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Alzheimer's disease (AD) and vascular dementia (VaD) are important causes of cognitive decline in the elderly. As a result of an ageing population worldwide, the incidence of dementia is expected to rise exponentially over the coming decades. Vascular risk factors are implicated in the pathogenesis of both AD and VaD. Hypertension in midlife is particularly associated with an increased risk of developing dementia. One might hope the treatment of high blood pressure in midlife would reduce the risk of developing dementia, as it does the risk of stroke. Divergent results have been reported in studies examining this effect, with the evidence suggesting that certain antihypertensives confer benefits beyond others. This implies that certain drugs may have neuroprotective properties separate to their blood pressure lowering capabilities. Recent trials have added to our understanding of these relationships.
Dementia is one of the most important medical conditions in the elderly. Alzheimer's disease (AD), vascular dementia (VaD), and mixed variants of the two account for the majority of cases of dementia [Fratiglioni et al. 2000]. AD is classified as a progressive neurodegenerative disorder with histopathological hallmarks of ß-amyloid plaques, neurofibrillary tangles of hyperphosphorylated tau, and cerebral amyloid angiopathy [Love 2005]. Vascular dementia occurs as a result of cerebrovascular insults in cortical and subcortical areas responsible for memory and executive function; however, there are no objective neuropathological criteria to indicate the exact vascular ‘threshold’ for making a diagnosis of VaD [Love 2005]. Mixed type dementia has features of both AD and VaD [Cohen et al. 1997]. As the populations of developed and developing countries get older, the incidence of dementia, which is largely an age-related condition, is increasing. Currently 24.3 million people have dementia worldwide, with an annual incidence of 4.6 million new cases [Ferri et al. 2005]. It is expected that the number of people affected will double every 20 years to 81.1 million by 2040 [Ferri et al. 2005]. Although current treatments for dementia offer some symptomatic benefit, more effective treatments and disease modification are required.
The risk for hypertension also increases with advancing age. The prevalence of hypertension in persons 60 years and older is double that of persons aged 49-50 years and, despite recent improvements, blood pressure (BP) control rates in older persons remain suboptimal (only 50% of elderly patients with hypertension being treated) [Ong and Cheung 2007]. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) [Lenfant et al. 2003] classified hypertension as a systolic BP (SBP) > 140 mmHg and/or a diastolic BP (DBP) > 90 mmHg. Hypertension has been identified as a major risk factor for the development of all types of dementia in numerous prospective epidemiological studies (Tables 1 and and2).2). Hypertension is the only risk factor for dementia with at least two positive clinical trials demonstrating a positive treatment effect [Tzourio et al. 2003; Forette et al. 2002]. As such, the effective control of hypertension presents us with an opportunity to reduce the incidence of dementia. However several epidemiological studies have also described low blood pressure (Table 3), especially in later life as a risk for the development of AD in particular, pointing to the potential risk of overtreating hypertension.
In this review we will describe the evidence from prospective longitudinal studies that examine the relationship between blood pressure and dementia, and its potential reversibility as a risk factor. We will then review the results from randomised control trials, and speculate on potential mechanisms of action for certain antihypertensives, especially in the treatment of AD.
Prospective longitudinal studies offer us the best methodology for examining a causal relationship between blood pressure and the incidence of dementia. Given the potentially long lag phase between the presence of hypertension and the onset of dementia, cross-sectional studies may miss the association. We will assess studies that specifically describe dementia as an outcome, and where possible the subtypes of dementia. We will not include studies describing cognitive impairment as an outcome, as this refers to a collection of heterogeneous conditions, which may represent a predementia state in some, or a transient and reversible state in others. We will examine data from population-based studies, to minimise selection bias from other methodological designs. For ease of analysis we will examine the evidence using two age categories: midlife (< 69 years) and late life (> 70 years).
Several studies have examined the relationship between elevated blood pressure in midlife (age 40–64 years) and the onset of dementia and AD later in life [Whitmer et al. 2005; Wu et al. 2003; Yamada et al. 2003; Kivipelto et al. 2001; Launer et al. 2000] (Table 1). The Honolulu Asia Aging Study [Launer et al. 2000] studied this relationship in 3703 Japanese-American men aged 45-68 years at their midlife examination, who were followed prospectively for 26 years in the Honolulu Heart programme. Of the total sample, 5.9% had a midlife SBP of < 160 mmHg. The Cognitive Abilities Screening Instrument (CASI) was used to evaluate their cognitive status. VaD and AD were diagnosed according to the DSM-III-R. Among men untreated for high blood pressure (57% of the sample), there was a strong association between midlife hypertension and both AD and VaD when 160/95 mmHg was used as the BP cut-off. A higher, although nonsignificant, risk was also associated with BP cut-offs of 140/90 mmHg. In patients receiving antihyper-tensive treatment, there was no identifiable association between elevated blood pressure and dementia. The autopsy follow-up of 243 participants [Petrovitch et al. 2000] demonstrated that elevated SBP in midlife was associated with vasculopathic changes, a lower brain weight and greater numbers of neuritic (ß-amyloid) plaques in both the neocortex and the hippocampus. Elevated DBP was associated with greater numbers of neurofibrillary (tau protein) tangles in the hippocampus. Neurofibrillary tangles and neuritic plaques, while they can occur as neuropathological features of aging, are classically associated with AD. A neuroimaging study [Korf et al. 2004] demonstrated an association between midlife untreated hypertension and hippocampal atrophy (OR 1.98; 95% CI 0.89-4.39). Although hippocampal atrophy can occur in the presence of either VaD or AD, it is considered a radiological hallmark of AD. The Kuopio and Joensuu [Kivipelto et al. 2001] studies also found that both elevated systolic and/or diastolic blood pressure in midlife was associated with an increased of both AD and VaD, independent of APOE genotype. When high SBP was combined with an elevated total cholesterol level, the risk for AD or VaD was greater than when either were present alone [Kivipelto et al. 2002]. The Adult Health Study in Japan [Yamada et al. 2003] was the only study that linked midlife systolic hypertension to late life VaD (OR per 10 mmHg 1.33; 95% CI 1.14-1.56), but not AD. Overall there is substantial evidence of a risk effect of midlife high blood pressure on the development of late-life dementia.
