyses according to the apoE genotype, smoking (ever versus never), and diabetes mellitus type 2. Analyses were conducted with the Statistical Analysis System (version 6.09).39
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Results |
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Not included in our analyses were subjects who participated at baseline in 1965 but who had died before 1991 (n=3328), subjects who refused participation in 1991 (n=937), or subjects who had missing data for the present analyses (n=186). Compared with those included in the analysis, those excluded were older at baseline (55.8 versus 52.7 years, P<0.001), and after adjustment for age, they had higher systolic and diastolic blood pressures (P<0.001), higher glucose levels (P<0.001), and higher triglyceride levels (P<0.001) at baseline.
The mean±SD age of the participants was 52.7±4.7 years at baseline
and 77.8±4.6 years at follow-up. At follow-up, 11% had a history of
stroke. Thirty-five percent of the men had diabetes at 1 of the 4
exams. Forty-two percent of the population had no elevated risk factors
(>1 SD higher than average), 29% had 1 elevated risk factor, and 30%
had 2 elevated risk factors. Men who were demented at follow-up were
older at baseline (57.4 versus 52.4 years, P<0.001), had
fewer years of education (9.1 versus 10.6 years, P<0.001),
had a higher systolic blood pressure (P=0.002), and
had a higher postload glucose level (P=0.05).
After adjustment for age and education, an increase of 1 SD of the
following risk factors increased the risk of dementia 25 years later:
BMI, skinfold thickness, and triglyceride levels
(Table 1
). None of these
individual risk factors was associated with AD (results not shown). All
of the metabolic cardiovascular risk
factors, except cholesterol and triglyceride
levels, were positively and significantly associated with VaD. Compared
with men with no risk factors, men with 1 elevated risk factor had no
increased risk of dementia (RR 0.91, 95% CI 0.62 to 1.32), whereas men
with 2 elevated risk factors had a 56% increased risk of dementia
(95% CI 1.12 to 2.18). The risk of VaD in this group was even stronger
(RR 2.97, 95% CI 1.70 to 5.18).
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The z-score sum of all 7 risk factors, as a measure of
metabolic risk factor burden, ranged from -12.8 to 13.4
(higher levels indicate a higher burden). There were 4.4% of the men
with a z-score sum >7, which means that all their risk
factors were, on average, 1 SD higher than the sample mean. The
proportion of men with a z-score sum >7 was higher in
demented men than in nondemented men (8.8% versus 4.1%,
P=0.001). The age- and education-adjusted z-score
sum was -0.06 (95% CI -0.20 to 0.08) for nondemented subjects and
0.74 (95% CI 0.17 to 1.30) for subjects with dementia
(P=0.008, Table 2). Men with
VaD had the highest z-score sum (1.68, 95% CI 0.73 to 2.63;
P<0.001 versus nondemented men).
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Per increase of 1 unit in the z-score sum, the risk of
dementia was increased by 5% (95% CI 1.02 to 1.09, Table 3). Per increase of 1 SD in the
z-score sum, the risk was highest for VaD (RR 1.11, 95% CI
1.05 to 1.18) and intermediate for mixed and other dementias; there was
no increased risk for AD (RR 1.00, 95% CI 0.94 to 1.05). If, for
example, all 7 risk factors would increase at least 1 SD, the risk of
dementia would be increased by 42% (RR 1.42, 95% CI 1.11 to 1.82),
and the risk of VaD would be increased by >2-fold (RR 2.10, 95% CI
1.40 to 3.16). Additional adjustment for occupation, alcohol
consumption, cigarette smoking, blood pressure medication, and years of
childhood lived in Japan did not appreciably alter the estimates.
Investigating quartiles of the z-score sum showed a gradual
and significant increase in the risk of dementia (RRs were 1.24, 1.28,
and 1.60 for quartiles 2, 3, and 4 versus quartile 1, respectively;
P for trend=0.03). Smoking history or the presence of the
apolipoprotein 4 allele did not modify the reported
associations. Among subjects without type 2 diabetes, the association
between the syndrome and VaD, but not all dementias, appeared to be
stronger than among those with diabetes (for nondiabetics, RR 1.16,
95% CI 1.07 to 1.26; for diabetics, RR 1.06, 95% CI 0.97 to 1.15;
P for interaction=0.10).
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Discussion |
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The cardiovascular metabolic syndrome (syndrome X) has long been recognized as a clustering of risk factors that leads to an increased risk of diabetes and cardiovascular disease.1 2 3 4 5 In this prospective population-based study among Japanese-American men, we found that a higher cardiovascular metabolic risk factor burden in middle age increased the risk of dementia 25 years later. The metabolic cardiovascular syndrome particularly increased the risk of VaD, not AD. Associations were independent of age, education, occupation, smoking, and alcohol consumption.
