The relationship between cognitive function and blood pressure has been the subject of numerous conflicts in the literature. The results of epidemiological studies vary with the methodology used. Cross-sectional studies have found not only positive (Starr et al 1993
; Seux et al 1998
) but also negative (Farmer et al 1987
; Scherr et al 1991
) correlations between arterial hypertension and cognitive impairment. Longitudinal studies are more informative since they evaluate the effect of “chronic” hypertension on cognitive function. Most of them indicate a positive relationship between the presence of hypertension in midlife and the onset of cognitive decline 15–20 years later (). Skoog et al (1996)
have demonstrated that blood pressure values measured at 70 years old were higher in patients developing dementia between the ages of 79 and 85 years than in non-demented subjects. Conversely, in the years preceding the onset of dementia, their blood pressures became identical to or less than those of patients who did not develop dementia. Others studies have observed a similar decrease in blood pressure in patients with AD (Hanon et al 2005b
; Verghese et al 2003
). Guo et al (1996)
reported that blood pressure was lower in individuals over 75 years old with AD compared to patients without dementia and that blood pressure levels decreased with increasing severity of dementia. The reason for the decrease in blood pressure in patients with dementia has not been fully clarified. Whether the blood pressure decline is a cause or an effect of AD is not known. Physical inactivity in those afflicted by advancing mental deterioration as well as body mass and metabolic changes may all play a role. Finally, a recent study including 700 patients with AD found a significant association between hypertension and increased cognitive decline over a 6-month period (odds ratio [OR] = 1.6 [95% CI = 1.0–2.7]) (Bellew et al 2004
Blood pressure (BP) and cognitive decline or dementia. Longitudinal studies
To conclude, the connection between blood pressure and cognitive functions is more complex than a simple linear relationship. Chronic hypertension predisposes to cognitive decline and the development of dementia, but a decrease in blood pressure can be observed in the late interval preceding the onset of dementia and afterward.
The role of lowering blood pressure for the prevention of cognitive decline and dementia is of central importance and has been assessed in both non-randomized studies and several randomized clinical trials.
Non-randomized studies have yielded divergent results concerning the effect of antihypertensive drugs on cognitive functions. A negative effect of antihypertensive drugs on cognitive functions was suspected (Heckbert et al 1997
; Maxwell et al 1999
). Instead, Guo et al (1999)
have shown a significant reduction in the risk of dementia as a result of antihypertensive treatment (relative risk [RR] of 0.7, 95% CI = 0.6–1.0). In the HOPE study (Starr et al 1996
), cognitive improvement was seen in subjects treated with diuretics or angiotensin converting enzyme inhibitors who had the greatest drop in blood pressure. Moreover, in the EVA cohort (Tzourio et al 1999
), the risk of cognitive decline after 4 years of follow up was significantly lower in hypertensive subjects who received treatment compared to untreated hypertensive subjects (1.9 [95% CI = 0.8–4.4] versus 4.3 [95% CI = 2.1–8.8]). Similarly, a study of 1617 elderly African-American subjects followed for 5 years, indicated a significant 38% decrease in cognitive decline in treated hypertensive subjects compared with untreated subjects (OR = 0.62, 95% CI = 0.45–0.84) (Murray et al 2002
). Moreover, a recent study found that in a sample of 1241 elderly patients, the odds ratio for AD was 0.58 (95% CI = 0.42–0.81) in treated compared with untreated hypertensive patients (Hanon et al 2006
). Lastly, the recent Cache County Study performed in 3,308 people (Mean age 75 years), followed up 3 years, indicated a significant reduction of the risk of AD from 36% (OR = 0.64, 95% CI = 0.41–0.98) (Khatchaturian et al 2006
). Moreover, data from the Honolulu Asia Aging Study showed that the duration of antihypertensive therapy also mattered: For each additional year of treatment, there was a reduction in the risk of dementia incidence (hazard ratio [HR] = 0.94, 95% CI = 0.89–0.99) (Peila et al 2006
By definition, however, observational studies are subject to bias, and randomized, placebo-controlled studies are necessary to investigate the relationship between antihypertensive treatment and cognitive functions.
Six large randomized placebo-controlled trials have evaluated the effects of antihypertensive drugs on cognitive functions. Their results are summarized in .
Effect of antihypertensive drugs on cognitive decline or dementia in randomised, placebo - controlled studies
In the MRC project (Prince et al 1996
), a subgroup of 2584 elderly subjects followed for 54 months showed no difference in neuropsychometric tests in the treated group (Diuretic or β-blocker) compared to the placebo group. In this study, however, the evaluation of cognitive functions was insufficiently detailed and the 54-month follow up period may have been too short to detect a difference between the 2 groups.
In the SHEP study (SHEP Cooperative research group 1991
) the incidence of dementia was not statistically different in the group receiving active treatment with diuretic and/or β-blocker (1.6%) compared to the group receiving placebo (1.9%), after 5 years of follow-up, although it was slightly lower in the first group. In this study, however, differential dropout biased the cognitive evaluations and may have obscured the assessment of a preventive effect of treatment on cognitive decline (Di Bari et al 2001
On the other hand, the Vascular Dementia project included in the SYST-EUR study (Forette et al 1998
) demonstrated for the first time a reduction in the incidence of dementia with antihypertensive treatment. The study was conducted over 2 years in patients with isolated systolic hypertension who were at least 60 years old, randomized to receive the active treatment (n = 1238) or placebo (n = 1180). The active treatment was a calcium channel blocker (nitrendipine), possibly combined with an ACE-inhibitor (enalapril) and/or a diuretic (hydrochlorothiazide). The incidence of dementia was reduced by 50% in the active treatment group compared with the placebo group (p = 0.05). These findings were based on only 32 incident cases. Nevertheless, the incidence of AD was reduced as well as the incidence of vascular or mixed dementia.
