ORIGINAL CONTRIBUTION. Obesity and Vascular Risk Factors at Midlife and the Risk of Dementia and Alzheimer Disease

ORIGINAL CONTRIBUTION Obesity and Vascular Risk Factors at Midlife and the Risk of Dementia and Alzheimer Disease Miia Kivipelto, MD, PhD; Tiia Ngandu, BM; Laura Fratiglioni, MD, PhD; Matti Viitanen, MD, PhD; Ingemar Kåreholt, PhD; Bengt Winblad, MD, PhD; Eeva-Liisa Helkala, PhD; Jaakko Tuomilehto, MD, MPolSci, PhD; Hilkka Soininen, MD, PhD; Aulikki Nissinen, MD, PhD Background: Vascular risk factors play a role in the development of dementia, including Alzheimer disease (AD). However, little is known about the effect of body mass index and clustering of vascular risk factors on the development of dementia. Objective: To investigate the relation between midlife body mass index and clustering of vascular risk factors and subsequent dementia and AD. Design and Setting: Participants of the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study were derived from random, population-based samples previously studied in a survey carried out in 1972, 1977, 1982, or 1987. After an average follow-up of 21 years, 1449 individuals (73%) aged 65 to 79 years participated in the reexamination in 1998. Main Outcome Measures: Dementia and AD. Results: Obesity at midlife (body mass index 30 kg/m 2 ) was associated with the risk of dementia and AD even after adjusting for sociodemographic variables (odds ratio [OR], 2.4 [95% confidence interval (CI), 1.2-5.1]). The association was somewhat modified by further adjusting for midlife blood pressure, total cholesterol level, and smoking (OR, 2.1 [95% CI, 1.0-4.6]) and also for apolipoprotein E genotype and history of vascular disorders (OR, 1.9 [95% CI, 0.8-4.6]). Midlife obesity, high total cholesterol level, and high systolic blood pressure were all significant risk factors for dementia with ORs of around 2 for each factor, and they increased the risk additively (OR, 6.2 for the combination). Conclusions: Obesity at midlife is associated with an increased risk of dementia and AD later in life. Clustering of vascular risk factors increases the risk in an additive manner. The role of weight reduction for the prevention of dementia needs to be further investigated. Arch Neurol. 2005;62:1556-1560 Author Affiliations: Aging Research Center, Division of Geriatric Epidemiology, Neurotec, Karolinska Institutet, Stockholm, Sweden (Drs Kivipelto, Fratiglioni, and Kåreholt and Ms Ngandu); Division of Geriatric Medicine, Karolinska University Hospital, Huddinge, Sweden (Drs Viitanen and Winblad); Departments of Public Health and General Practice (Dr Helkala) and Neuroscience and Neurology (Drs Kivipelto and Soininen), University of Kuopio, Kuopio, Finland; Department of Geriatric Medicine, University of Turku, Turku, Finland (Dr Viitanen); the National Public Health Institute, Helsinki, Finland (Drs Tuomilehto and Nissinen). THE PREVALENCE OF OBESITY is on the increase all over the world. 1,2 Obesity is related to vascular diseases, and there is increasing evidence linking vascular risk factors to dementia and Alzheimer disease (AD). Nevertheless, the association between obesity and the risk of dementia has not been extensively studied, and the few long-term follow-up studies conducted so far have yielded somewhat conflicting results. 3-6 Further, although vascular risk factors are interrelated and tend to cluster together, earlier studies have focused on a single risk factor alone. 7-10 To our knowledge, no population-based study has yet evaluated the association between midlife body mass index (BMI) and clustering of various vascular risk factors with dementia and AD in late life in both sexes. Herein, we first evaluated the association between midlife BMI and the later development of dementia and AD in a population-based cohort. Second, we investigated how vascular risk factors independently and in clusters could influence the occurrence of dementia and AD. METHODS SUBJECTS The participants of the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study were derived from 4 separate and independent population-based, random samples examined within the framework of the North Karelia Project and the FINMONICA study in 1972, 1977, 1982, or 1987. 11 Participation rates of these surveys ranged from 82% to 90%. Those individuals still alive, aged 65 to 70 years at the end of 1997, and living in 2 geographically defined areas in or close to the towns of Kuopio and Joensuu, Finland, were the target of this study (n=2293). From these subjects, a random sample of 2000 persons was invited to a reexamination carried out during 1998. 12 Altogether, 1449 people (73%) participated. These 900 women (62%) and 549 men (38%) had a mean (SD) age of 50.6 (6.0) years at the time of the midlife examination and 71.6 (4.1) years at the follow-up examination. The mean (SD) length of follow-up was 21 (4.9) years. The study was approved by 1556