Although several longitudinal studies (Table 2) have addressed the issue, only two Swedish studies identified an association between hypertension in late-life and dementia [Qiu et al. 2003; Skoog et al. 1996]. In the Kungsholmen project, a community-based cohort of 1270 participants (aged > 75 years) were followed up for a period of 6 years, 339 subjects had a diagnosis of dementia according to DSM-IV criteria, 256 with AD [Qiu et al. 2003]. Subjects with very high SBP (> 180 mmHg) had an adjusted relative risk of 1.5 for AD (95% CI 1.0-2.3), and 1.6 (95% CI 1.1-2.2) for dementia. High DBP (> 90 mmHg) was not associated with an increased risk. Low DBP (< 65 mmHg) was associated with an adjusted relative risk of 1.7 for the development of AD (95% CI 1.1-2.4), and 1.5 for dementia (95% CI 1.1-2.1). Only one study [Skoog et al. 1996] described an association between both elevated systolic and diastolic blood pressure and a subsequent diagnosis of AD or dementia. In 382 subjects (aged 70 years) followed for 15 years, participants who developed dementia at age 79-85 had higher SBP and DBP at age 70 than those who did not develop dementia. Higher DBP at age 70 and 75 years was associated with a higher incidence of both AD and VaD. Interestingly this study also described that blood pressure declined in the years preceding the onset of dementia, and was then similar to, or lower than that in nondemented individuals. Recently the Adult Changes in Thought Study [Li et al. 2007] assessed the association between BP and the risk for both AD and dementia across a spectrum of older ages and examined BP changes before dementia onset. The 2356 participants were all dementia-free and > 65 years, but for analyses were grouped into three age categories at baseline (65-74 years, 75-84 years and > 85 years) and during 8 years, cognition was assessed using the Cognitive Abilities Screening Instrument (CASI) [Teng et al. 1994]. BP was measured at enrolment and at each biennial examination. SBP was divided into three categories: high (> 160 mmHg), borderline high (140-159mmHg), and normal (<140mmHg). Similarly DBP was categorised as high (> 90 mmHg), borderline high (80-89 mmHg), and normal (<80mmHg). During follow-up 380 of the 2356 participants received a diagnosis of all cause dementia, 204 had probable AD. After adjustment for sex, race, years of education and the presence of APOE E4 allele, the youngest age group showed a significant association between high SBP (> 160 mmHg) and all cause dementia (HR 1.6; 95%CI 1.01-2.55). The risk estimates were similar although not statistically significant for this group and the development of AD (HR 1.38; 95% CI 0.71-2.71). The risk estimates for both AD and dementia associated with SBP declined with advancing age. In fact there was a trend towards a lower AD and dementia risk with high SBP in the oldest age group (>85 years) (HR for AD 0.70; 95% CI 0.25-1.95) (HR for dementia 0.64; 95% CI 0.32-1.30). Results with DBP showed weaker but similar trends. Strengths of this study include its community based prospective design, with a relatively long follow-up period.
Several longitudinal studies failed to demonstrate any relationship between late life hypertension and the incidence of AD and dementia [Borenstein et al. 2005; Petitti et al. 2005; Kuller et al. 2003; Lindsay et al. 2002; Posner et al. 2002; Tyas et al. 2001; Brayne et al. 1998; Yoshitake et al. 1995] (Table 2). Some of these studies did describe an association between hypertension and VaD but not AD [Posner et al. 2002; Yoshitake et al. 1995]. However, in many of these studies the diagnosis of hypertension was ascertained by self-report rather than objective measurements [Borenstein et al. 2005; Kuller et al. 2003; Lindsay et al. 2002; Posner et al. 2002; Tyas et al. 2001; Brayne et al. 1998].
