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Hypertension. 2007;49:389-400
Published online before print February 5, 2007, doi: 10.1161/01.HYP.0000258151.00728.d8
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(Hypertension. 2007;49:389.)
© 2007 American Heart Association, Inc.

Brief Reviews

Less Atherosclerosis and Lower Blood Pressure for a Meaningful Life Perspective With More Brain

Jan A. Staessen; Tom Richart; Willem H. Birkenhäger

From the Studies Coordinating Centre (J.A.S., T.R.), Division of Hypertension and Cardiovascular Rehabilitation, Department of Cardiovascular Diseases, University of Leuven, Leuven, Belgium; and Erasmus University (W.H.B.), Rotterdam, the Netherlands.

Correspondence to Jan A. Staessen, Studies Coordinating Centre, Laboratory of Hypertension, Campus Gasthuisberg, Herestraat 49, Box 702, B-3000 Leuven, Belgium. E-mail jan.staessen{at}med.kuleuven.be


*    Introduction
up arrowTop
 *Introduction
down arrowEpidemiology of Dementia
 down arrowPathogenesis of Dementias
 down arrowNeurodegeneration and...
 down arrowBlood Pressure as Risk...
 down arrowReversibility of Risk Associated...
 down arrowReferences
 
Traditional teaching subdivides the dementia syndrome into neurodegenerative Alzheimer’s disease (AD), vascular dementia (VaD), and mixed variants. In spite of the vast and continuing literature on the dichotomy between AD and VaD, new emerging concepts highlight the role of cardiovascular risk factors in the pathogenesis of AD, especially in older patients.1,2 Hypertension is the major player in the pathogenesis of stroke, poststroke dementia, and VaD. AD is the most common cause of dementia, contributing from 45% to >75% of the cases in Asians and whites, respectively.3 This review will focus on the role of hypertension as a reversible risk factor in the development of dementia, in particular AD. To set the stage, we will first summarize current insights in the epidemiology of AD, the pathogenesis of VaD and AD, and the association between neurodegeneration and atherosclerosis.


*    Epidemiology of Dementia
up arrowTop
 up arrowIntroduction
 *Epidemiology of Dementia
down arrowPathogenesis of Dementias
 down arrowNeurodegeneration and...
 down arrowBlood Pressure as Risk...
 down arrowReversibility of Risk Associated...
 down arrowReferences
 
Across 36 cross-sectional studies, the prevalence of dementia increased exponentially from 0.3% to 1.0% in subjects aged 60 to 64 years to 10% to 20% in octogenarians and to >40% in the ninth decade of life.3 In 15 longitudinal studies, the incidence of dementia showed a similar age-related dependency with rates expressed in new cases per 1000 person-years ranging from 0.4 to 4 at 60 to 64 years to 20 to >40 at 80 to 85 years.3 Currently, 24.3 million people have dementia with an annual worldwide incidence of 4.6 million new cases.4 Because of the aging of populations, the number of demented patients will increase 2-fold every 20 years to 81.1 million by 2040, with >60% living in developing countries.4 The 2003 World Health Report5 estimated that adults aged ≥60 years lost {approx}8.6 million disability-adjusted life years because of AD or other dementias. In this age group, only ischemic heart disease (31.5), cerebrovascular disease (29.6), and chronic obstructive pulmonary disease (14.4) caused more premature disability and mortality.5 In the United States, the number of demented patients with roughly triple, from 4.6 million in 1998 to 16 million by 2050.6


*    Pathogenesis of Dementias
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 up arrowIntroduction
 up arrowEpidemiology of Dementia
 *Pathogenesis of Dementias
down arrowNeurodegeneration and...
 down arrowBlood Pressure as Risk...
 down arrowReversibility of Risk Associated...
 down arrowReferences
 
VaD
Poststroke dementia is the most common form of VaD. In a case–control study nested within the Framingham cohort, the relative risk of dementia in stroke survivors compared with controls varied from 2.0 to 2.8, depending on the covariates considered for adjustment.7 Of the incident dementia cases, 51% were diagnosed as having VaD or mixed dementia, whereas this proportion was only 4% among the control subjects without a history of stroke.7

VaD may result from a single stroke interrupting brain circuits critical for memory and cognition (strategic infarct dementia) or from multiple strokes (multi-infarct dementia).8,9 Of particular importance in older patients is subcortical small vessel disease of the medullary arteries, which perpendicularly penetrate the brain cortex into the subjacent white substance without intertwining branches other than very fine capillaries, thus constituting many independent small vascular territories. Exposure of these small brain vessels to highly pulsatile pressure and flow explains microvascular damage,10 resulting in white matter damage, lacunas, and loss of cortical connections.8 Multiple infarction dementia exhibits a stepwise but unpredictable course, depending on the size, localization, and number of ischemic insults.9 Subcortical VaD has a more insidious character without sensory-motor manifestations but with progressive changes in personality, mood, behavior, or cognition (Figure 1).


Figure 1
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  		Figure 1. Time course of cognitive functions (reproduced with permission from Reference 9).

AD
AD is a neurodegenerative disease with an inexorably progressive, disabling and fatal course (Figure 1), of which the clinically overt phase usually spans from 3 to 10 years.2 The disease primarily affects cholinergic neurotransmission in the medial temporal lobe, the entorhinal cortex, and the hippocampus.1,2 Interaction between these brain structures plays a crucial role in memory consolidation, memory optimization during sleep, and spatial orientation. The prevailing viewpoint on the pathogenesis of AD rests on the extraneuronal and intraneuronal accumulation of misfolded protein, amyloid ß-peptide (Aß), which starts a pathogenetic cascade resulting in neurotoxicity.2 Aß has selective toxicity for the hippocampus and entorhinal cortex, while sparing the cerebellum. Deposits of Aß form senile plaques. Neurofibrillary tangles are the second histopathologic hallmark of AD.2 They consist of hyperphosphorylated microtubule-associated protein {tau}. They aggregate as pairs of filaments that twist around one another: so-called paired helical filaments. These filamentous inclusions displace organelles, destabilize the cytoskeleton, and impair axoplasmatic flow, thereby affecting nutrition of axon terminals and dendrites.