the local ethics committee, and written informed consent was obtained from all participants. METHODS The survey methods used during the baseline (midlife) visits were carefully standardized and comply with international recommendations. They also followed the World Health Organization MONICA protocol 13 in 1982 and 1987 and were comparable with the methods used in 1972 and 1977. In brief, the baseline survey included a self-administered questionnaire on health behavior, health status, and medical history. A venous blood specimen was taken to determine serum total cholesterol level. Systolic (SBP) and diastolic (DBP) blood pressure were measured from the right arm of the subjects after they had been seated for 5 minutes. Height and weight were measured, and BMI was calculated as weight in kilograms divided by the square of height in meters. Duringthereexaminationin1998, thesurveymethodsfollowed those used in the previous surveys in all aspects. Furthermore, the apolipoproteine(apoe)genotypeswereanalyzed. 14 Cognitivestatus was assessed using a 3-step protocol for the diagnosis of dementia: a screening, a clinical, and a differential diagnostic phase (Figure). 12 A total of 61 participants were diagnosed as having dementia according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, 15 and 48 of them fulfilled the diagnostic criteria of AD according to the NINCDS-ADRDA. 16 The dementiadiagnoses(n=56)ofthenonparticipantswerederivedfrommedical records of hospitals and health care centers. In the main analyses, we used only dementia and AD diagnoses from the study to ensure diagnostic accuracy, but we reran the analyses also including dementia cases from the medical records. Midlife Surveys in 1972, 1977, 1982, or 1987 Late-Life Examination in 1998 Random Sample N = 2000 1449 (72.5%) Screening Phase (Phase 1) 294 MMSE Score 24 254 Clinical Phase (Phase 2) 78 Differential Diagnostic Phase (Phase 3) for Persons With Possible Dementia 61 (4.3%) Dementia 48 AD 13 Other Dementias 117 (5.9% of Total Population) Dementia 76 AD 1348 Without Dementia 1883 Without Dementia 551 Nonparticipants 440 Refused 101 Refused Owing to Poor Health 7 Nursing Home Residents 3 Died 40 Not Evaluated 33 Refused 7 Refused Owing to Poor Health 2 Died Diagnoses From Patient Records 56 Dementia 28 AD 9 Other Dementias 19 Dementia Undefined STATISTICAL ANALYSES We categorized BMI into 3 groups using widely recognized cutoff points 2 : BMI lower than 25, BMI of 25 to 30, and BMI higher than 30 kg/m 2. Differences between the study groups were analyzed with the 2 test, t test, and analysis of variance as appropriate. The association between midlife BMI and subsequent dementia and AD was investigated with multiple logistic regression analyses, using normal weight as the reference category. We conducted the first analyses adjusting for age, sex, education, and follow-up time (model 1) and then adjusting further for midlife vascular risk factors including SBP, DBP, total cholesterol level, and smoking (model 2). Finally, we conducted analyses also adjusting for ApoE ε4 status and history of myocardial infarction, stroke, and diabetes mellitus (model 3). The putative multiplicative interactions between BMI and ApoE ε4 and between BMI and sex were analyzed by adding an interaction term into the model. To analyze the effect of clustering of vascular risk factors for dementia and AD, we created binary variables of midlife vascular risk factors (BMI 30, SBP 140 mm Hg, DBP 95 mm Hg, total cholesterol level 251 mg/dl [6.49 mmol/l], and smoking (yes/ no). The association between each of these factors and dementia wasfirstinvestigatedinalogisticregressionmodeladjustedforage, sex, education, and follow-up time. Second, risk factors that were