Several longitudinal studies have also identified low BP as a risk factor for the development of AD and dementia [Nilsson et al. 2007; Verghese et al. 2003; Ruitenberg et al. 2001; Morris et al. 2001] (Table 3). The Bronx Aging Study [Verghese et al. 2003] followed an elderly nondemented cohort (> 75 years old), for up to 21 years. Dementia was diagnosed following detailed neuropsychological testing, clinical examination and neuroimaging. Individual's cases were then discussed at a consensus meeting and diagnosed according to DSM-III-R criteria. Over a median follow-up of 6.7 years 122 subjects developed dementia, of these 65 had AD. Particpants with a DBP of < 70 mmHg were twice as likely to develop AD when compared to those with a DBP > 90 mmHg. The risk was higher in individuals with a persistently low DBP. An association was not described for SBP, or for a relationship between low DBP and VaD. The Kungsholmen Project's 6-year longitudinal follow-up of 1270 dementia-free individuals reported similar results with low DBP (< 65 mmHg) at baseline being associated with an adjusted relative risk for AD of 1.7 (95% CI 1.1-2.4), and 1.5 (95% CI 1.0-2.1) for dementia in general [Qiu et al. 2003a]. This relationship was especially pronounced in subjects who were on antihypertensives, or in individuals who carried the APOE-ε allele [Qiu et al. 2003b]. Similarly, the pooled data from the Gothenburg-H (n = 317 aged > 85 years) study and the Rotterdam (n = 6,668 aged > 55 years) studies demonstrated that BP measured as a continuous variable was inversely related to dementia risk (both AD and VaD), in users of antihypertensive medication [Ruitenberg et al. 2001]. More recently a population-based study of 599 individuals (mean age at baseline 82.8 years), low SBP and DBP were associated with a higher incidence of AD, whereas higher SBP was associated with better cognitive performance as measured by MMSE [Nilsson et al. 2007].
Several issues need to be considered when analysing the above data. Given the potentially lengthy lag period that may exist between the onset of hypertension/hypotension and the onset of cognitive deficits longitudinal studies are superior when trying to identify a causal relationship between these variables. The length of the follow-up period is also of great importance in that trials with shorter follow-up periods may miss the association. Population-based studies in specific age categories assist our understanding with less potential for bias. Studies looking at older persons are particularly helpful given the higher incidence of dementia in this group. One must also consider how blood pressure was diagnosed and recorded within these trials. Trials that record hypertension on a self-report basis depend on patients being aware that they have hypertension, or that cognitive restraints at baseline don't impede their recall of this fact. Blood pressure was analysed as a continuous variable in some studies while it was categorised in different cut-off values in others. There are merits to both these methods of analyses in that when it is measured as a continuous variable it enables general associations between blood pressure and dementia to be observed, whereas categorically analysing blood pressure enables us to draw conclusions on the relationship for specific BP cut-offs. The classification of cognitive disorders is also of importance. Studies offering a definite diagnosis of dementia, AD and VaD according to internationally accepted guidelines are superior to trials that merely described altered performance on cognitive testing. Diminished scoring on cognitive tests, especially when performed at a single point may not represent a progressive deficit, and therefore multiple point measurements over a longer follow-up period, with a definite diagnosis are preferred.
Midlife hypertension increases the risk for VaD by the same pathological mechanism as it increases the risk for lacunar infarcts and stroke. Chronically elevated blood pressure leads to vessel wall thickening and reduced luminal diameter in microvessels. Within larger cerebral arteries thickening of the media and atheromatous plaques also leads to narrowing of the vessel lumens. Rupture of these plaques can result in complete occlusion of arteries and infarction of the surrounding cerebral tissue [Swales 1994]. Heart failure, atrial fibrillation, and atheromatous disease are more prevalent in hypertensive patients. Consequent thrombotic material can become unstable, break down into circulating microemboli, and lodge in and occlude the smaller cerebral arteries, resulting in infarction of the surrounding cerebral tissue. The extreme vulnerability of the cornu ammonis 1 (CA1) sector of the hippocampus, even relative to other areas of the brain has been well described [Pulsinelli 1985]. In this region, a global ischaemic episode induces selective neuronal death of pyramidal neurons, whereas most of the inter-neurons survive, even several months after the ischaemic insult [Schmidt-Kastner and Freund 1991]. The death of CA1 pyramidal cells leads to the loss of anterograde memory and results in a major impairment of cognitive processes [Zola-Morgan et al. 1986]. The CA1 hippocampal sector is also very vulnerable to AD-type neurofibrillary degeneration, and both conditions may lead to similar losses in hippocampal volume [Schuff et al. 2003]. As with hypertension in midlife, several studies have described an association between atherosclerosis [Hofman et al. 1997], high cholesterol, diabetes mellitus, obesity [Kivipelto et al. 2002; Peila et al. 2002; Romas et al. 1999; Chandra and Pandav 1998] and the incidence of AD. What is less clear is the mechanism underlying the relationship between these vascular risks and the development of AD. An important pathologic feature of AD is the formation of extracellular senile plaques in the brain, whose major components are small pep-tides called ß-amyloid (Aß) derived from jß-amyloid precursor protein (APP) [Buxbaum et al. 1998]. Given the association between the development of ß-amyloid plaques and AD progression, interplay between these vascular risk factors and the increased accumulation of jß-amyloid is hypothesised. Several studies have indicated that cerebral ischemia/stroke significantly increases not just the risk of VaD, but also that of AD [Kalaria 2000; Kokmen et al. 1996; Tatemichi et al. 1994]. Moreover, APP expression is elevated in the post-ischaemic brain, and cleavage of APP leading to amyloidogenic Aß peptides may hence be increased by ischemia [Badan et al. 2004; Nihashi et al. 2001; Shi et al. 2000]. Recently evidence has emerged that hypoxia-induced factors (HIF) may potentiate these amyloidogenic mechanisms, which may ultimately result in AD expression [Zhang et al. 2007; Sun et al. 2006]. These hypoxic factors induce BACE (beta-site APP cleaving enzyme) a protein associated with the production of ß-amyloid. This evidence suggests that the cerebral ischaemia arising from both cortical and subcortical infarcts, as well as diminished cerebral perfusion as a result of luminal narrowing may lead to the development of AD.