Mild cognitive impairment indicates a syndrome defined as a cognitive decline greater than expected for an individual’s age and education. In adults >65 years of age, it has a prevalence ranging from 3% to 19%.11 Many patients with mild cognitive impairment have minor histopathologic AD changes, and more than half progress to full blown AD.11,12


*    Neurodegeneration and Atherosclerosis
up arrowTop
 up arrowIntroduction
 up arrowEpidemiology of Dementia
 up arrowPathogenesis of Dementias
 *Neurodegeneration and...
down arrowBlood Pressure as Risk...
 down arrowReversibility of Risk Associated...
 down arrowReferences
 
Accumulating evidence suggests a strong link among AD, cardiovascular risk factors, and atherosclerosis. In multivariate-adjusted longitudinal studies, the incidence of dementia independently increased with pre-existing cardiovascular disease, the metabolic syndrome, skinfold thickness, body mass index, hypercholesterolemia, diabetes mellitus, hyperhomocysteinemia, smoking, and/or high-sensitivity C-reactive protein, whereas higher education, more exercise at middle age, and moderate alcohol consumption were protective.1,13

Neuroimaging14 and postmortem histopathologic15 studies indicate that up to one third of AD patients have some degree of vascular pathology, whereas in a similar proportion of VaD patients AD lesions are also present. The summation of vascular brain lesions, white matter damage reflecting small vessel disease, and typical AD pathology interactively lead to dementia, even when each type of lesion, on its own, would not be severe enough to cause dementia.9 Moreover, recent evidence suggests that cholinergic neuronal processes are not only involved in cognition, per se, but in the preservation of cerebral blood flow as well (Figure 2). Indeed, cholinergic agents stimulate regional cerebral blood flow in patients with AD or VaD.16


Figure 2
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  		Figure 2. Overlap between neurodegenerative and VaD and interaction between cholinergic factors and cerebral blood flow.

Experimental studies likewise support the convergence between Aß and vascular factors in the pathogenesis of dementia. Aß constricts human cerebral arteries.17 Aß attenuates endothelium-mediated dilatation in cerebral arteries by production of reactive oxygen radicals and impairs the increase in neocortical blood flow in response to somatosensory activation.18 Furthermore, transgenic mice overexpressing mutated forms of amyloid precursor protein, from which misfolded Aß originates, show a reduction in resting17 and stimulated18 cerebral blood flow and an impaired autoregulation of the cerebral circulation.19 Human platelets contain membrane-associated amyloid precursor protein.20 Macrophages in human carotid plaque, which phagocytize platelets after intraplaque microhemorrhages, can process amyloid precursor protein into Aß.20

Other studies suggest the involvement of cholesterol metabolism in the pathogenesis of AD. In cell cultures, increased21 and decreased22 cholesterol concentrations stimulate or repress the generation of Aß from amyloid precursor protein, respectively. The apolipoprotein E {epsilon}4 allele represents a major risk factor for AD in all ethnic groups, across all ages between 40 and 90 years, and in both women and men.23 The {epsilon}4 allele enhances the risk 3-fold in heterozygotes and by a factor 15 in homozygotes.23 Each allele copy lowers the age of onset by {approx}10 years.24 Apolipoprotein E acts as a cholesterol transporter in the brain, with the {epsilon}4 variant being less efficient in the reuse of membrane lipids and neuronal repair.25 The {epsilon}3 and {epsilon}4 variants play a critical and isoform-specific role in plaque formation.26 The apolipoprotein E {epsilon}4 allele accounts for most of the genetic risk in AD.1,2


*    Blood Pressure as Risk Factor for Dementia
up arrowTop
 up arrowIntroduction
 up arrowEpidemiology of Dementia
 up arrowPathogenesis of Dementias
 up arrowNeurodegeneration and...
 *Blood Pressure as Risk...
down arrowReversibility of Risk Associated...
 down arrowReferences
 
In middle-aged and older adults, hypertension is the predominant and most frequent cardiovascular risk factor. Any man normotensive at 50 years has a probability of >90% to become hypertensive during the remainder of his lifetime.27 Studies on the association between cognition and blood pressure can be subdivided into those with a cross-sectional versus longitudinal design. The end point in these studies can be disease outcomes, such as dementia, AD, or VaD; morphological or functional alterations of the brain, as documented by histopathologic autopsy studies or modern neuroimaging techniques; or cognitive function, as assessed by batteries of tests, each covering varying cognitive domains, or more global tests of cognition, such as the Mini Mental State Examination, or composite scores of specific tests.

Cross-Sectional Studies
Cross-sectional studies, reviewed elsewhere,28 observed positive and independent associations of blood pressure, analyzed as a continuous or dichotomized variable, with cognitive impairment as assessed by the Mini Mental State Examination or multiple cognitive tests. By contrast, other cross-sectional studies did not find any association or noticed a U-shaped relation.

Cross-sectional studies, in which outcome and exposure are simultaneously recorded, obviously have limited capability to assess the association between cognition and blood pressure. The extensive lag phase between the onset of hypertension and subsequent cognitive impairment together with the insidious clinical course of neurodegenerative dementia necessitate long-term prospective studies. Histological lesions, such as neurofibrillary tangles or an accelerated rate of neuronal atrophy in the medial temporal lobe of the brain, for decades, may precede overt dementia. Two Framingham reports29,30 dramatically illustrated the shortfall of the cross-sectional approach. In stroke-free Framingham participants, there was no relation between the scores of 8 cognitive tests, administered in 1976–1978, and the concurrently measured blood pressure, irrespective of whether the analysis included or excluded patients on antihypertensive drug treatment.29 However, higher blood pressure levels over 5 earlier biennial examinations (1956–1964), when few hypertensive patients were taking antihypertensive medications, significantly predicted lower scores of attention, memory, and global cognition in 1976–1978.30 This inverse temporal association was consistent for systolic and diastolic blood pressure and withstood adjustment for sex, age, cigarette smoking, alcohol consumption, education, and occupation.30