significantly related to dementia (BMI, SBP, total cholesterol level) were put into the same model simultaneously to evaluate the independent effect of each risk factor. Third, a summary variable was composed of these binary variables (presence or absence of high BMI, SBP, and total cholesterol level) to analyze how an increase inthenumberofriskfactorswasassociatedwithdementiaandad. The participants with missing information for 1 or several of the covariates were excluded from the respective analyses. Data on the covariates used in models 1 and 2 were available for all 1409 persons and on the covariates used in model 3 for 1290 persons (92%). The level of significance was P.05. The analyses were conducted using SPSS for Windows, release 11.0 (SPSS Inc, Chicago, Ill). Figure. Formation of the study population. Asterisk indicates diagnoses for participants who went through the diagnostic procedures of the study (used in the main analyses); dagger, diagnoses for the whole sample including dementia diagnoses from the medical records for the nonparticipants; AD, Alzheimer disease; MMSE, Mini-Mental State Examination. RESULTS SOCIODEMOGRAPHIC AND CLINICAL CHARACTERISTICS The mean (SD) BMI at midlife was 26.6 (3.7). One third of the study population had a BMI lower than 25 (normal weight), half had a BMI from 25 to 30 (overweight), and the remaining 16% had a BMI higher than 30 (obese) at midlife. Those individuals with a higher BMI were older, less educated, and had higher SBP and DBP at midlife (Table 1). The main midlife vascular risk factors were only modestly correlated with each other: BMI and SBP, Pearson r=0.27 (P.001); BMI and total cholesterol level, r=0.05 (P=.09); and SBP and total cholesterol level, r=0.12 (P.001). Dementia and AD were significantly more often found among those with a higher midlife BMI. Also, a history of myocardialinfarctionanddiabetesmellitusweremoreprevalent among those with the highest midlife BMI (Table 1). The mean (SD) BMI at the reexamination was 27.8 (4.3) kg/m 2, and it did not differ between persons with dementia(28.2[4.5]kg/m 2 )andwithout(27.8[4.3]kg/m 2 )(P=.49). MIDLIFE BMI AND RISK OF DEMENTIA AND AD Subjects who were obese at midlife had an increased risk for dementia when compared with subjects at a 1557

Table 1. Sociodemographic and Clinical Characteristics of the Participants According to Midlife Body Mass Index (BMI)* Characteristic BMI 25 (n = 494) BMI 25-30 (n = 693) BMI 30 (n = 222) P Value Age, y 70.7 (3.9) 71.4 (3.9) 72.1 (4.2).001 Men/women, % 33.4/66.6 43.0/57.0 32.0/68.0.001 Education, y 9.2 (3.5) 8.6 (3.5) 7.6 (3.0).001 Follow-up time, y 21.6 (4.6) 20.8 (4.9) 19.5 (5.2).001 ApoE ε4, % 33.0 36.0 40.2.18 Midlife (baseline) Systolic blood pressure, mm Hg 139.9 (18.4) 144.4 (19.3) 153.5 (21.5).001 Diastolic blood pressure, mm Hg 85.7 (10.1) 90.1 (10.6) 94.2 (11.0).001 Total cholesterol, mg/dl 257.92 (46.33) 259.85 (45.56) 262.93 (49.04).37 Smokers, % 42.9 44.1 39.6.51 Late-life (follow-up) Dementia, No. (%) 14 (2.8) 26 (3.8) 21 (9.5).001 Alzheimer disease, No. (%) 12 (2.4) 21 (3.1) 15 (6.9).007 Diabetes mellitus, % 2.3 5.9 19.1.001 Myocardial infarction, % 11.1 16.0 20.5.003 Stroke, % 5.8 7.4 10.0.14 Abbreviation: ApoE, apolipoprotein E. SI conversion factor: To convert total cholesterol to millimoles per liter, multiply by 0.0259. *Values are expressed as mean (SD) unless otherwise stated, and analysis of variance was used unless otherwise indicated. BMI was calculated as weight in kilograms divided by the square of height in meters. The 2 test was used. Information was obtained from a detailed questionnaire about medical conditions and events diagnosed by a physician during the reexamination. Table 2. Association Between Midlife Body Mass Index (BMI) and Risk of Dementia* Odds Ratio (95% Confidence Interval) Model 1 Model 2 Model 3 All participants BMI 25 1 1 1 BMI 25-30 1.05 (0.54-2.08) 1.04 (0.52-2.08) 0.99 (0.47-2.15) BMI 30 2.44 (1.18-5.06) 2.10 (0.97-4.55) 1.88 (0.76-4.63) *Model 1 was adjusted with age, sex (where appropriate), education, and follow-up time. Model 2 was adjusted additionally with midlife systolic blood pressure, diastolic blood pressure, total cholesterol level, and smoking. Model 3 was additionally adjusted with apolipoprotein E and history of diabetes mellitus, myocardial infarction, and stroke. BMI