Low BP in later life may also be associated with an increased risk of dementia, and in particular AD. Ageing itself acts as a significant contributor to the presence of vascular disease. Vascular ageing is associated with changes in the mechanical and the structural properties of vessel walls, which leads to the loss of arterial elasticity and reduced arterial compliance [Jani and Rajkumar 2006]. This leads to a dampening down of the autoregulatory capabilities of cerebral arteries, which ordinarily maintains cerebral perfusion at a constant rate despite fluctuations in systemic BP. This diminished autoregulatory capacity means the brain may be more vulnerable to ischaemic insults when systemic blood pressure dips below a critical threshold for maintaining perfusion [De La Torre 2002]. A recent study in 809 elderly men demonstrated that nocturnal dips in DBP were associated with diminished cerebral perfusion, especially in temporal and inferoparietal areas [Siennicki-Lantz et al. 2007]. Subjects with AD also have a higher incidence of orthostatic hypotension than nondemented age matched controls [Allan et al. 2007]. Orthostatic hypotension is arbitrarily defined as a fall in systolic BP of > 20 mmHg, and/or a fall in DBP of > 10 mmHg on standing, but when associated with symptoms suggestive of cerebral hypoperfusion (e.g. dizziness), a smaller drop in BP may be of equal importance [Mathias and Kimber 1999]. One study has demonstrated that systolic blood pressure reduction during orthostasis is associated with cognitive decline as measured by performance on MMSE during a 5-year follow-up [Elmstahl and Rosen 1997]. It also appears that cerebral autoregulation is severely impaired in patients with symptomatic orthostatic hypotension [Novak et al. 1998]. These episodes of reduced blood pressure are most likely associated with frequent episodes of diminished cerebral perfusion. One hypothesis is that hypoperfused areas may have transient ischaemic periods where the hypoxic driven amyloidogenesis is activated [Zhang et al. 2007; Sun et al. 2006].
Given the association between hypertension and the development of dementia, a reasonable hypothesis is that antihypertensive (AH) therapy may protect against the development of dementia. However, the association with hypotension in later life and the risk of AD in particular, raises the possibility that this treatment may in fact contribute to the development of dementia. Several observational studies have longitudinally examined the effect of AH treatment on cognitive function and dementia (Table 4).
The Kungsholmen Project [Guo et al. 1999] demonstrated that the use of diuretics in 1301 dementia-free hypertensive patients (aged > 75 years) was related to a lower prevalence of dementia (RR 0.7; 95% CI 0.5-1.0). Participants were followed up over 3 years and cognition was screened using the Mini Mental State Examination (MMSE) as well as additional neuropsychological testing in a random sample. All participants with MMSE scores of <24 points had detailed neuropsychological assessments. Nine-hundred and eight seven subjects were still alive at the end of the follow-up period. Dementia was diagnosed according to DSM-III-R criteria but no differentiation between AD and VaD cases were made. A slower cognitive decline was also noted in patients with dementia who received a diuretic compared to patients with dementia who did not (regression coefficient =0.07, p = 0.04). This study was limited in that information on treatment was only available at baseline and subjects may have commenced other antihypertensives in the intervening period. Also information on the duration of treatment and the indication was not available. The Rotterdam Study, a community cohort of 6416 nondemented people followed up for 2.2 years, reported a significant association between antihypertensive therapy and VaD but not AD [In't Veld et al. 2001]. The Baltimore Longitudinal Study of Aging, [Yasar et al. 2005], and the Cache County study [Khachaturian et al. 2006] also found that the use of AH therapy was associated with a reduced risk of developing AD. The majority of people included in the above trials were Caucasian. A 5-year follow-up study on a community sample of 1617 African Americans demonstrated that the use of medications that mediate vascular risk factors (mainly AH drugs, and among others antihyperlipidaemic and anti-diabetic drugs) reduced the risk of incident dementia by 40% (odds ratio 0.60; 95% CI 0.45-0.81) [Murray et al. 2002].
The Honolulu-Asia Ageing Study (HAAS) was conducted on a sample of Asian American men between 1965 and 1995 [Launer et al. 2000]. The relationship between the use of AH drugs and hippocampal atrophy (radiological feature of AD) was analysed in a random sample of 543 participants [Korf et al. 2004]. The risk of hippocampal atrophy was increased in patients who never received AH drugs (OR 1.7; 95% CI 1.12-2.65), compared to those who received AH therapy. A further report of 848 participants from the HAAS [Peila et al. 2006] who had a history of mid-life hypertension and were dementia-free in 1991, compared 446 participants who were normotensive throughout the study period until 1991. The study patients were assigned to one of four groups: never treated with AH, treated <5 years, treated for 5-12 years, and treated for >12 years. Longer duration of AH treatment was associated with a reduced risk of dementia, AD and VaD. Each year of AH therapy was associated with a 6% reduction in the risk for dementia and subtypes (HR 0.94; 95% CI 0.89-0.99), and those treated for > 12 years had the lowest risk (HR 0.40 95% CI 0.22-0.75), compared with those never treated.