Longitudinal Cohort Studies
In 1996, Skoog et al31 published one of the first longitudinal studies on the incidence of dementia in relation to blood pressure. They recruited 382 nondemented 70-year–old residents of Göteborg, Sweden (57.8% women), of whom 302, 205, and 94 were available for reassessment at 75, 79, and 85 years, respectively. Participants who developed dementia at age 79 to 85 had higher systolic blood pressure at 70 years (178 versus 164 mm Hg) and higher diastolic blood pressure at ages 70 (101 versus 92 mm Hg) and 75 (97 versus 90 mm Hg).31 Patients specifically developing AD or VaD had higher diastolic blood pressure at ages 70 and 75, respectively.31

Although based on relatively few subjects, the seminal report by Skoog et al31 set the stage for subsequent studies published in the second half of the 1990s.32–35 These multivariate-adjusted analyses confirmed that at a relatively high diastolic blood pressure (≥75 mm Hg versus ≤70 mm Hg) at age 50,32 a persistently elevated systolic blood pressure (≥140 mm Hg) at ages ranging from 4334 to 7533 years, or stage 2 hypertension (≥160 mm Hg systolic and ≥95 mm Hg diastolic) within the 59 to 71 age bracket35 consistently predicted worse cognitive performance32–35 or more severe white-matter lesions34 at ages ranging from 6335 to 7934 years. To further clarify the role of blood pressure in the pathogenesis of cognitive impairment, we performed a systematic review of the prospective studies published since 2000 until early 2006, from which we extracted or computed summary statistics. The outcome variables were either levels of or changes in single or composite cognitive scores (Table 1)36–47; the incidence of cognitive dysfunction, dementia, AD, or VaD (Table 2Down)42,48–61; or the appearance of brain lesions in histopathologic or neuroimaging studies (Table 3).62–65 For each of these 3 end points, we ordered the reports according to the age at enrollment.


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  		TABLE 1. Association Between Cognitive Function and Blood Pressure Indexes


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  		TABLE 2. Association Between Risk of Dementia and Blood Pressure Indexes


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  		TABLE 2. (Continued)


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  		TABLE 3. Association Between Brain Lesion and Blood Pressure Indexes

All of the studies of cognitive function, involving subjects on average <70 years old at enrollment (Table 1),36–41 uniformly showed a significantly lower performance or a more rapid decline of cognitive function with higher blood pressure, although in 1 cohort only for stage 3 hypertension.41 At more advanced age,42–47 point estimates went in the same direction but only reached significance in the normotensive Hispanic Established Populations for Epidemiologic Studies of the Elderly cohort44 and in the Active Cognitive Training for Independent and Vital Elderly Trial.46

Among the studies with cognitive impairment as a categorical end point (Table 2Up),42,48–61 those using a dichotomized test score53,57 classified from 15%53 to 50%57 of the participants as cognitively impaired and reported positive associations with hypertension. Two studies50,56 found no association of mild cognitive impairment with hypertension earlier in life. Studies with dementia,48,52,54 AD,42,49,51,52,54,55,58–61 or VaD49,54,59 as the end point demonstrated a significantly positive association with ≥1 blood pressure index, if follow-up started from middle age rather than old age.48,51,52,54 Remarkably, 1 study found an inverse association of AD with blood pressure in subjects recruited at the upper end of the age spectrum (mean age 87 years).55 In keeping with the estimates listed in Table 2Up, the Baltimore Longitudinal Survey of Aging, based on 11 years of multivariate adjusted follow-up of 847 subjects (mean age: 70.6 years; 41% women) described age as an important modifier of the effects of blood pressure on cognition.66 Among younger participants (60 years at baseline), those with higher systolic blood pressure performed worse on tests of nonverbal memory and confronting naming, although the test results improved over time because of a learning effect.66 Among older participants (80 years), those with higher systolic blood pressure not only performed worse than subjects with normal blood pressure, but also experienced a decline in cognitive performance over time.66

In summary, our overview shows that hypertension, especially when already present at middle age, adversely affects cognition later in life. In old and very old adults, the association between impaired cognition and hypertension becomes weaker and more difficult to demonstrate, perhaps because, in prospective population studies, diastolic blood pressure decreases after age 5067 or because systolic blood pressure falls in the very old.31 Finally, 1 autopsy report62 and 3 brain imaging studies63–65 with longitudinal perspective observed independent and positive associations between brain lesions and blood pressure indexes (Table 3).62–65

Low Blood Pressure as Manifestation of Dementia
Already in 1996, Skoog et al31 noticed that with advancing age all of the subjects in his study experienced a decrease in blood pressure but that the fall in systolic and diastolic blood pressure was larger in patients who developed dementia than in their nondemented counterparts. A retrospective review of the medical charts of 1133 women (≥75 years) covering 10 years68 revealed that systolic blood pressure increased with time in 568 unimpaired subjects but that it increased less in 274 and 291 women who either developed cognitive impairment or became demented. Diastolic blood pressure declined significantly with time in all 3 of the groups.68 In a cohort of 242 French patients with moderate AD (mean age: 78 years; 74% women)69 blood pressure significantly fell over 1 year of follow-up, independent of sex, age, body mass index, and antihypertensive drug treatment.

Progressive physical inactivity in those blemished by advancing mental deterioration may be a substantial factor leading to a fall in blood pressure in the years immediately preceding and after overt dementia. In addition, neuronal death and defective cholinergic neurotransmission affecting the autonomic centers in the brain probably results in a dysregulation of blood pressure (Figure 2). Orthostatic or postprandial dips in blood pressure, pari passu with episodes of impaired cerebrovascular blood flow, might actually contribute to further brain damage, sustaining a perpetuating vicious circle.70


*    Reversibility of Risk Associated With Hypertension
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 up arrowIntroduction
 up arrowEpidemiology of Dementia
 up arrowPathogenesis of Dementias
 up arrowNeurodegeneration and...
 up arrowBlood Pressure as Risk...
 *Reversibility of Risk Associated...
down arrowReferences
 
Nonrandomized Observational Studies
Ten prospective studies (Table 4)35,71–79 explored in multivariate-adjusted analyses the possible influence of antihypertensive treatment on the incidence of cognitive impairment or overt dementia. Differences in the definition of the cognitive end point, the wide range of age at baseline and duration of follow-up, varying sampling frames, and adjustment for different sets of covariates or effect modifiers, such as the apolipoprotein E {epsilon}4 polymorphism,35,79 made the computation of a pooled association size impossible. Nevertheless, of the 10 studies (Table 4),35,71–79 8 reported that antihypertensive drug treatment lowered the risk of cognitive decline, the reduction being significant in 5 reports,71,72,75,77,78 and proportional to duration of treatment.80 No single study observed a multivariate-adjusted significantly elevated risk in treated hypertensive patients.


