Journal of the Neurological Sciences 280 (2009) 79–83

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Journal of the Neurological Sciences

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Cardiovascular risk factors and dementia mortality: 40 years of follow-up in theSeven Countries Study

Alvaro Alonso a,b,⁎, David R. Jacobs Jr. a,c, Alessandro Menotti d, Aulikki Nissinen e, Anastasios Dontas f,Anthony Kafatos g, Daan Kromhout a,h

a Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USAb Department of Preventive Medicine and Public Health, School of Medicine, University of Navarra, Pamplona, Spainc Department of Nutrition, University of Oslo, Oslo, Norwayd Association for Cardiac Research, Rome, Italye Department of Health Promotion and Chronic Disease Prevention, National Public Health Institute, Helsinki, Finlandf Center of Studies of Age-Related Changes in Man, Athens Home for the Aged, Athens, Greeceg Department of Social Medicine, Preventive Medicine and Clinical Nutrition, School of Medicine, University of Crete, Crete, Greeceh Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands

Abbreviations: BMI, Body mass index; BP, Blood preFVC, Forced vital capacity; ICD, International Classificatio⁎ Corresponding author. Division of Epidemiology and

Public Health, University of Minnesota. 1300 S 2nd St55454, USA. Tel.: +1 612 626 8597; fax: +1 612 624 03

E-mail address: aalogut@alumni.unav.es (A. Alonso)

0022-510X/$ – see front matter © 2009 Elsevier B.V. Adoi:10.1016/j.jns.2009.02.004

a b s t r a c t

a r t i c l e i n f o

Article history:Received 4 December 2008Received in revised form 31 January 2009Accepted 3 February 2009Available online 28 February 2009

Keywords:DementiaSmokingHypertensionHypercholesterolemiaCardiovascular diseaseCohortEpidemiology

Previous research shows that cardiovascular risk factors in mid-adulthood could increase the risk of dementialater in life, but studies with very long follow-up are still scarce. We assessed whether cardiovascular riskfactors measured in midlife were associated with dementia mortality during a 40-year follow-up. 10,211 men,aged 40–59 at baseline, from 13 cohorts of the Seven Countries Study were followed for 40 years. Informationon cardiovascular risk factors was obtained at baseline from questionnaires and a physical examination.Dementia death was assigned if there was any mention of dementia on the death certificate. Associationsbetween cardiovascular risk factors and death from dementia were estimated through Cox proportionalhazards models. We identified 160 dementia deaths during the follow-up. Smoking, hypercholesterolemia,high blood pressure, low forced vital capacity and previous history of cardiovascular disease at baseline wereassociatedwith a higher risk of death fromdementia in the follow-up. The hazard ratio (HR) of dementia deathamong heavy smokers was 1.58 (95% confidence interval (CI) 1.03, 2.43) compared to non-smokers. Similarly,the HR (95% CI) among those with systolic BP≥160 or diastolic BP≥95 mm Hg compared to normotensives(b140/90) was 1.55 (1.02, 2.35). Individuals with the largest forced vital capacity had a lower risk of dying ofdementia (HR 0.54, 95% CI 0.30, 0.98). Finally, total serum cholesterolwas directly associatedwith higher risk ofdementia mortality (p for trend=0.03). In men, cardiovascular risk factors in midlife are associated withincreased risk of dementia death later in life.

© 2009 Elsevier B.V. All rights reserved.

1. Introduction

Dementia is a clinical syndrome characterized by multiplecognitive deficits including significant impairment in memory andat least one other sphere of mental activity [1]. Multiple disorders cancause dementia, but its two most common etiologies are Alzheimer'sdisease and vascular dementia. Although the cause for most cases ofdementia is not clearly established [2], several reports suggest thatcardiovascular risk factors could affect the neurodegenerative processleading to dementia in general, and Alzheimer's disease and vascular

ssure; CI, Confidence interval;n of Diseases; HR, Hazard ratio.Community Health, School of, Suite 300. Minneapolis, MN15..

ll rights reserved.