Two population studies failed to show any association between AH therapy and dementia. The East Boston [Morris et al. 2001] cohort (n = 634 subjects > 65 years of age) and the Canadian Study of Health and Aging [Lindsay et al. 2002] (n = 3238 subjects, > 65 years of age), with follow-up periods of 4 and 5 years respectively, demonstrated no benefit for AH treatment. Of note, these two studies did not find any association between high BP and incident AD.
Several large randomised, placebo-controlled trials on hypertension have evaluated the effects of antihypertensive drugs on cognition with divergent results Tables 5. Most trials were designed to assess the impact of AH medication on cardiovascular and stroke outcomes, and only referred to cognitive outcomes as a secondary measure. No trials have been conducted with a primary focus on the prevention of cognitive decline per se.
This double-blind placebo controlled trial  included 4736 patients with a mean age of 72 years. Active treatment consisted of the diuretic chlorthalidone, with the possible addition of atenolol or reserpine. SHEP failed to demonstrate a significant effect of antihypertensive treatment on the incidence of dementia, despite between-group blood pressure differences of > 10 mmHg SBP, and > 4 mmHg DBP. The average follow-up BP was (SBP/DBP) 155/72 mmHg in the placebo group, versus 143/68 mmHg in the treatment group. The rates on placebo and active treatment were 4.2 and 3.6 dementia cases per 100 patient-years, (RRR: 14%; 95% CI 26-54%; p = 0.44). Cognition was assessed using the short-Comprehensive Assessment and Referral evaluation (short-CARE) test. A subsequent report [Di Bari et al. 2001] noticed that although retention to the two 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. This may well have biased the analysis of cognitive effects toward the null hypothesis of no differences between the treatment groups. Also the follow-up period was only for 5 years, which may not have been long enough to demonstrate a treatment effect.
In this prospectively planned Medical Research Council (MRC) [Prince et al. 1996] trial of treatment in 2584 patients (age 65-74) with hypertension subjects were randomised to a diuretic, jß-blocker, or placebo. There was a mean fall in SBP following treatment of 33.5 mmHg in the diuretic group, 30.9 mmHg in the ß-blocker group, and 16.4mmHg in the placebo group (p50.0001). Subjects were followed up for 54 months and no significant difference in neuropsychological testing was observed between the treatment and placebo groups. Although this study failed to demonstrate any positive effect of AH therapy, it did reassure doctors at that time that treating hypertension in older patients did not adversely affect cognition. Numerous subjects crossed over from placebo to active treatment group, and confounded the ‘intention to treat’ analysis. Only 2 cognitive tests, the paired associate learning test, and the trail making test (part A) were used to assess cognitive function, and it is argued that more detailed testing could have revealed a treatment effect. Moreover the 54-month follow-up period may have been too short to detect a difference between groups. A follow-up study of 387 surviving MRC [Cervilla et al. 2000] patients for 9-12 years revealed that less decline in systolic blood pressure led to poorer cognitive outcomes on MMSE testing, even with adjustments applied for a family history of dementia, cognitive function at baseline, aging, and alcohol intake.
The vascular dementia project included in the Systolic Hypertension in Europe study [Forette et al. 1998] demonstrated for the first time a reduction in the incidence of dementia following AH treatment. Participants who were at least 60 years old (n = 2418) with isolated systolic hypertension were randomised to placebo or initially treated with the dihydropyridine calcium channel blocker (DHP-CCB) nitrendipine. If necessary they received an ACE inhibitor (enalapril), or a diuretic (hydrochlorothiazide), or both drugs to achieve adequate BP control. Median follow-up was short at only 2 years. The trial was stopped prematurely because active treatment resulted in a 42% reduction in the primary endpoint of fatal and nonfatal stroke. Nitrendipine was the only antihypertensive used in 60% of patients in the active treatment group. Cognitive function was assessed using the MMSE. If the MMSE score was < 23, diagnostic tests for dementia were done, and dementia was diagnosed according to DSM-III-R criteria. The cause of dementia was established using the modified ischaemic score with brain imaging or the Hachinski score. The incidence of dementia was reduced by 50%, from 7.7 cases in the placebo group to 3.7 cases per 100 patient years in the active treatment group (p = 0.05). However these findings were based on only 32 incident cases. The incidence of AD, VaD and mixed dementia was reduced.
Following the initial double blind, placebo-controlled period, all patients were invited to continue on or commence the study medication for a further follow-up period of 2 years (Syst-Eur 2) [Forette et al. 2002]. The incidence of dementia was updated in patients treated since randomisation (4 years) compared with patients actively treated since the end of the double blind period only (2 years). After 4 years there was still a significant difference in blood pressure between the two groups SBP/DBP was 7.0/3.2 mmHg higher in the 1417 former placebo than in the 1485 subjects initially allocated to active treatment. The risk of dementia increased with age and baseline DBP. Compared with the controls, long-term antihypertensive therapy reduced the incidence of dementia (using the same criteria as Syst-Eur 1) by 55% (CI: 24-73%; p50.001) from 7.4 to 3.3 cases per 1000 patient years (p50.001). Both the incidence of AD and VaD were reduced. After adjustment for sex, age, education and initial blood pressure, the relative hazard rate associated with the use of a calcium channel blocker was 0.38 (95% CI 0.23-0.64; p50.001). These results indicate that the treatment of 1000 patients for 5 years can prevent 20 cases of dementia (95% CI 7-33).