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  		TABLE 4. Association Between Cognitive Impairment and Antihypertensive Drug Treatment in Nonrandomized Studies

Several researchers tried to dissect the correlation between cognitive impairment and antihypertensive treatment according to the main classes of antihypertensive drugs (Table 4).35,71–79 Although plagued by low numbers and overexploitation of scarce data, the mainstream of these analyses suggests that diuretics71,78 might confer particular benefit in the prevention of cognitive impairment. All of the nonrandomized longitudinal studies of cognitive function have to be interpreted within the context of their limitations, such as reverse causality, patients with more severe hypertension being more likely to be treated, self-selection of patients consenting to follow-up, and the arbitrary nonrandomized definition of the drug class used as reference.

Randomized Clinical Trials
The trial conducted by the Medical Research Council in older adults81 was the first outcome study that investigated the effects of antihypertensive drug treatment on cognitive function. The patients were randomly assigned to a diuretic (hydrochlorothiazide plus amiloride), a ß-blocker (atenolol), or placebo.81 Both active treatments reduced blood pressure below the placebo level. Over a period of 54 months, 2584 patients underwent elaborate psychometric tests.81 No significant differences in the test scores occurred. However, follow-up of 387 surviving Medical Research Council patients for 9 to 12 years revealed that less decline in systolic blood pressure led to a poorer cognitive outcome, even with adjustments applied for a family history of dementia, cognitive function at baseline, aging, and alcohol intake.82

The Medical Research Council study,81 unfortunately, did not report on the incidence of overt dementia. In 4 outcome trials of blood pressure lowering treatment,83–86 dementia was a secondary outcome in its own right. The double-blind placebo-controlled Systolic Hypertension in the Elderly Program (SHEP)83 included 4736 patients with a mean age of 72 years. Active treatment consisted of chlorthalidone with the possible addition of atenolol or reserpine. SHEP failed to demonstrate a significant effect of antihypertensive treatment on the incidence of dementia (Figure 3) despite between-group blood pressure differences >10 mm Hg systolic and 4 mm Hg diastolic. The rates on placebo and active treatment were 4.2 and 3.6 cases per 1000 patient-years (relative risk reduction; RRR: 14%; 95% CI: –26% to 54%; P=0.44).83 A subsequent report87 noticed that, although retention to the clinical examinations was very high, SHEP patients who missed cognitive assessments were more likely to be older, less educated, nonwhite, randomly assigned to placebo, and to have a higher occurrence of nonfatal cardiovascular events before each follow-up visit. The interpretation was that selective attrition might have biased the SHEP dementia results toward the null hypothesis of no differences between the treatment groups.87


Figure 3
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  		Figure 3. Incidence of dementia in the Systolic Hypertension in Europe Trial (Syst-Eur84) and the SHEP83,87. In the Syst-Eur trial, the number of cases of new-onset AD was 29 of 43 and 12 of 21 in the patients randomly assigned to placebo and active treatment, respectively.84 The corresponding incidence of vascular dementia was 12 of 43 and 7 of 21.84 The SHEP reports83,87 did not differentiate between AD and VaD.

In the double-blind placebo-controlled Systolic Hypertension in Europe Trial, active treatment consisted of the dihydropyridine calcium-channel blocker, nitrendipine, which could be combined with enalapril, hydrochlorothiazide, or both add-on drugs to achieve blood pressure control.13 Median follow-up lasted only 2 years. The trial had to be stopped prematurely, because active treatment resulted in a 42% decrease in the primary end point of fatal and nonfatal stroke. Of 4695 randomly assigned patients, 2418 participated in the substudy on dementia (mean age: 70 years).13 Compared with placebo, active treatment reduced blood pressure by 8.3 mm Hg systolic and 3.8 mm Hg diastolic and the incidence of dementia by 50% from 7.7 to 3.8 cases per 1000 patient-years.13 After the double-blind trial had stopped in 1997, all of the patients were offered therapy with the same active medication. Median follow-up lengthened to 3.9 years. The number of dementia cases doubled from 32 to 64 (41 with Alzheimer’s disease).84 Immediate compared with delayed antihypertensive therapy reduced the risk of dementia by 55% (CI: 24% to 73%; P<0.001) from 7.4 to 3.3 cases per 1000 patient-years (Figure 3).84

In the Perindopril Protection Against Recurrent Stroke Study,85 combination therapy with perindopril plus indapamide (RRR: 23%; CI: 0% to 41%; P=0.05) but not monotherapy with perindopril alone (RRR: –8%; CI: –48% to 21%; P=0.60), compared with placebo, reduced the incidence of dementia in 6105 patients with pre-existing cerebrovascular disease (mean age: 64 years). The systolic/diastolic blood pressure differences averaged 12/5 mm Hg and 5/3 mm Hg in the combination therapy and monotherapy arms, respectively. There was no apparent effect of active treatment among participants (16.4%) with evidence of cognitive impairment at baseline (RRR: –5%; CI: –42% to 22%; P=0.70), whereas among patients without such impairment (84.2%), active treatment protected against poststroke dementia (RRR: 31%; CI: 6% to 49%; P=0.02).85

The Study on Cognition and Prognosis in the Elderly was set up as a double-blind, placebo-controlled trial in 4964 patients (mean age: 76 years).86 However, open-label antihypertensive drugs, which mainly consisted of diuretics, ß-blockers, or both classes of old drugs, were added to the double-blind study medication in a considerably greater proportion of the patients randomly assigned to placebo than in those allocated candesartan.86 The achieved blood pressure was 3.2/1.6 mm Hg lower in the candesartan group. In a posthoc analysis,88 patients with cognitive impairment at baseline (Mini Mental State Examination score: 24 to 28) experienced less further decline in this test on candesartan than in the control group.