dementia in particular [3–6]. Thus, for example, smoking [7], obesity[5,8–10], high blood pressure [5,11], hypercholesterolemia [12], poorrespiratory function [13], or previous history of cardiovascular disease[4] have been associated with dementia incidence in differentprospective studies. Most of the studies conducted to date haveassessed this hypothesis in elderly people. Recent systematic reviews,however, suggest that smoking, hypertension and hypercholesterole-mia could be better predictors of dementia if measured in midliferather than later in life [12,14,15]. Few studies have assessed theassociation between other cardiovascular risk factors in midlife andsubsequent risk of dementia [9,16,17].

The Seven Countries Study, a longitudinal study includingmore thanten thousand men from seven different countries recruited between1958 and 1964 and followedup for 40 years, offers a unique opportunityto determine whether cardiovascular risk factors measured in midlifepredict dementia at advanced age. Therefore, our objective was toassess the association between different cardiovascular risk factors and

Table 1Selected characteristics of cohort participants at baseline, Seven Countries Study, 1958–1964.

N 10,211Age (years) 49.2 (5.6)Smoking status [%]Non-smokers 38.6Current smokers, b20 cigarettes/day 39.2Current smokers, ≥20 cigarettes/day 22.2

BMI (kg/m2) 24.3 (3.4)Serum cholesterol (mg/dL) 217.5 (54.1)Systolic blood pressure (mm Hg)a 139.4 (21.1)Diastolic blood pressure (mm Hg)a 84.6 (12.0)Forced vital capacity (L)b 4.1 (0.8)Previous history of CVD [%] 10.5

Values refer to means (standard deviations) unless otherwise stated.a Antihypertensive medication use was rare at the baseline of the Seven Countries

Study.b Baseline for forced vital capacity was 5 or 10 years later in some cohorts.

80 A. Alonso et al. / Journal of the Neurological Sciences 280 (2009) 79–83

the risk of dementia mortality during 40 years of follow-up in the SevenCountries Study.

2. Methods

2.1. Study population

The Seven Countries Study is a longitudinal prospective study ofrisk factors for cardiovascular disease including 16 cohorts in 7countries: Finland, Greece, Italy, the Netherlands, former Yugoslavia(Serbia and Croatia), Japan, and the United States. Eleven cohortsincluded men in geographically defined rural areas of Finland (Eastand West Finland), Italy (Crevalcore, Montegiorgio), Croatia (Dalma-tia, Slavonia), Serbia (Velika Krsna), Greece (Crete, Corfu), and Japan(Tanushimaru, Ushibuka). A four-ninths sample of all men aged 40–59was enrolled in Zutphen, a small commercial town in the Netherlands.Another cohort was provided by a large agro-industrial cooperative inZrenjanin, Serbia, and another was made up of faculty members of theUniversity of Belgrade, Serbia. Two cohorts of railroad employees fromspecified occupations were enrolled, one from the mid- and north-west of the United States, and the second from the Rome Division ofthe Italian State Railroad. The baseline examination was performedbetween 1958 and 1964 on 12,763 men aged 40 to 59. Examinationswere repeated at 5 and 10 years after baseline. Overall participation atbaseline was greater than 90%, with several cohorts reaching close to100% [18,19].

For this analysis, we excluded three cohorts whose follow-upstopped after 25 years (Dalmatia and Slavonia, in Croatia, and RomeRailroad workers) (n=2135); only 2 of the deaths through 25 years inthese cohorts were classified as dementia death, as defined below.Additionally, we excluded individuals with missing information forsmoking, weight, blood pressure and serum cholesterol (n=417).From the initial sample, 10,211 individuals met inclusion criteria.Participantswere followed-up until dead or 40 years after recruitment.At the end of follow-up, 1561 participants (15.3%) were still alive.