was calculated as weight in kilograms divided by the square of height in meters. normal weight, even after controlling for sociodemographic characteristics and follow-up time (Table 2, model 1). The association was somewhat modified by further adjusting for other midlife vascular risk factors (model 2) and also for ApoE ε4 and history of vascular disorders (model 3). Point estimates for the association between midlife obesity and the risk of AD were fairly similar as those for all dementias, even though confidence intervals (CIs) were wider, probably reflecting the smaller sample size (model 1, odds ratio [OR], 1.88 [95% CI, 0.83-4.24]; model 2 OR, 1.76 [95% CI, 0.74-4.15]; model 3 OR, 1.76 [95% CI, 0.67-4.61]). Midlife overweight was not significantly associated with dementia later in life (Table 2). Adjustments in midlife physical activity and fat intake did not change the association between obesity and dementia (model 1, OR, 2.45 [95% CI, 1.17-5.11]). When diabetes mellitus was added to the model with sociodemographic factors, the OR for obesity was 2.15 (95% CI, 1.00-4.59). In the stratified analyses among those without diabetes mellitus (n=1258), obesity still increased the risk for dementia (model 1, OR, 2.48 [95% CI, 1.10-5.62]). For those with diabetes mellitus, it was not possible to get reliable estimates owing to a small number of participants with the disorder (n=57). Among women and men separately, obesity was associated with an increased risk of dementia, but the associations did not reach significance (results not shown). There were no significant interactions between BMI and sex (P value for the overall interaction was.82) or between BMI and the ApoE ε4 carrier status (P value for the overall interaction term was.33) for the risk of dementia. CLUSTERING OF VASCULAR RISK FACTORS AND RISK OF DEMENTIA AND AD Midlife obesity, high SBP, and high total cholesterol level were all significant risk factors for late-life dementia even when they were placed simultaneously into the model. All of these midlife vascular risk factors added to the risk of dementia approximately 2-fold (Table 3). Further controlling for fat intake and physical activity did not change the results (results not shown). For AD specifically, high total cholesterol level was a significant risk factor (OR, 2.12 [95% CI, 1.05-4.30]) and obesity (OR, 1.77 [95% CI, 0.90-3.47]) and high SBP (OR, 1.57 [95% CI, 0.78-3.14]) were border- 1558

line significant when they were all simultaneously in a model adjusted for age, sex, education, and follow-up time. The combination of these midlife vascular risk factors increased the risk of dementia and AD in an additive manner (ie, the risk increased as more risk factors were added) (P value for linear trend.001) (Table 4). The OR for dementia in participants who had all 3 risk factors was 6.21 (95% CI, 1.94-19.92) compared with participants who had none. There were no multiplicative interactions between BMI and SBP and total cholesterol level for the risk of dementia and AD. NONPARTICIPANTS When the dementia diagnoses for the nonparticipants were included and the analyses thereby conducted for the whole sample (N=2000), the association between obesity and the risk of dementia became somewhat stronger; obesity was a significant risk factor for dementia even in model 3 (OR, 1.89 [95% CI, 1.09-3.29]). In the analyses for the clustering of vascular risk factors, the risk for dementia increased in an additive manner (results not shown). COMMENT This study shows that obesity at midlife may increase the risk of dementia and AD later in life. The association was attenuated somewhat by adjustment for other vascular risk factors and diseases, indicating that the effect of obesity on dementia might be partly mediated through these vascular factors. However, midlife obesity, high SBP, and high total cholesterol level were all significant risk factors for dementia, each of them increasing the risk around 2 times. Clustering of these vascular risk factors increased the risk of dementia and AD in an additive manner so that persons with all 3 risk factors had around a 6 times higher risk for dementia than persons having no risk factors. Our results are in accordance with a Swedish study reporting an association between higher BMI at ages 70 to 79 years and subsequent dementia among women. 