Overall, the 4 dementia trials83–86 included 18 196 patients and 642 dementia cases. The P value for heterogeneity across trials was not significant (P=0.18). Based on a fixed-effects model, the pooled odds ratio for the prevention of dementia was 0.89 (CI: 0.75 to 1.04) and did not reach statistical significance (P=0.15). However, sensitivity analyses revealed a difference in the pooled odds ratios, depending on whether active treatment started with an inhibitor of the renin system or not (Figure 4). The pooled odds ratios were 0.75 (CI: 0.60 to 0.94; P=0.01) for SHEP,83 Systolic Hypertension in Europe,84 and the combination therapy arm of Perindopril Protection Against Recurrent Stroke Study85 and 1.08 (CI: 0.84 to 1.38; P=0.54) for Study on Cognition and Prognosis in the Elderly86 and the perindopril-only subgroup of the Perindopril Protection Against Recurrent Stroke Study trial.85 The difference between the latter summary statistics was significant (P=0.04).


Figure 4
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  		Figure 4. Effects of blood pressure–lowering treatment on the incidence of dementia in placebo-controlled trials. {blacksquare}, odds ratios in individual trials and have a size proportional to the inverse of the variance of the odds ratios. Horizontal lines and {diamondsuit}, 95% CIs for individual trials and summary statistics, respectively. Pooled estimates were computed from a fixed-effect model. Three trials refers to SHEP,83 Syst-Eur,84 and PROGRESS combined treatment with perindopril and indapamide.85 The vertical dotted line marks the position of the point estimate of the pooled effect sizes for all trials combined.

Perspectives and Conclusions
Although hypertension has long been recognized to play a central role in the pathogenesis of VaD, our review underscores that it is an equipotent risk factor for AD. Early treatment of hypertension is an effective way to prevent dementia, including AD. Our review also illustrates that research into dementia requires a comprehensive multidisciplinary approach, in which basic researchers, neurologists, geriatricians, and cardiovascular physicians should join forces. Reviewers and editors can facilitate this process. In scrutinizing submitted research articles, they might adhere to more stringent standards with regard to the diagnostic instruments that have been administered, and they might check whether essential confounders have been sufficiently accounted for. Lack of standardization in the conduct and analysis of studies prevented the computation of pooled statistic from Tables 1 to 4UpUpUpUp. Finally, publication of cross-sectional and nonrandomized studies, which only provide the lowest level of scientific evidence and which, at best, are hypothesis generating, should be discouraged in favor of prospective surveys and randomized clinical trials, respectively.


*    Acknowledgments
 
We acknowledge Sandra Covens, Katrien Staessen, and Renilde Wolfs for their expert help in searching the literature and keeping the Reference Manager database updated.

Disclosures

J.A.S. consulted for pharmaceutical companies and received funding for studies, seminars, and travel from manufacturers of drugs that lower blood pressure. T.R. and W.H.B. have no conflict of interest to declare.


*    Footnotes
 
The corresponding author had full access to all data and had final responsibility for the decision to submit the manuscript for publication.

Received September 19, 2006; first decision October 6, 2006; accepted January 5, 2007.


*    References
up arrowTop
 up arrowIntroduction
 up arrowEpidemiology of Dementia
 up arrowPathogenesis of Dementias
 up arrowNeurodegeneration and...
 up arrowBlood Pressure as Risk...
 up arrowReversibility of Risk Associated...
 *References
 