2.2. Exposure assessment

Information on cardiovascular risk factors was collected at baselineusing a standardized questionnaire and a physical examination.Participants were classified as non-smokers, light-moderate currentsmokers (less than 20 cigarettes/day) and heavycurrent smokers (20 ormore cigarettes/day) based on self-reported information. Height andweight were measured with the participant wearing light clothes. Bodymass index (BMI)was defined as theweight in kilograms divided by thesquare of height in meters. Systolic and diastolic blood pressure (BP)weremeasured once using amercury sphygmomanometer at the end ofthe physical examination, with the participant lying in supine position(use of antihypertensive medication was very rare at study baseline).Forced vital capacity (FVC) was determined using a spirometer. Timingof FVC assessment varied between study sites (at baseline or atexaminations 5 or 10 years after baseline). Additionally, because notthe same brand of spirometer was used in all cohorts, we categorizedFVC in quartiles according to cohort-specific cutoffs and adjusted forheight in analysis including this variable. A non-fasting blood samplewas obtained at the time of the physical examination. Serum cholesterolwas measured according to the Abell–Kendall method as modified byAnderson and Keys [20]. Based on information from the initial interviewand physical examination, previous history of cardiovascular disease atbaseline was defined as presence of a definite diagnosis of myocardialinfarction, peripheral arterial disease or cerebrovascular disease.Occupation was categorized according to a previously publishedclassification in the following groups: professional, business/govern-ment official, foreman, clerical, food handler, skilled light craft,transportation, building trader,metalworker, farmer/fisherman, factoryworker/mining, services, retired, miscellaneous [18]. This classification

was intended to identify the general character of the occupation and tosuggest the study participant's probable socio-economic status andeducational level.

2.3. Outcome ascertainment

Data on vital status and causes of death over the 40 years of follow-up were collected from death certificates, clinical records, andinterviews of physicians and relatives by local investigators. After acohort-specific follow-up time (10 years in the US Railroad cohort, 15in the Finnish cohorts, 25 in Italy, Greece, Japan, and 40 in Serbia andZutphen), only information from death certificates was available. Astudy physician adjudicated final causes of death based on the WorldHealth Organization's International Classification of Diseases, EightRevision (ICD-8). Mortality follow-up for the study population washigher than 99%.

Dead individuals could receive up to 4 different codes for cause ofdeath; the average number of death codes, though, was different ineach cohort (higher in the Serbian cohorts, lower in Japan andGreece). Pre-established criteria were followed to determine theprimary cause of death, using the following hierarchy: violent death,cancer in advanced stage, coronary heart disease, stroke, others. Forthis study, we defined dementia death as the presence of ICD-8 code290 (senile and presenile dementia) listed among any of the causes ofdeath. Although the sensitivity of this ascertainment method isexpected to be low, particularly for vascular dementia [21–23], a smallvalidation study conducted in the Doll and Peto's cohort of Britishdoctors observed an excellent positive predictive value (100%, 95%confidence interval 96%–100%) for the diagnosis of dementia in deathcertificates [24].

2.4. Statistical analysis

We estimated mortality rate of dementia in each cohort, age-standardized to the entire Seven Countries Study population. Theassociation between cardiovascular risk factors and the risk of deathfrom dementia was estimated using Cox proportional hazards model,with time to death from dementia since beginning of follow-up as thedependent variable. All models were adjusted for age, cohort andoccupation.

3. Results

Table 1 shows selected characteristics for study participants atbaseline. We identified 160 dementia deaths among 258,104 person-years of follow-up (62 cases per 100,000 person-years, 95% confidenceinterval (CI) 53 to 72). Dementia mortality increased exponentiallywith age, from 2 deaths per 100,000 person-years among individuals

Fig. 1. Age-specific unadjusted dementia mortality rates, Seven Countries Study, 1958–2004.

81A. Alonso et al. / Journal of the Neurological Sciences 280 (2009) 79–83

younger than 60 to 602 per 100,000 among those 80 or older (Fig. 1).Dementia mortality rates varied widely between cohorts, withhigher rates in Finland, Serbia and the Netherlands, and lower inGreece, Japan and Italy (Table 2). As shown in Table 2, dementiamortality was higher in cohorts with a higher average of ICD codes indeath certificates.