5 Our study extends these findings to younger age groups and to a population including both men and women. We did not find significant interaction between sex and BMI for dementia, but because of the limited number of cases, we cannot draw firm conclusions about the possible sex differences. In the male cohort of the Honolulu-Asia Aging Study, an increased risk for vascular dementia, but not for AD, with increasing BMI was found. 3 Another study conducted among Japanese individuals found no association between midlife BMI and late-life dementia or AD. 4 The differences between the present study and their results may be due to the differences in the genetic, demographic, and lifestyle characteristics of the populations. Obesity is an essential feature in the metabolic syndrome, which is otherwise characterized by dyslipidemia, hypertension, glucose intolerance, and insulin resistance. InsulinresistancemaybeimportantinthepathogenesisofAD, 17,18 and thus, it could partly confer the risk of dementia associated with obesity. Information concerning insulin resistance was not available for our analyses. However, we did have information about the history of diabetes mellitus and Table 3. Independent Effects of Midlife Vascular Risk Factors for Risk for Dementia Dementia OR Risk Factor (95% CI)* BMI 30 (vs 30) 2.09 (1.16-3.77) SBP 140 mm Hg (vs 140 mm Hg) 1.97 (1.03-3.77) Total cholesterol level 251 mg/dl (vs 251 mg/dl) 1.89 (1.02-3.49) Age, y 1.18 (1.10-1.27) Women (vs men) 0.59 (0.34-1.03) Education, y 0.86 (0.78-0.96) Follow-up time, y 1.00 (0.94-1.06) Abbreviations: BMI, body mass index; CI, confidence interval; OR, odds ratio; SBP, systolic blood pressure. SI conversion factor: To convert total cholesterol to millimoles per liter, multiply by 0.02586. *Values were determined by putting risk factors into a model simultaneously. BMI was calculated as weight in kilograms divided by the square of height in meters. Table 4. Clustering of Midlife Vascular Risk Factors and the Risk of Dementia* Subgroup (No. of Subjects in Each Group) No. of Risk Factors Present OR (95% CI) 283 0 1 577 1 1.37 (0.44-4.27) 448 2 3.03 (1.03-8.89) 101 3 6.21 (1.94-19.92) Abbreviations: CI, confidence interval; OR, odds ratio. *The ORs and CIs presented are for the risk of dementia according to the number of risk factors present at midlife. When the subject had a value higher than the cutoff (Body Mass Index 30, systolic blood pressure 140 mm Hg, total cholesterol level 251 mg/dl [6.49 mmol/l]), the risk factor was considered to be present. Those who had none of these risk factors served as the reference group. Analyses are adjusted for age, sex, education, and follow-up time. The P value for linear trend (P value for the number of vascular risk factors given linear representation) is.001. when this variable was added into the model with sociodemographic variables only, the association between BMI and dementia became somewhat weaker but remained significant. The association between obesity and dementia was significant also among those without diabetes mellitus, suggesting that diabetes mellitus may not totally explain the association. However, wecannotruleoutresidualconfounding. The design of our study as a population-based, longitudinal study with a large cohort of participants increases the credibility of the findings. Since we had measurements of BMI and other risk factors already at midlife and a long follow-up period, we can reasonably assume that the presence of preclinical dementia did not affect the association observed, which may be the case in studies with shorter follow-up periods and with the baseline evaluation in later life. However, some limitations do need to be discussed. It would have been interesting to have information about midlife lipoprotein, glucose, and insulin levels and waisthip ratio to be able to further elucidate the apparently complex associations between vascular risk factors. Further, survival bias and nonparticipation at the follow-up may have somewhat influenced our results. Our previous study in the same population showed that obesity at midlife is 1559