  1. Casserly I, Topol E. Convergence of atherosclerosis and Alzheimer’s disease : inflammation, cholesterol, and misfolded proteins. Lancet. 2004; 363: 1139–1146.[CrossRef][Medline] [Order article via Infotrieve]
  2. Blennow K, de Leon MJ, Zetterberg H. Alzheimer’s disease. Lancet. 2006; 368: 387–403.[CrossRef][Medline] [Order article via Infotrieve]
  3. Fratiglioni L, De Ronchi D, Agüero-Torres H. Worldwide prevalence and incidence of dementia. Drugs Aging. 1999; 15: 365–375.[CrossRef][Medline] [Order article via Infotrieve]
  4. Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, Hall K, Hasegawa K, Hendrie H, Huang Y, Jorm A, Mathers C, Menezes PR, Rimmer E, Scazufca M, for Alzheimer’s Disease International. Global prevalence of dementia: a Delphi consensus study. Lancet. 2005; 366: 2112–2117.[CrossRef][Medline] [Order article via Infotrieve]
  5. Beaglehole R, Irwin A, Prentice T. The World Health Report 2003 - Shaping the Future. Geneva, Switzerland: World Health Organization; 2003.
  6. Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer’s disease in the United States and the public health impact of delaying disease onset. Am J Public Health. 1998; 88: 1337–1342.[Abstract/Free Full Text]
  7. Ivan CS, Seshadri S, Beiser A, Au R, Kase CS, Kelly-Hayes M, Wolf PA. Dementia after stroke. The Framingham study. Stroke. 2004; 35: 1264–1269.[Abstract/Free Full Text]
  8. Román GC. Vascular dementia. Advances in nosology, diagnosis, treatment and prevention. Panminerva Med. 2004; 46: 207–215.[Medline] [Order article via Infotrieve]
  9. Pasquier F, Leys D. Why are stroke patients prone to develop dementia? J Neurol. 1997; 244: 135–142.[CrossRef][Medline] [Order article via Infotrieve]
  10. O’Rourke MF, Safar ME. Relationship between aortic stiffening and microvascular disease in brain and kidney. Cause and logic of therapy. Hypertension. 2006; 46: 200–204.
  11. Gauthier S, Reisberg B, Zaudig M, Petersen RC, Ritchie K, Broich K, Belleville S, Brodaty H, Bennett D, Chertkow H, Cummings JL, De Leon M, Feldman H, Ganguli M, Hampel H, Scheltens P, Tierney MC, Whitehouse P, Winblad B, on behalf of the participants of the International Psychogeriatric Association Expert Conference on Mild Cognitive Impairment. Mild cognitive impairment. Lancet. 2006; 367: 1262–1270.[CrossRef][Medline] [Order article via Infotrieve]
  12. Jicha GA, Parisi JE, Dickson DW, Johnson K, Cha R, Ivnik RJ, Tangalos EG, Boeve BF, Knopman DS, Braak H, Petersen RC. Neuropathologic outcome of mild cognitive impairment following progression to clinical dementia. Arch Neurol. 2006; 63: 674–681.[Abstract/Free Full Text]
  13. Forette F, Seux ML, Staessen JA, Thijs L, Birkenhäger WH, Babarskiene MR, Babeanu S, Bossini A, Gil-Extremera B, Girerd X, Laks T, Lilov E, Moisseyev V, Tuomilehto J, Vanhanen H, Webster B, Yodfat Y, Fagard R, on behalf of the Syst-Eur Investigators. Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet. 1998; 352: 1347–1351.[CrossRef][Medline] [Order article via Infotrieve]
  14. Schneider JA, Wilson RS, Bienias JL, Evans DA, Bennett DA. Cerebral infarctions and the likelihood of dementia from Alzheimer disease. Neurology. 2004; 62: 1148–1155.[Abstract/Free Full Text]
  15. Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer’s disease. The nun study. JAMA. 1997; 277: 813–817.[Abstract]
  16. Lojkowska W, Ryglewicz D, Jedrzejczak T, Minc S, Jakubowska T, Jarosz H, Bochynska A. The effect of cholinesterase inhibitors on the regional blood flow in patients with Alzheimer’s disease and vascular dementia. J Neurol Sci. 2003; 216: 119–126.[CrossRef][Medline] [Order article via Infotrieve]
  17. Paris D, Humphrey J, Quadros A, Patel N, Crescentini R, Crawford F, Mullan M. Vasoactive effects of Aß in isolated human cerebrovessels and in a transgenic mouse model of Alzheimer’s disease: role of inflammation. Neurol Res. 2003; 25: 642–651.[CrossRef][Medline] [Order article via Infotrieve]
  18. Niwa K, Younkin L, Ebeling C, Turner SK, Westaway D, Younkin S, Ashe KH, Carlson GA, Iadecola C. Aß1–40-related reduction in functional hyperemia in mouse neocortex during somatosensory activation. Proc Natl Acad Sci U S A. 2000; 97: 9735–9740.[Abstract/Free Full Text]
  19. Niwa K, Kazama K, Younkin L, Younkin SG, Carlson GA. Cerebrovascular autoregulation is profundly impaired in mice overexpressing amyloid precursor protein. Am J Physiol. 2002; 283: H315–H323.
  20. De Meyer GRY, De Cleen DMM, Cooper S, Knaapen MWM, Jans DM, Martinet W, Herman AG, Bult H, Kockx MM. Platelet phagocytosis and processing of ß-amyloid precursor protein as a mechanism of macrophage activation in atherosclerosis. Circ Res. 2002; 90: 1197–1204.[Abstract/Free Full Text]
  21. Frears ER, Stephens DJ, Walters CE, Davies H, Austin BM. The role of cholesterol in the biosynthesis of ß-amyloid. Neuroreport. 1999; 10: 1699–1705.[Medline] [Order article via Infotrieve]
  22. Simons M, Keller P, De Strooper B, Beyreuther K, Dotti CG, Simons K. Cholesterol depletion inhibits the generation of ß-amyloid in hippocampal neurons. Proc Natl Acad Sci U S A. 1998; 95: 6460–6464.[Abstract/Free Full Text]
  23. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM, for the APOE and Alzheimer Disease Meta Analysis Consortium. Effect of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. JAMA. 1997; 278: 1349–1356.[Abstract]
  24. Meyer MR, Tschanz JT, Norton MC, Welsh-Bohmer KA, Steffens DC, Wyse BW, Breitner JCS. APOE genotype predicts when —not whether —one is predisposed to develop Alzheimer’s disease. Nat Genet. 1998; 19: 321–322.[CrossRef][Medline] [Order article via Infotrieve]
  25. Poirier J. Apolipoprotein E in animal models of CNS injury and in Alzheimer’s disease. Trends Neurosci. 1994; 17: 525–530.[CrossRef][Medline] [Order article via Infotrieve]
  26. Holtzman DM, Bales KR, Tenkova T, Fagan AM, Parsadanian M, Sartorius LJ, Mackey B, Olney J, McKeel D, Wozniak D, Paul SM. Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A. 2000; 97: 2892–2897.[Abstract/Free Full Text]