In a multivariable analysis, smoking, hypercholesterolemia, high BP,and previous history of cardiovascular disease at baselinewere associatedwith a higher risk of dementia mortality, while large FVC was associatedwith lower risk (Table 3). The hazard ratio (HR) of dementia death amongheavy smokers was 1.58 (95% CI 1.03, 2.43) compared with non smokers.High total cholesterol was directly associated with the risk of dementiamortality (HR 1.73, 95% CI 1.05, 2.84, in individuals with N250 mg/dLcompared to those with≤200 mg/dL). Similarly, the HR (95% CI) amongthose with systolic BP≥160 or diastolic BP≥95 compared withnormotensives (b140/90) was 1.55 (1.02, 2.35). Individuals in theupper quartile of FVC had a lower risk of dying of dementia comparedto those in the lower quartile of FVC (HR 0.54, 95% CI 0.30, 0.97). Finally,participants with previous history of cardiovascular disease had higherdementia mortality than those without it (HR 1.94, 95% CI 0.99, 3.80).BMI, on the other hand, was not associated with the risk of dementiamortality. Results were similar after excluding from the analysis variablesthat could be considered intermediate steps in the causal pathway

Table 2Cohort-specific dementia mortality rates, Seven Countries Study, 1958–2004.

Cohorta Country N Dementia deaths Person-years

East Finland Finland 786 23 17,449West Finland Finland 833 17 19,854Zutphen Netherlands 826 18 20,355Velika Krsna Serbia 496 13 12,009Belgrade Serbia 536 14 16,006Zrenjanin Serbia 515 2 11,721US Railroad United States 2,541 47 64,178Crevalcore Italy 945 10 23,125Montegiorgio Italy 704 3 18,417Tanushimaru Japan 417 3 11,162Ushibuka Japan 446 2 10,783Crete Greece 645 7 19,088Corfu Greece 521 1 13,839

a Sorted from highest to lowest between-country dementia mortality rate.b Average number of ICD codes in death certificate.c Age-standardized dementia mortality rate (deaths per 100,000 person-years).

between BMI and dementia (hypercholesterolemia, high BP, history ofcardiovascular disease, reduced FVC).

We performed an additional analysis to assess the risk of dementiamortality associated with cumulative presence of the followingcardiovascular risk factors: heavy smoking, systolic BP≥160 ordiastolic BP≥95, serum cholesterol N250 mg/dL, lowest quartile offorced vital capacity, and history of cardiovascular disease. The HR(95% CI) of dementia mortality in those with 3 or more risk factorsversus those without risk factors was 2.52 (1.17, 5.44) (p fortrend=0.0004) (Table 4).

Finally, we explored whether study participants with cardiovas-cular disease listed as a cause of death were more or less likelier tohave dementia also listed. Of 8650 dead participants at the end offollow-up, 4984 had cardiovascular disease included as a cause ofdeath, and 3666 did not. In those with cardiovascular disease death,84 (1.7%) had dementia also listed as a cause of death, while this figurewas 76 (2.0%) in those without cardiovascular disease death. Thedifferences were not significant (chi-square test=1.75, p=0.19).

4. Discussion

In this prospective study ofmore than 10,000men, with 40 years offollow-up, we observed that smoking, hypercholesterolemia,

Number of ICD codesb Dementia mortality ratec 95% confidence interval

1.5 185.3 106.0, 264.71.6 91.2 47.8, 134.51.9 97.3 52.2, 142.52.6 143.8 64.4, 223.32.7 93.8 44.5, 143.12.6 45.2 5.5, 163.21.7 64.5 45.9, 83.01.6 43.0 16.4, 69.71.7 16.6 3.4, 48.51.1 25.6 5.2, 74.81.2 19.6 2.4, 70.71.3 23.9 5.4, 42.31.2 6.7 0.2, 37.5

Table 3Hazard ratios (95% confidence intervals) for dementia mortality according to selected cardiovascular risk factors at baseline, Seven Countries Study, 1958–2004.