The PROGRESS study was a randomised, double blind, placebo controlled clinical trial [Tzourio et al. 2003] on 6105 patients from 19 countries (mean age 64 years). The primary aim of the study was to examine whether a defined blood pressure lowering regimen could lower the risk of recurrent stroke and other vascular events in patients with a prior history of stroke or transient ischaemic attack (TIA). The active treatment group received the angiotensin converting enzyme (ACE) inhibitor perindopril for all participants, and the diuretic indapamide for those with neither an indication for, nor a contraindication to, a diuretic. The main outcomes for the cognitive analyses were dementia (using DSM-IV criteria) and cognitive decline (a decline of 3 or more points on the MMSE score). Following a mean follow-up period of 3.9 years, active treatment reduced the risk of cognitive decline by 19% (95% CI 4-32%, p = 0.01) in the whole population, particularly in subjects with recurrent strokes (RR 45%; 95% CI 21-61%; p = 0.001). The risk of dementia in the whole population was reduced by 12% (95% CI —8% to 28%) in the active treatment group, to 12 cases per 1000 patient-years compared to 19 cases per 1000 thousand patient years in the placebo group. Similar to the effect on cognitive decline, a significant reduction of 34% (95% CI 3-55%, p = 0.03) was observed in the incidence of dementia in patients with recurrent strokes receiving active treatment. The effect was similar in hypertensive or nonhypertensive subjects. Combination therapy with perindopril and indapamide induced a mean reduction of blood pressure of 12/5 mmHg (SBP/DBP) and was more effective in reducing the risk of dementia (23% [95% CI 0-41%]; p = <0.05), than monotherapy with perindopril alone (—8% [95% CI —48% to 21%]; p = 0.60) where the mean decrease in blood pressure was 5/3 mmHg (SBP/DBP). There was no apparent effect of active treatment among participants (n=1001 patients) with evidence of cognitive impairment at baseline (—5% [95% CI: —42% to 22%], p = 0.70), whereas among patients without such impairment (84.2%), active treatment prevented poststroke dementia by 31% (CI 6-49%; p = 0.02).
The SCOPE [Lithell et al. 2003] study evaluated the effect of the angiotensin receptor blocker candesartan, with or without diuretic, in 4964 non-demented (MMSE score > 24) elderly (mean age 76 years), hypertensive patients. Although it was a double-blind, placebo-controlled study; a considerably greater proportion of the patients randomly assigned to the placebo group received open-label antihypertensive drugs, which mainly consisted of diuretics and ß-blockers. After 3.7 years of follow-up, there was no significant difference between the two groups for cognitive function and dementia. Although originally designed as a trial comparing the effects of an angiotensin receptor blocker with placebo, it evolved as a study comparing two active treatment groups. As a result, only small blood pressure differences were observed between the active treatment group and the placebo group (3.2/1.6 mmHg, SBP/DBP), which dramatically reduced the power to detect a difference.
Cognitive evaluation was based on the MMSE, and the lack of sensitivity of this test to detect a cognitive decline in nondemented subjects could have biased the results toward the null effect, and made the comparison between the two groups difficult. Within the PROGRESS trial the greatest effect on the incidence of dementia was seen in the group on combination therapy, who also had the largest reduction in their BP. However, a later substudy [Saxby et al. 2008] using more specific neuropsychological testing (Cognitive Drug Research Computerized Assessment Battery, trail-making tests, and verbal fluency tests), described a ‘small to moderate’ effect on attention and speed of cognition, but no effect on working memory or executive function.
The Hypertension in the Very Elderly Trial (HYVET) was designed to assess the risks and benefits of treatment of hypertension in elderly patients and included a cognitive assessment, the HYVETCOG [Peters et al. 2008]. Nondemented (n = 3336) patients with hypertension (SBP 160–200 mmHg; DBP< 110 mmHg) aged > 80 years of age were enrolled. Participants were randomly assigned to receive 1.5 mg slow release indapamide, with the option of 2-4 mg perindopril, or placebo. The target SBP and DBP was 150 mmHg and 80 mmHg respectively. The main trial was stopped early because a substantial reduction in mortality and stroke was established at the second preplanned interim analysis. As a result of this the mean follow-up was short at 2.2 years. Cognitive function was assessed at baseline and annual follow-up using the MMSE, and patients with a three-point decline on follow-up, or whose score fell to <24 points had more detailed assessment. Patients were diagnosed with dementia according to DSM-IV criteria, clinical history, neuroimaging and a modified Hachinski ischaemic score (HIS) were used to differentiate subtypes. Forty-four per cent (1469) of patients attended a 2-year follow-up visit. There were fewer adverse events reported in the treatment group than in the placebo group. The mean decrease in SBP at 2 years was 14.6 mmHg on placebo versus 29.6 mmHg on treatment (mean difference 15 mmHg; p<0.0001). The mean reduction in DBP was 7.2 mmHg in the placebo group versus 13.1 mmHg on treatment, (mean difference 5.9mmHg; p<0.0001). No statistical differences were found between treatment and placebo groups with regard to cognitive decline or dementia. In total 971 patients were categorised with cognitive decline, of which 263 cases of dementia were diagnosed (164 with AD, 84 with VaD and 15 with unspecified cause of dementia). The rates of all incident dementia diagnosed were 38 per 1000 patient years in the placebo group versus 33 per 1000 patient years in the treatment group. The unadjusted hazard ratio (HR) for cognitive decline on AH treatment was 0.93 (95% CI 0.82–1.05), 0.85 for AD (95% CI 0.63–1.15), 0.87 for VaD (95% CI 0.57–1.34), and 0.86 for all cause dementia (95% CI 0.67–1.09).