associated with an increased mortality. 19 Thus, if we assume that among the dead there were more obese persons and that they would have been more likely to develop dementia as well, then our results would represent an underestimation of the true risk associated with obesity. The prevalence of obesity and other vascular risk factors in midlife was higher among nonparticipants. Also, people with cognitive decline are less likely to participate in clinical studies. 20 Dementia diagnoses from medical records used for nonparticipants usually underestimate the prevalence of dementia. Hence, if the nonparticipants were at an increased risk for dementia, then our results would again represent an underestimate of the true effect of obesity and vascular risk factors rather than the opposite. The fact that the association between obesity and dementia became somewhat stronger when the nonparticipants were included confirms that our main results were not due to the selective participation but they may underestimate the true effect. Body mass index is an easily available and inexpensive measurement for assessing the nutritional status of an individual, and high BMI can serve as a useful indicator of the increased risk of dementia. The effect of obesity on dementia may be partly mediated through other vascular factors. However, this does not mean that body weight control should be viewed as less important. On the contrary, lowering BMI has beneficial effects on a range of other risk factors, 21,22 and thus, one could hypothesize that it may prevent dementia more than estimated from analyses of BMI alone. As our data have shown, the more vascular risk factors, the greater the risk for dementia and AD. Therefore, elimination of even 1 risk factor could decrease this risk. The role of weight reduction for the prevention of dementia needs to be further investigated. Accepted for Publication: July 14, 2005. Correspondence: Miia Kivipelto, MD, PhD, Aging Research Center, Division of Geriatric Epidemiology, Neurotec, Karolinska Institutet, Box 6401, S-11382 Stockholm, Sweden (miia.kivipelto@neurotec.ki.se). Author Contributions: Study concept and design: Kivipelto, Helkala, Tuomilehto, Soininen, and Nissinen. Acquisition of data: Kivipelto, Helkala, Tuomilehto, and Nissinen. Analysis and interpretation of the data: Kivipelto, Ngandu, Fratiglioni, Viitanen, Kåreholt, and Winblad. Drafting of the manuscript: Kivipelto and Ngandu. Critical revision of the manuscript for important intellectual content: Kivipelto, Ngandu, Fratiglioni, Viitanen, Kåreholt, Winblad, Helkala, Tuomilehto, Soininen, and Nissinen. Statistical analysis: Kivipelto, Ngandu, and Kåreholt. Obtained funding: Kivipelto, Winblad, and Soininen. Administrative, technical, and material support: Kivipelto and Soininen. Study supervision: Kivipelto, Fratiglioni, Tuomilehto, Nissinen, and Soininen. Funding/Support: This study was supported by the Aging Program of the Academy of Finland, Helsinki; EVO grants 5772708 and 5772720 from Kuopio University Hospital, Kuopio, Finland; Academy of Finland grants 103334 and 206951 (Dr Kivipelto); and the Gamla Tjänarinnor Foundation (Dr Kivipelto), grant 2004-1200 from the Swedish Council for Working Life and Social Research (Dr Kivipelto), and the SADF (Insamligsstiftelsen för Alzheimeroch Demensforskning) (Ms Ngandu), Stockholm. Additional Information: None of the funding organizations played a role in the design and conduct of this study; collection, management, analysis, and interpretation of the data; or preparation, review, and approval of the manuscript. Dr Kivipelto had full access to the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Nissinen and Tuomilehto were involved in the baseline surveys for the study and in the planning of the reexamination. Drs Kivipelto and Helkala were the principal investigators in the reexamination in diagnosing dementia. Acknowledgment: We thank our colleagues in the Cardiovascular Risk Factors, Aging, and Dementia study group for their cooperation in data collection and management. REFERENCES 1. Mokdad AH, Marks JS, Stroup DF, Gerberding JL. Actual causes of death in the United States, 2000. JAMA. 2004;291:1238-1245. 2. World Health Organization. Obesity: Preventing and Managing the Global Epidemic. Geneva, Switzerland: World Health Organization; 2000. 3. Kalmijn S, Foley D, White L, et al. Metabolic cardiovascular syndrome and risk of dementia in Japanese-American elderly men: the Honolulu-Asia Aging Study. 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