Dementia deaths Person-years Model 1a Model 2b p for trend

SmokingNon smoker 77 106,540 1 (ref.) 1 (ref.)Current b20 49 98,374 0.96 (0.66, 1.39) 0.96 (0.66, 1.39)Current ≥20 34 53,190 1.64 (1.08, 2.49) 1.58 (1.03, 2.43) 0.18

BMI (kg/m2)≤25 96 155,815 1 (ref.) 1 (ref.)N25–≤30 59 87,654 0.97 (0.68, 1.37) 0.88 (0.62, 1.26)N30 5 14,635 0.71 (0.28, 1.77) 0.59 (0.23, 1.49) 0.55

Serum cholesterol (mg/dL)≤200 44 107,471 1 (ref.) 1 (ref.)N200–≤250 62 88,444 1.58 (1.01, 2.45) 1.50 (0.96, 2.34)N250 54 62,188 1.84 (1.13, 3.00) 1.73 (1.05, 2.84) 0.03

Hypertensionb140/90 79 143,651 1 (ref.) 1 (ref.)≥140/90–b160/95 45 63,010 1.45 (0.99, 2.12) 1.49 (1.01, 2.19)≥160/95 36 51,444 1.53 (1.01, 2.31) 1.55 (1.02, 2.35) 0.02

Forced vital capacityc

Quartile 1 29 45,001 1 (ref.) 1 (ref.)Quartile 2 32 53,454 0.72 (0.43, 1.20) 0.77 (0.46, 1.28)Quartile 3 47 59,475 0.92 (0.57, 1.48) 1.03 (0.63, 1.68)Quartile 4 25 63,264 0.43 (0.25, 0.76) 0.54 (0.30, 0.98) 0.28Missing 27 36,911 0.88 (0.48, 1.61) 0.98 (0.53, 1.79)

Previous history of CVDNo 136 234,314 1 (ref.) 1 (ref.)Yes 24 23,790 2.11 (1.08, 4.14) 1.94 (0.99, 3.80)

BMI: body mass index; CVD: cardiovascular disease.a Model 1: proportional hazards model adjusting for age, study cohort and occupation.b Model 2: proportional hazards model including age, study cohort, occupation, height and all the variables in the table.c Cohort specific quartiles, given different devices used at different sites. The primary reason for missing FVC was non-response at the later examination in those cohorts in which

FVC was not measured at year 0.

Table 4Hazard ratios (HR) (95% confidence intervals (CI)) for dementia mortality according tonumber of existing cardiovascular (CV) risk factors at baseline, Seven Countries Study,1958–2004.

N. of CV risk factorsa Dementia deaths Person-years HR (95% CI)b p for trend

0 44 96,539 1 (ref.)1 65 101,759 1.59 (1.06, 2.38)2 42 47,387 2.18 (1.38, 3.45)3+ 9 12,420 2.52 (1.17, 5.44) 0.0004

a Smoker ≥20, serum cholesterol N250 mg/dL, blood pressure ≥160/95, 1st quartileforced vital capacity, previous history of cardiovascular disease.

b Proportional hazards model adjusting for age, study cohort, occupation, height, andbody mass index.

82 A. Alonso et al. / Journal of the Neurological Sciences 280 (2009) 79–83

hypertension, and previous history of cardiovascular disease atbaseline were associated with a higher risk of dementia mortality,while large FVC was associated with a lower risk. These results areconsistent with the hypotheses that cardiovascular risk factors duringmidlife affect dementia mortality possibly through increasing the riskof developing dementia, and that early interventions to reducecardiovascular risk could have a role in the prevention of dementia.A previous assessment of survivors of the Finish cohorts of the SevenCountries Study found an association between hypercholesterolemiaand incidence of Alzheimer's disease [25]. In the present analysis, weevaluated a larger population and extended the follow-up.