The authors combined the results of the HYVET in a meta-analysis with three other placebo-controlled trials of AH treatment that assessed incident dementia: Syst-Eur, PROGRESS, and the SHEP trial (see above). The pooled ratio was borderline significant (with the random effects model); relative risk 0.87 (95% CI 0.76–1.00; p¼0.045). A previous meta-analysis had been inconclusive [McGuinness et al. 2006] although this meta-analysis included data from the SCOPE trial, which focused on cognitive decline rather than dementia.
Several methodological factors might explain the lack of marked benefit of AH treatment on dementia in some of these trials. The majority have only measured effects of short-term treatment (2–5 years), whereas the results from observational studies suggests that treatment of hypertension many years earlier in midlife has the greatest effect. Thus, the length of follow-up may have been too short to detect any effect on the incidence of dementia. Most of these AH trials have included participants who are mentally healthy at baseline, but selective dropout in relation to dementia, and the difficulties associated with the diagnosis of dementia in large trials limits their power to detect a relationship. Comparisons between placebo and treatment groups in some of the trials have been hampered because of crossover from placebo to active treatment, resulting in some trials comparing different AH treatments, rather than treatment versus no treatment as per the original design. Furthermore, these trials mostly used brief cognitive assessments such as the MMSE, to detect changes in cognition over time, which may not be sensitive enough to detect changes, especially after short follow-up periods. The HYVET trial has added further to the field in that it focused on individuals older than 80 years, an age group with a high incidence of dementia. Reassuringly HYVET demonstrated that treatment did not increase the risk of dementia or cognitive decline in this group. There may however be a selection bias in that hypertensive subjects who survive to 80 years with no prior vascular event may not be representative of most elderly patients with vascular disease. Owing to the benefit of treatment on cardiovascular outcomes, future long-term, placebo controlled studies will probably not be possible for ethical reasons.
Are these potential benefits of AH treatment solely related to their blood pressure lowering properties, or are other mechanisms involved? Given that none of the randomised, placebo control trials were mechanistic, it is not possible to draw any conclusions on how antihypertensives contribute to dementia prevention. The ACE inhibitor perindopril and the diuretic indapamide were the treatment arm in the PROGRESS and HYVET studies, while the DHP-CCB nitrendipine was used as the primary treatment in the Syst-Eur trial with the possible addition of an ACE inhibitor or diuretic. The SHEP and MRC trials failed to detect any improvement in cognitive outcomes following treatment with diuretics and ß blockers or reserpine, despite significant decreases in blood pressure on treatment. The SCOPE trial also failed to demonstrate any benefit on cognitive scores following treatment of elevated BP with the ARB candesartan, although a follow on substudy did describe a possible benefit. As a result of the general limitations of these studies: duration of treatment, neuropsychological tests used, study population, one couldn't attribute a treatment effect on the ability of these medications to reduce blood pressure alone. Given that some of these trials had positive results after a relatively short duration of treatment it begs the question do certain AH medications confer benefits above and beyond their ability to reduce BP?
Several studies have proposed that CCBs may possess neuroprotective properties, especially DHP-CCB's [Khachaturian et al. 2006; Yasar et al. 2005]. A Cochrane review of the clinical efficacy of nimodipine [Lopez-Arrieta and Birks 2002] in treating dementia, found benefit associated with nimodipine (90mg/day at 12 weeks) compared with placebo on cognitive function (SMD 0.61; 95% CI 0.42-0.81; p50.00001), and this benefit was similar for AD and VaD. Lipophilic CCBs cross the blood-brain barrier with ease enabling more local effects within the brain. In a comparison between two DHP-CCBs the highly lipophillic nilvadipine but not amlodipine improved cognitive outcomes and increased regional cerebral blood flow in a group of patients with mild cognitive impairment (MCI), despite similar reductions in blood pressure in both groups [Hanyu et al. 2007]. Over a further follow-up period of 20 months patients treated with nilvadipine were less likely to progress to AD [Hanyu et al. 2007]. It is hypothesised that DHP-CCBs exert these effects by correcting the cerebral hypoperfusion that can precede clinical symptoms of both AD and VaD. DHP-CCBs appear to antagonise the ß-amyloid-induced vasoconstriction associated with AD [Paris et al. 2004]. The ageing brain loses its ability to efficiently regulate intracellular calcium levels, leading to cell death [Khachaturian 1994] and contributing to the development of AD [Kawahara and Kuroda 2001]. It is hypothesised that DHP-CCBs may alter this disruption [Pascale and Etcheberrigaray 1999].