After the double-blind, placebo-controlled period, all patients withdrawing from double-blind were invited to continue or start the study antihypertensive treatment for a median 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 to patients who were actively treated only since the end of the double blind period (2 years). After 4 years, there was still a significant difference in blood pressure between the two groups. Compared with the controls, long-term antihypertensive therapy reduced the incidence of dementia by 55% from 7.4 to 3.3 cases per 1000 patient-years (p < 0.001). Both types of dementia (AD and Vad or mixed dementia) were reduced.
Dementia and cognitive decline were secondary outcomes of the placebo-controlled trial PROGRESS (Tzourio et al 2003
). Treatment consisted of perindopril possibly combined with indapamide or a matching placebo. After 4 years of follow up, active treatment significantly reduced the risk of cognitive decline by 19% in the whole population. The risk of dementia was reduced by 12% (95% CI = −8% to 28%) in the active treatment-group and significantly by 34% in patients with recurrent stroke. Similarly, in patients receiving the combination therapy, the risk of dementia was significantly reduced by 23% (95% CI = 0%–41%).
Data from the HOPE study (Bosch et al 2002
) of 9297 patients with vascular disease or diabetes and an additional vascular risk factor followed over 4.5 years, have demonstrated a significant 41% reduction in cognitive decline associated with stroke in the ACE inhibitor group (ramipril 2.5–10 mg) compared to placebo.
Finally, the SCOPE study (Lithell et al 2003
) has evaluated the effect of an angiotensin receptor blocker ± diuretic on the cognitive function of 4964 elderly (70–89 years) hypertensive patients without dementia. After 3.7 years of follow up, no significant difference between the two groups was found for cognitive function and dementia. However, this lack of benefit could probably be attributed to the fact that most patients in the placebo group were treated with other antihypertensive drugs for ethical reasons. Moreover, the cognitive evaluation was based solely on the MMSE (Mini Mental State Examination) which lacks the sensitivity to detect a slight cognitive decline in subjects without dementia. Lastly, a recent analysis of SCOPE (Skoog et al 2005
) has indicated a significant reduction of cognitive decline in the subgroup of subjects with already low cognitive function at baseline (MMSE score between 24 and 28), whereas no benefit was observed in people with normal cognitive function.
Some recent meta-analyses concerning these randomized, placebo-controlled studies were able to give a more complete picture of the effects of antihypertensive treatments on cognition. Some of them have supported a benefit of antihypertensive treatments for preventing dementia (Feigin et al 2005
; Birkenhager and Staessen 2006
) or cognitive disorders (Birns et al 2006
Alternatively, the Cochrane review concluded that blood pressure reduction resulted in an 11% reduction in the relative risk of dementia in patients with no prior cerebrovascular disease, but this effect was not statistically significant (p = 0.38). Nevertheless, this review takes into account only 3 studies (SCOPE, SHEP, and SYST-EUR) which could minimize the effects of antihypertensive therapy (McGuiness et al 2006).
There are multiple underlying pathophysiological mechanisms that could give an explanation for the association between hypertension and dementia.
Data from histopathological studies indicate a major overlap between vascular lesions and AD (Arregui et al 1982
; Victoroff et al 1995
; Snowdon et al 1997
). By promoting arteriosclerosis and lipohyalinosis of the small vessels, hypertension might be the origin of stroke and/or chronic hypoperfusion of the white matter, thus contributing to the early expression of a still subclinical AD. It has been shown that patients with high midlife systolic blood pressure (SBP) experience cognitive dysfunctions as well as increased volume of white matter hyperintensities in late life (Swan et al 1998a
). A significant interaction between hypertension, ApoE ε4 allele and white matter lesions has been found (de Leeuw et al 2004
). It is also pointed out that the progression of the white matter lesions is highly correlated with cognitive decline. Furthermore, longitudinal studies found an increased risk of AD in people with periventricular white matter lesions (Prinds et al 2004
). In this way, a very recent study found that white matter hyperintensities on magnetic resonance imaging scan, were significantly associated with cognitive decline in MCI patients (mean follow-up = 3.8 ± 1.6 years) (Debette et al 2007
). Moreover, antihypertensive therapy has been showed to reduce white matter lesions progression in a longitudinal study including patients with a history of stroke (Dufouil et al 2005a). In this way, such presence of cerebral white matter lesions could be an indication for early neuroprotection. Microcirculation disorders and endothelial dysfunctions are also given as explanations for the cognitive impairment seen in hypertensive subjects. Hypertension is associated with degenerative changes of intracerebral capillaries and arterioles and ADis associated with lesions in the cerebral microvasculature (Perlmutter et al 1991). These vessel changes may compromise the function of the blood-brain barrier, leading to an increased vascular permeability and protein extravasation into the brain parenchyma, resulting in beta-amyloid accumulation (Hardy et al 1986
). Likewise, hypertension and beta amyloid act on endothelial cells to produce an excess of free radicals suggesting that oxidative stress is involved in the mechanisms of both vascular disorders and AD. Finally, periods of hypotension, hypoperfusion and hypoxia, observed in hypertensive subjects, might contribute to cognitive deficits in AD patients via reduced cerebral perfusion causing ischemic neuronal lesions in vulnerable areas of the brain.
In summary, hypertension may impair cognitive functions and is related to the occurrence of not only vascular dementia but also AD. Randomized, placebo-controlled trials have demonstrated that blood pressure-reducing agents decrease the incidence of dementia in stroke patients (PROGRESS, HOPE) and in elderly patients with isolated systolic hypertension (SYST-EUR), but this was not found in SCOPE and SHEP.
In this context, the incidence of dementia should be a major outcome measure of future trials comparing different antihypertensive drugs.