Growing evidence suggests that atherosclerosis is a major riskfactor for both Alzheimer's disease and vascular dementia [3]. In fact,previous studies have found a higher risk of incident dementia amongindividuals with higher risk for atherosclerotic and cardiovasculardisease, including smokers [7], hypertensives [11,26], hypercholester-olemics [12,26], those with reduced respiratory function [13], orparticipants with previous cardiovascular disease [4]. Our study ismostly consistent with these reports. In addition, we offer furtherevidence that cardiovascular risk factors are associated with dementiamortality as far as four decades before the outcome.

The present analysis has several limitations. First, we have useddementia mortality and not incidence of new cases of dementia as theoutcome of interest. Although death certificates have an excellentpositive predictive value for the diagnosis of dementia (100% in asample of 81 dementia deaths from Doll and Peto's cohort of Britishdoctors [24]), the sensitivity of this ascertainment method is far fromideal, particularly for vascular dementia [21–23]. As a consequence,we are most likely underestimating the burden of dementia in ourpopulation. Indeed, age-specific dementia mortality rates in the SevenCountries Study were 3 to 10 times lower than rates of dementiareported in previous studies conducted in similar populations [27]. Ofspecial concern is the underreporting of dementia in death certificatesof individuals affected by other chronic diseases, as well as misseddiagnosis in individuals with only one cause of death reported.Individuals with higher cardiovascular risk would have a greater

probability of dying of cardiovascular disease, reducing the likelihoodthat, if the study participant had dementia, the diagnosis appeared inthe death certificate. This hypothesis is partly supported by ourobservation of a slightly lower probability of dementia listed as a causeof death in those with cardiovascular disease death compared to thosewithout it (1.7% vs. 2.0%). Also, cardiovascular disease early in lifecould represent a substantial competing risk, reducing chances ofdeveloping dementia in old age. These problems are of special concernfor vascular dementia, more strongly associated with cardiovascularrisk factors. Nevertheless, if this were the case, the true associationbetween cardiovascular risk factors and dementia death would beeven higher than observed. In other words, the misclassification of theoutcome is most likely biasing downwards the association estimates.A related limitation is our inability to distinguish Alzheimer's diseasefrom vascular dementia and dementia from other sources.

Second, exposures were assessed in everyone only once atbaseline. In 40 years of follow-up, the study participants' risk factorsprofile almost certainly changed (some quit smoking, developedhypertension, etc). Though risk factors were reassessed in many menin several of the cohorts, restricting analyses to these individualswould considerably limit sample size and failing to reexaminenonrespondents might introduce selection bias. Because exposure

83A. Alonso et al. / Journal of the Neurological Sciences 280 (2009) 79–83

information was collected many years before the development of theoutcome, measurement error is non-differential and probably biasedresults towards the null value. If this is the case, the associationbetween cardiovascular risk factors and dementia mortality obtainedif we had ideally updated exposure information could have beenhigher than the observed.

In the third place, measures influencing both the presence ofcardiovascular risk factors and the risk of dementia mortality couldaccount for the observed associations. For example, education is amajor determinant of dementia and also predicts the occurrence ofcardiovascular risk factors [28,29]. Therefore, a direct associationbetween a particular cardiovascular risk factor and dementiamortality could be confounded by education; and educationalavailability and attainment was strongly differential between cohorts.To avoid this problem, we adjusted for occupation as a proxy foreducational level. Still, other unmeasured variables could confoundthe observed association. A final limitation is that results from thiscohort cannot be generalized to women, since the Seven CountriesStudy only included men.