Several observational studies noted an improvement in cognitive outcomes following treatment with diuretics [Guo et al. 1999], and potassium-sparing diuretics in particular [Khachaturian et al. 2006]. It is unclear why potassium-sparing diuretics in particular should be associated with a reduced risk of AD, but it is well known that both loop and thiazide diuretics reduce potassium concentration, whereas K+ sparing diuretics typically lead to increased concentrations. Low potassium concentrations are associated with increased oxidative stress [Ishimitsu et al. 1996], increased inflammation [Ishimitsu et al. 1996], platelet aggregation [Young and Ma, 1999], and vasoconstriction [Chen et al. 1972], all of which are potential contributors to AD pathogenesis.
There is some evidence that components of the renin-angiotensin system have a role in learning and memory processes [Savaskan et al. 2001]. ACE inhibitors are effective and well-tolerated antihypertensive medication, which inhibit the formation of angiotensin II, a potent vasoconstrictor [Chiu et al. 1989]. There is conflicting evidence about the potential benefits, or otherwise, of ACE inhibitors for the treatment of AD. Angiotensin-receptor blockers (ARB), which are newer agents act in the same biological pathway as ACE inhibitors and are widely used antihypertensives. Conflicting results have been reported for the effect of ACE inhibitors on cognition. Findings from the Syst-Eur, PROGRESS and HYVET trials suggest that ACE inhibitors with and without diuretics seem to reduce cognitive decline, especially in stroke-related dementia. In contrast, ACE inhibitors were the only AH drug class potentially associated with a slight increased risk for AD (adjusted hazard ratio 1.13), in the Cache County cohort [Khachaturian et al. 2006]. One explanation may that lipophilic ACE inhibitors, capable of crossing the blood-brain barrier (e.g. captopril, perindopril) are associated with decreased rates of cognitive impairment and dementia [Ohrui et al. 2004]. Studies in hypertensive rats have shown that treatment with the ACE inhibitor captopril, but not the AH drug hydralazine, significantly attenuated age related impairment in learning and memory, despite similar effects by both drugs on lowering blood pressure [Wyss et al. 2003]. It is likely that an additional mechanism to blood pressure lowering accounts for these variable neuroprotective observations. Possible candidates are modulation of cerebral blood flow [Lipsitz et al. 2005], pleiotropic effects on the musculoskeletal system and nervous system, or effects on inflammation and oxygen free radicals [Cesari et al. 2005; Von Haehling et al. 2005]. The progression of white matter intensities on MRI, implicated in the pathogenesis of both AD and VaD, is also modified by ACE inhibitors [Dufouil et al. 2005].
There have been several studies regarding the impact of yß-blockers on cognitive function in patients with [Gliebus and Lippa 2007] and without [Hajjar et al. 2005; Perez-Stable et al. 2000] cognitive impairment. While the studies examining the use of ß-blockers in cognitively normal subjects failed to demonstrate any negative influence, a more recent study of patients with cognitive impairment and dementia at baseline found that lipophilic central nervous system (CNS) yß-blocker use was associated with poorer cognitive scores [Gliebus and Lippa 2007]. Growing evidence suggests that adrenergic signalling plays a role in the retrieval of intermediate-term contextual memories, because the hippocampus receives dense input from adrenergic terminals [Murchison et al. 2004]. In particular norepinephrine may be important in retrieval of memories that are at the early stages of consolidation [Murchison et al. 2004]. Theoretically this process could be affected by the use of ß-blockers with negative consequences. There is insufficient evidence for this assertion currently, but further studies should investigate the effects of ß-blockers in patients with cognitive impairment or dementia.
Midlife hypertension is a significant risk factor for the later development of both AD and VaD. It is less clear how hypertension in later life affects the development of dementia; however its treatment at this stage of life has demonstrated considerable benefits with regard to cardiovascular outcomes. Hypotension in later life appears associated with the development of AD in particular, and more careful prospective studies of the relationship between hypotension, hypertension and dementia, particularly in older persons are warranted. Although most studies suggest that AH therapy is not associated with a negative outcome, some highlighted a risk associated with AH therapy in hypotensive individuals [Qiu et al. 2003; Ruitenberg et al. 2001]. Accumulating evidence suggests that treatment with AH medications may lower the incidence of dementia, but the exact mechanisms of action of these compounds remains unclear. Ethical approval is unlikely for future placebo controlled trials of AH therapy in hypertensive patients, given the clear benefits for these treatments on cardiovascular disease and mortality. Whether certain AH medications may benefit normotensive patients with cognitive impairment or dementia, given that these compounds may have neuroprotective properties independent of blood pressure lowering effect remains unclear. Future trials should address this question.
Sean P. Kennelly, St James Hospital, Dublin, Ireland ; Email: moc.liamtoh@6791yllenneks.
Brian A. Lawlor, Department of Old Age Psychiatry, Trinity College Dublin, Dublin, Ireland.
Rose Anne Kenny, Department of Medical Gerontology, Trinity College Dublin, Dublin, Ireland.