Limitations of the present study must be taken into account when interpreting these findings. At the time of the diagnosis of dementia, the men were relatively old. Therefore, selective participation, most of which was due to death, may have influenced our findings. Men who did not participate at the fourth examination were older and less healthy at baseline in 1965 than those who did participate. Possibly, subjects with a clustering of metabolic risk factors and susceptibility to dementia were more likely to die or to refuse to participate. In this case, the observed association may underestimate the real association. Furthermore, risk factors ascertained at the baseline examination may have changed during the 25 years of follow-up, which could ultimately modify the risk of dementia. Furthermore, insulin resistance is viewed as an underlying cause for the clustering of risk factors.1 2 3 4 5 However, fasting insulin, a surrogate measure of insulin resistance, was not measured at baseline. When we included fasting insulin levels measured at the fourth examination in the z-score sum, the results did not change appreciably.
The present study has a number of strengths. It had a long duration
of follow-up (25 years). Therefore, it is not likely that risk factor
levels were affected by subclinical dementia. In addition, it is a
large study, which enabled us to examine the relationship of subtypes
of dementia and to investigate whether diabetes, smoking, or the
apolipoprotein 4 allele modified the associations of interest.
Furthermore, a very high percentage of cases had neuroimaging, which
allowed us to separate out cases with AD and concomitant contributing
CVD.
The calculation of a z score allowed us to combine data with different units. The analyses of the individual risk factors suggested that some, such as body weight, body fat distribution, and triglycerides, were more strongly related to the risk for all dementia than were other factors. However, because these risk factors are interrelated and are thought to exert a synergistic effect on the risk of cardiovascular disease and diabetes, we were interested in the relationship between the clustering of these risk factors and dementia. Most previous studies of the risk factors for VaD focus on stroke and hypertension.6 Recent studies have identified other risk factors, including diabetes mellitus,7 atrial fibrillation,40 triglyceride levels,13 a high saturated fat intake,41 and LDL cholesterol levels.42 From the present study, we see that the clustering of traditional metabolic cardiovascular risk factors contributes to the risk of VaD. There was no association of the metabolic syndrome with AD, and there was a moderately increased risk in cases of AD with CVD. The results of other studies on the association of cardiovascular risk factors with AD have been inconsistent, with some showing a positive association,9 10 11 12 18 19 some showing no association,14 15 21 and some showing an inverse association.13 16 17 Discrepancies may depend on the duration of follow-up or the proportion of mixed AD with CVD cases included in the AD group. It is also possible that genetic or other environmental factors not taken into account in these studies can account for differences. Furthermore, the HAAS does not include women, whose risk patterns for AD may differ from those of men.43
Additional studies are needed to determine whether the results can be extrapolated to other ethnic groups or to women. Social, environmental, and genetic factors may be different in this population of Japanese-American men. Although the prevalence of AD in this cohort was similar to the prevalence in US and European studies, the prevalence of VaD was substantially higher, as is the case in other Japanese populations.23 However, the clustering of these risk factors among ethnic groups shows striking similarities, despite the difference in prevalence of the individual risk factors.3 In addition, a relationship between the cardiovascular metabolic syndrome and cardiovascular disease has been observed in western populations as well as in this population.
Cardiovascular disease and subclinical atherosclerosis did not strongly mediate the association between the metabolic cardiovascular syndrome and (vascular) dementia. Perhaps these are not good measures of atherosclerosis in the brain. Alternatively, the cardiovascular metabolic syndrome may influence dementia by mechanisms other than atherosclerosis. In subjects with diabetes type 2, the association between the syndrome and VaD was lower than in those without diabetes, suggesting that part of the influence of the syndrome on VaD is mediated through diabetes.
In conclusion, we found that the clustering of metabolic risk factors at middle age increased the risk of late-age dementia and, in particular, of VaD. Modification of metabolic risk factors at middle age may reduce not only the risk of cardiovascular disease but also the most prevalent neurodegenerative disease of old age, dementia.
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Acknowledgments |
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This study was funded by the National Heart, Lung, and Blood Institute (contract No. N01-HC-05102) and the National Institute on Aging (contract No. N01-AG-4-2149). We gratefully acknowledge Dr R.D. Abbott for his advice on the statistical analyses.
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Footnotes |
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Reprint requests to Lenore J. Launer, PhD, Epidemiology, Demography and Biometry Program, National Institute on Aging, National Institutes of Health, Room 3c, 309 Gateway Building, 7201 Wisconsin Ave, Bethesda, MD 20892.
Received June 7, 2000; accepted June 26, 2000.
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