Strengths of our study include the population-based sample withexcellent response rates, the large sample size, the long follow-up, andthe diversity in the study population. Interestingly, we have found animportant between-country variability in the values for dementiamortality, with very low figures in Greece, Japan and Italy, and higherin Finland. Heterogeneity in outcome ascertainment in each studycohort could explain the difference. For example, the average numberof ICD codes in death certificates was lower in Japan and Greece, andhigher in Serbia. Furthermore, we have no information aboutbetween-cohort differences in the probability of mentioning demen-tia on the death certificate in amanwho did have dementia but died ofanother cause. Therefore, we caution against any causal interpretationof the geographic variation of our data given the obvious limitations ofdifferential completeness of outcome ascertainment between cohortsand the potential that the ranking of countries in diagnosis ofdementia could be different with complete ascertainment. Never-theless, existing evidence points to marked geographical heterogene-ity in dementia death rates from dementia, consistently with our data.On the one hand, a pooled analysis of incidence studies of dementia inEurope showed a more elevated dementia incidence in northernEurope compared to southern areas of the continent, a pattern similarto our results [27]. On the other hand, distribution of dementiamortality resembled that of total and coronary heart disease mortalityin the Seven Countries Study cohorts: higher rates in Finland and theNetherlands, and lower in Japan and Greece [30]. This parallelismfurther suggests that factors associated with cardiovascular or totalmortality could additionally affect the risk of dementia mortality.

In conclusion, our results provide additional evidence for the linkbetween cardiovascular risk factors in midlife and the risk ofdementia. Future research should aim to determine the effectivenessof interventions to improve cardiovascular profile in the future risk ofdementia.

Acknowledgments

The authors acknowledge the late Professor Ancel Keys, who wasthe founder and leader of the Seven Countries Study for many years.Appreciation is also expressed to the first and second generation ofprincipal investigators in each country participating in the SevenCountries Study.

References

[1] American Psychiatric Association. Diagnostic and Statistical Manual of MentalDisorders, Fourth Edition, Text Revision. Arlington, VA: American PsychiatricAssociation; 2000.

[2] Borenstein Graves A. Alzheimer's disease and vascular dementia. In: Nelson LM,Tanner CM, Van Den Eeden SK, McGuire V, editors. Neuroepidemiology: fromprinciples to practice. New York: Oxford University Press; 2004. p. 102–30.

[3] van Oijen M, de Jong FJ, Witteman JCM, Hofman A, Koudstaal PJ, Breteler MMB.Atherosclerosis and risk for dementia. Ann Neurol 2007;61:403–10.

[4] Newman AB, Fitzpatrick AL, Lopez O, Jackson S, Lyketsos C, Jagust W, et al.Dementia and Alzheimer's disease incidence in relationship to cardiovascular diseasein the Cardiovascular Health Study Cohort. J Am Geriatr Soc 2005;53:1101–7.

[5] Hayden KM, Zandi PP, Lyketsos CG, Khachaturian AS, Bastian LA, Charoonruk G, etal. Vascular risk factors for incident Alzheimer disease and vascular dementia: theCache County Study. Alzheimer Dis Assoc Disord 2006;20:93–100.

[6] Akomolafe A, Beiser A, Meigs JB, Au R, Green RC, Farrer LA, et al. Diabetes mellitus andrisk of developing Alzheimer disease: results from the Framingham Study. ArchNeurol 2006;63:1551–5.

[7] Anstey KJ, von Sanden C, Salim A, O'Kearney R. Smoking as a risk factor fordementia and cognitive decline: a meta-analysis of prospective studies. Am JEpidemiol 2007;166:367–78.

[8] Gustafson D, Rothenberg E, Blennow K, Steen B, Skoog I. An 18-year follow-up ofoverweight and risk of Alzheimer disease. Arch Intern Med 2003;163:1524–8.

[9] Kivipelto M, Ngandu T, Fratiglioni L, Viitanen M, Kareholt I, Winblad B, et al.Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimerdisease. Arch Neurol 2005;62:1556–60.

[10] Rosengren A, Skoog I, Gustafson D, Wilhelmsen L. Body mass index, othercardiovascular risk factors, and hospitalization for dementia. Arch Intern Med2005;165:321–6.

[11] Launer LJ, Ross GW, Petrovitch H, Masaki K, Foley D, White LR, et al. Midlife bloodpressure and dementia: the Honolulu–Asia aging study. Neurobiol Aging2000;21:49–55.

[12] Anstey KJ, Lipnicki DM, Low LF. Cholesterol as a risk factor for dementia andcognitive decline: a systematic review of prospective studies with meta-analysis.Am J Geriatr Psychiatry 2008;16:343–54.