  27. Vasan RS, Beiser A, Larson MG, Kannel WB, D’Agostino RB, Levy D. Residual lifetime risk of developing hypertension in middle-aged women and men. The Framingham Heart Study. JAMA. 2002; 287: 1003–1010.[Abstract/Free Full Text]
  28. Qiu C, Winblad B, Fratiglioni L. The age-dependent relation of blood pressure to cognitive function and dementia. Lancet Neurol. 2005; 4: 487–499.[CrossRef][Medline] [Order article via Infotrieve]
  29. Farmer ME, White LR, Abbott RD, Kittner SJ, Kaplan E, Wolz MM, Brody JA, Wolf PA. Blood pressure and cognitive performance: the Framingham study. Am J Epidemiol. 1987; 126: 1103–1114.[Abstract/Free Full Text]
  30. Elias MF, Wolf PA, D’Agostino RB, Cobb J, White LR. Untreated blood pressure level is inversely related to cognitive functioning: the Framingham Study. Am J Epidemiol. 1993; 138: 353–364.[Abstract/Free Full Text]
  31. Skoog I, Lernfelt B, Landahl S, Palmertz B, Andreasson LA, Nilsson L, Persson G, Odén A, Svanborg A. 15-year longitudinal study of blood pressure and dementia. Lancet. 1996; 347: 1141–1145.[CrossRef][Medline] [Order article via Infotrieve]
  32. Kilander L, Nyman H, Boberg M, Hansson L, Lithell H. Hypertension is related to cognitive impairment. A 20-year follow-up of 999 men. Hypertension. 1998; 31: 780–786.[Abstract/Free Full Text]
  33. Swan GE, Carmelli D, Larue A. Systolic blood pressure tracking over 25 to 30 years and cognitive performance in older adults. Stroke. 1998; 29: 2334–2340.[Abstract/Free Full Text]
  34. Swan GE, DeCarli C, Miller BL, Reed T, Wolf PA, Jack LM, Carmelli D. Association of midlife blood pressure to late-life cognitive decline and brain morphology. Neurology. 1998; 51: 986–993.[Abstract/Free Full Text]
  35. Tzourio C, Dufouil C, Ducimetière P, Alpérovitch A, for the EVA Study Group. Cognitive decline in individuals with high blood pressure. A longitudinal study in the elderly. Neurology. 1999; 53: 1948–1952.[Abstract/Free Full Text]
  36. Elias PK, Elias MF, Robbins MA, Budge MM. Blood pressure-related cognitive decline: does age make a difference? Hypertension. 2004; 44: 625–630.[Abstract/Free Full Text]
  37. Kilander L, Nyman H, Boberg M, Lithell H. The association between low diastolic blood pressure in middle age and cognitive function in old age. A population-based study. Age Ageing. 2000; 29: 243–248.[Abstract/Free Full Text]
  38. Knopman D, Boland LL, Mosley T, Howard G, Liao D, Szklo M, McGovern P, Folsom AR. Cardiovascular risk factors and cognitive decline in middle-aged adults. Neurology. 2001; 56: 42–48.[Abstract/Free Full Text]
  39. Alves de Moraes S, Szklo M, Knopman D, Sato R. The relationship between temporal changes in blood pressure and changes in cognitive function: Atherosclerosis Risk In Communities (ARIC) Studies. Prev Med. 2002; 35: 258–263.[CrossRef][Medline] [Order article via Infotrieve]
  40. Elias MF, Elias PK, Sullivan LM, Wolf PA, D’Agostino RB. Lower cognitive function in the presence of obesity and hypertension: the Framingham Heart Study. Int J Obes (Lond). 2003; 27: 260–268.
  41. André-Petersson L, Elmståhl S, Hagberg B, Janzon L, Reinprecht F, Steen G. Is blood pressure at 68 an independent predictor of cognitive decline at 81? Results from follow-up study ’Men born in 1914', Malmö, Sweden. Aging Ment Health. 2003; 7: 61–72.[CrossRef][Medline] [Order article via Infotrieve]
  42. Shah RC, Wilson RS, Bienias JL, Arvanitakis Z, Evans DA, Bennett DA. Relation of blood pressure to risk of incident Alzheimer’s disease and change in global cognitive function in older persons. Neuroepidemiology. 2006; 26: 30–36.[CrossRef][Medline] [Order article via Infotrieve]
  43. Bohannon AD, Fillenbaum GG, Pieper CF, Hanlon JT, Blazer DG. Relationship of race/ethnicity and blood pressure to change in cognitive function. J Am Geriatr Soc. 2002; 50: 424–429.[CrossRef][Medline] [Order article via Infotrieve]
  44. Insel KC, Palmer RF, Stroup-Benham CA, Markides KS, Espino DV. Association between change in systolic blood pressure and cognitive decline among elderly Mexican Americans: data from the hispanic established population for epidemiology study of the elderly. Exp Aging Res. 2005; 31: 35–54.[CrossRef][Medline] [Order article via Infotrieve]
  45. Hebert LE, Scherr PA, Bennett DA, Bienias JL, Wilson RS, Morris MC, Evans DA. Blood pressure and late-life cognitive function change. A biracial longitudinal population study. Neurology. 2004; 62: 2021–2024.[Abstract/Free Full Text]
  46. Kuo HK, Jones RN, Milberg WP, Tennstedt S, Talbot L, Morris JN, Lipsitz LA. Effect of blood pressure and diabetes mellitus on cognitive and physical functions in older adults: a longitudinal analysis of the advanced cognitive training for independent and vital elderly cohort. J Am Geriatr Soc. 2005; 53: 1154–1161.[CrossRef][Medline] [Order article via Infotrieve]
  47. Hassing LB, Hofer SM, Nilsson SE, Berg S, Pedersen NL, McClearn G, Johansson B. Comorbid type 2 diabetes mellitus and hypertension exacerbates cognitive decline: evidence from a longitudinal study. Age Ageing. 2004; 33: 355–361.[Abstract/Free Full Text]
  48. Whitmer RA, Sidney S, Selby J, Johnston SC, Yaffe K. Midlife cardiovascular risk factors and risk of dementia in late life. Neurology. 2005; 64: 277–281.[Abstract/Free Full Text]
  49. Yamada M, Kasagi F, Sasaki H, Masunari N, Mimori Y, Suzuki G. Assocociation between dementia and midlife risk factors: the Radiation Effects Research Foundation Adult Health Study. J Am Geriatr Soc. 2003; 51: 410–414.[CrossRef][Medline] [Order article via Infotrieve]
  50. Kivipelto M, Helkala EL, Hänninen T, Laakso MP, Hallikainen M, Alhainen K, Soininen H, Tuomilehto J, Nissinen A. Midlife vascular risk factors and late-life mild cognitive impairment. A population-based study. Neurology. 2001; 56: 1683–1689.[Abstract/Free Full Text]
  51. Kivipelto M, Helkala EL, Laakso MP, Hänninen T, Hallikainen M, Alhainen K, Soininen H, Tuomilehto J, Nissinen A. Midlife vacsular risk factors and Alzheimer’s disease in later life: longitudinal population based study. BMJ. 2001; 322: 1447–1451.[Abstract/Free Full Text]