[13] Guo X, Waern M, Sjogren K, Lissner L, Bengtsson C, Bjorkelund C, et al. Midliferespiratory function and incidence of Alzheimer's disease: a 29-year longitudinalstudy in women. Neurobiol Aging 2007;28:343–50.

[14] Hernán MA, Alonso A, Logroscino G. Cigarette smoking and dementia: potentialselection bias in the elderly. Epidemiology 2008;19:448–50.

[15] Staessen JA, Richart T, Birkenhager WH. Less atherosclerosis and lower bloodpressure for a meaningful life perspective with more brain. Hypertension2007;49:389–400.

[16] Kalmijn S, Foley D, White L, Burchfiel CM, Curb JD, Petrovitch H, et al. Metaboliccardiovascular syndrome and risk of dementia in Japanese–American elderly men:the Honolulu–Asia Aging Study. Arterioscler Thromb Vasc Biol 2000;20:2255–60.

[17] Whitmer RA, Sidney S, Selby J, Claiborne Johnston S, Yaffe K. Midlife cardiovascularrisk factors and risk of dementia in late life. Neurology 2005;64:277–81.

[18] Keys A, Aravanis C, Blackburn HW, Van Buchem FS, Buzina R, Djordevic BD, et al.Epidemiological studies related to coronary heart disease: characteristics of menaged 40–59 in seven countries. Acta Med Scand Suppl 1966;460:1–392.

[19] Keys A, Aravanis C, Blackburn H, Buzina R, Djordevic BS, Dontas AS, et al. SevenCountries Study. A multivariate analysis of death and coronary heart disease.Cambridge, MA: Harvard University Press; 1980.

[20] Anderson JT, Keys A. Cholesterol serum and lipoprotein fractions: its measurementand stability. Clin Chem 1956;2:145–9.

[21] Ganguli M, Rodriguez EG. Reporting of dementia on death certificates: acommunity study. J Am Geriatr Soc 1999;47:842–9.

[22] Thomas BM, Starr JM, Whalley LJ. Death certification in treated cases of presenileAlzheimer's disease and vascular dementia in Scotland. Age Ageing 1997;26:401–6.

[23] Macera CA, Sun RK, Yeager KK, Brandes DA. Sensitivity and specificity of deathcertificate diagnoses for dementing illnesses, 1988–1990. J Am Geriatr Soc1992;40:479–81.

[24] Doll R, Peto R, Boreham J, Sutherland I. Smoking and dementia in male Britishdoctors: prospective study. BMJ 2000;320:1097–102.

[25] Notkola IL, Sulkava R, Pekkanen J, Erkinjuntti T, Ehnholm C, Kivinen P, et al. Serumtotal cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's disease.Neuroepidemiology 1998;17:14–20.

[26] Kivipelto M, Helkala EL, Laakso MP, Hanninen T, Hallikainen M, Alhainen K, et al.Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal,population based study. BMJ 2001;322:1447–51.

[27] Fratiglioni L, Launer LJ, Andersen K, Breteler MMB, Copeland JRM, Dartigues JF, etal. Incidence of dementia and major subtypes in Europe: a collaborative study ofpopulation-based cohorts. Neurology 2000;54(Suppl 5):S10–5.

[28] Caamaño-Isorna F, Corral M, Montes-Martínez A, Takkouche B. Education anddementia: a meta-analytic study. Neuroepidemiology 2006;26:226–32.

[29] Fernández E, García M, Schiaffino A, Borrás JM, Nebot M, Segura A. Smokinginitiation and cessation by gender and educational level in Catalonia, Spain. PrevMed 2001;32:218–23.

[30] Menotti A, LantiM, KromhoutD, BlackburnH,NissinenA, Dontas A, et al. Forty-yearcoronary mortality trends and changes in major risk factors in the first 10 years offollow-up in the seven countries study. Eur J Epidemiol 2007;22:747–54.