  52. Kivipelto M, Ngandu T, Fratiglioni L, Viitanen M, Kåreholt I, Winblad B, Helkala EL, Tuomilehto J, Soininen H, Nissinen A. Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol. 2005; 62: 1556–1560.[Abstract/Free Full Text]
  53. Peila R, White LR, Petrovich H, Masaki K, Ross GW, Havlik RJ, Launer LJ. Joint effect of the APOE gene and midlife systolic blood pressure on late-life cognitive impairment. The Honolulu-Asia aging study. Stroke. 2001; 32: 2882–2889.[Abstract/Free Full Text]
  54. Launer LJ, Webster Ross G, Petrovitch H, Masaki K, Foley D, White LR, Havlik RJ. Midlife blood pressure and dementia: the Honolulu-Asia Aging Study. Neurobiol Aging. 2000; 21: 49–55.[Medline] [Order article via Infotrieve]
  55. Ruitenberg A, Skoog I, Ott A, Aevarsson O, Witteman JCM, Lernfelt B, van Harskamp F, Hofman A, Breteler MMB. Blood pressure and risk of dementia: results from the Rotterdam study and the Gothenburg H-70 study. Dement Geriatr Cogn Disord. 2001; 12: 33–39.[CrossRef][Medline] [Order article via Infotrieve]
  56. Solfrizzi V, Panza F, Colacicco AM, D’Introno A, Capurso C, Torres F, Grigoletto F, Maggi S, Del Parigi A, Reiman EM, Caselli RJ, Scafato E, Farchi G, Capurso A, for the Italian Longitudinal Study on Aging Working Group. Vascular risk factors, incidence of MCI, and rates of progression to dementia. Neurology. 2004; 63: 1882–1891.[Abstract/Free Full Text]
  57. Elkins JS, Yaffe K, Cauley JA, Fink HA, Hillier TA, Johnson SC. Pre-existing hypertension and the impact of stroke on cognitive function. Ann Neurol. 2005; 58: 68–74.[CrossRef][Medline] [Order article via Infotrieve]
  58. Borenstein AR, Wu Y, Mortimer JA, Schellenberg GD, McCormick WC, Bowen JD, McCurry S, Larson EB. Developmental and vascular risk factors for Alzheimer’s disease. Neurobiol Aging. 2005; 26: 325–334.[CrossRef][Medline] [Order article via Infotrieve]
  59. Posner HB, Tang MX, Luchsinger J, Lantigua R, Stern Y, Mayeux R. The relationship of hypertension in the elderly to AD, vascular dementia, and cognitive function. Neurology. 2002; 58: 1175–1181.[Medline] [Order article via Infotrieve]
  60. Luchsinger JA, Reitz C, Honig LS, Tang M-X, Shea S, Mayeux R. Aggregation of vascular risk factors and risk of incident Alzheimer disease. Neurology. 2005; 545–551.
  61. Kuller LW, Lopez OL, Newman A, Beauchamps NJ, Burke G, Dulberg C, Fitzpatrick A, Fried L, Haan MN. Risk factors for dementia in the Cardiovascular Health Cognition Study. Neuroepidemiology. 2003; 22: 13–22.[CrossRef][Medline] [Order article via Infotrieve]
  62. Petrovitch H, White LR, Izmirilian G, Ross GW, Havlik RJ, Markesbery W, Nelson J, Davis DG, Hardman J, Foley DJ, Launer LJ. Midlife blood pressure and neuritic plaques, neurofibrillary tangles, and brain weight at death: the HAAS. Neurobiol Aging. 2000; 21: 57–62.[Medline] [Order article via Infotrieve]
  63. de Leeuw FE, de Groot JC, Oudkerk M, Witteman JCM, Hofman A, van Gijn J, Breteler MMB. Hypertension and cerebral white matter lesions in a prospective cohort study. Brain. 2002; 125: 765–772.[Abstract/Free Full Text]
  64. den Heijer T, Skoog I, Oudkerk M, de Leeuw FE, de Groot JC, Hofman A, Breteler MMB. Association between blood pressure levels over time and brain atrophy in the elderly. Neurobiol Aging. 2003; 24: 307–313.[CrossRef][Medline] [Order article via Infotrieve]
  65. Goldstein IB, Bartzokis G, Guthrie D, Shapiro D. Ambulatory blood pressure and the brain. A 5-year follow-up study. Neurology. 2005; 64: 1846–1852.[Abstract/Free Full Text]
  66. Waldstein SR, Giggey PP, Thayer JF, Zonderman AB. Nonlinear relations of blood pressure to cognitive function. The Baltimore Longitudinal Study of Aging. Hypertension. 2005; 45: 374–379.[Abstract/Free Full Text]
  67. Zhang H, Thijs L, Kuznetsova T, Fagard RH, Li X, Staessen JA. Progression of hypertension in the non-hypertensive participants in the Flemish Study on Environment, Genes and Health Outcomes. J Hypertens. 2006; 24: 1719–1727.[Medline] [Order article via Infotrieve]
  68. Petitti DB, Crooks VC, Buckwalter JG, Chiu V. Blood pressure levels before dementia. Arch Neurol. 2005; 62: 112–116.[Abstract/Free Full Text]
  69. Hanon O, Latour F, Seux ML, Lenoir H, Forette F, Rigaud AS, the REAL.FR Group. Evolution of blood pressure in patients with Alzheimer’s disease: a one year survey of a French cohort (REAL.FR). J Nutr Health Aging. 2005; 9: 106–111.[Medline] [Order article via Infotrieve]
  70. Kario K, Pickering TG, Matsuo T, Hoshide S, Schwartz JE, Shimada K. Stroke prognosis and abnormal nocturnal blood pressure falls in older hypertensives. Hypertension. 2001; 38: 852–857.[Abstract/Free Full Text]
  71. Guo Z, Fratiglioni L, Zhu L, Fastbom J, Winblad B, Viitanen M. Occurrence and progression of dementia in a community population aged 75 years and older. Relationship with medication use. Arch Neurol. 1999; 56: 991–996.[Abstract/Free Full Text]
  72. in’t Veld BA, Ruitenberg A, Hofman A, Stricker BHC, Breteler MMB. Antihypertensive drugs and incidence of dementia: the Rotterdam Study. Neurobiol Aging. 2001; 22: 407–412.[CrossRef][Medline] [Order article via Infotrieve]
  73. Morris MC, Scherr PA, Hebert LE, Glynn RJ, Bennett DA, Evans DA. Association of incident Alzheimer disease and blood pressure measured from 13 years before to 2 years after diagnosis in a large community study. Arch Neurol. 2001; 58: 1640–1646.[Abstract/Free Full Text]
  74. Lindsay J, Laurin D, Verreault R, Hebert R, Helliwell B, Hill GB, McDowell I. Risk factors for Alzheimer’s disease: a prospective analysis from the Canadian Study of Health and Aging. Am J Epidemiol. 2002; 156: 445–453.[Abstract/Free Full Text]
  75. Murray MD, Lane KA, Gao S, Evans RM, Unverzagt FW, Hall KS, Hendrie H. Preservation of cognitive function with antihypertensive medications. A longitudinal analysis of a community-based sample of African Americans. Arch Intern Med. 2002; 162: 2090–2096.[Abstract