Treatment of hypertension a key factor in the prevention of dementia
8 September 2008
Treatment of hypertension has been proved to reduce cardiovascular risk
substantially, but a large proportion of people with hypertension in the
general population are not even diagnosed or treated, writes Professor
Ingmar Skoog, of the Institute of Neuroscience and Physiology, Göteborg
As a risk factor
for stroke, ischemic brain lesions and silent brain infarcts, general
atherosclerosis, myocardial infarction and cardiovascular morbidity,
hypertension may also be a risk factor for dementia related to cerebrovascular disease. After a stroke event dementia occurs in up to
25–30% of patients above age 70.
Dementia: a growing public health challenge
Due to the aging population and the tragic effects of dementia, this
age-related disease is a growing medical, social, and economic problem.
Dementia is characterised by significant decline in memory and other
cognitive abilities. It is a major cause of disability and mortality,
and causes a high burden of suffering for patients and their families.
It is one of the most common diseases in the elderly, with crude
prevalence rates between 5.9–9.4% for subjects aged over 65 in the
European Union (Berr et al., 2005). Dementia drastically affects daily
life and everyday personal activities. Often the disease is associated
with behavioural symptoms, personality change and numerous clinical
complications, increasing the risk for urinary incontinence, hip
fracture, and — most markedly — dependence on nursing care. Thus, it is
not surprising that the costs of care for patients with dementia are
The two most common causes of dementia are Alzheimer's disease (AD)
and vascular dementia. AD accounts for 50–70% of all cases of dementia,
and about 20–30% have either vascular dementia or a combination of vascular
dementia and AD (Boustani et al., 2003).
In older patients, the brain
lesions associated with each dementia type often occur together. AD and
vascular brain lesions interact in important ways to impair cognition,
suggesting common pathways of the two neurological diseases. In the
absence of effective therapies (in terms of disease modification), it is
essential that all potentially reversible causes of dementia be fully
Dementia is one of the major challenges of the 21st century due to
the enormous burden these disorders impose on healthcare systems.
Searching for a breakthrough
Today there is tremendous interest in developing effective treatments
that will interfere with some step in the etiologic process or even
prevent the clinical onset of dementia.
With regard to AD, the sequence
of the molecular and cellular events leading to progressive cognitive
decline and the steps that are most amenable to intervention have been
discussed controversially, but now there is substantial agreement that
certain biochemical changes in the brain occur many years or decades
before clinical symptoms. However, no effective prevention measures can
be recommended so far.
Advancing age is the major risk factor for dementia, with a doubling
of risk every five years after the age of 65 (Jorm et al., 1987; Kawas,
During the last decade, evidence has accumulated that high blood
pressure may be a risk factor for both AD and vascular dementia,
independent of the presence of cerebrovascular disease. Several
longitudinal studies suggest an association between AD and previous
In addition, observational studies indicate that the use
of antihypertensive drugs may reduce the incidence of AD and dementia.
Conversely, no study reports that antihypertension treatment increases
the risk for dementia.
Treatment of hypertension might be a key factor in the prevention of
dementia and cognitive decline.
Risk and antihypertensive treatment
Most trials of
antihypertensive treatment in relation to dementia and cognitive decline
have been accomplished as part of large trials where dementia is of
secondary interest alongside the primary investigation of cardiovascular
So far five hypertension trials including in total
approximately 22.600 patients have reported on dementia or cognitive
function in association with antihypertensive treatment:
- SHEP: Systolic Hypertension in the Elderly Program evaluating the
effects of antihypertensive treatment using a diuretic (chlorthalidon);
- MCR: Medical Research Council’s Treatment Trial of Hypertension using a
beta-blocker (atenolol) or a diuretic (hydrochlorthiazide);
The Systolic Hypertension in Europe Study using a calcium-channel
- SCOPE: The Study on Cognition and Prognosis in
the Elderly using an angiotensin II type 1 (AT1) receptor blocker (candesartan
- PROGRESS: Perindopril Protection against Recurrent Stroke
Study using an ACE-inhibitor (perindopril) and a diuretic (indapamide).
These trials observed significant reductions in cardiovascular
outcomes, but only one study (Syst-Eur) reported a significantly reduced
incidence of dementia under antihypertensive treatment.
cognitive outcomes, two studies reported a reduction of 11–19% for
‘significant cognitive decline’. Only one study (PROGRESS) showed a
significantly lesser decline in cognitive function under
antihypertensive treatment compared to placebo, while the other studies
observed no differences between the groups in different cognitive tests.
No study reported a higher risk for dementia or cognitive decline in the
groups treated with antihypertensive drugs.
With regard to subanalyses of these data, the PROGRESS study showed
that dementia in combination with recurrent stroke was reduced by 34%.
SCOPE found that cognitive function declined significantly less under
antihypertensive treatment among patients with mild cognitive
dysfunction (compared to controls). In SHEP, antihypertensive treatment
reduced incidence of dementia if drop-outs were assigned a prevalence of
20–30% of dementia.
Dementia prevention: is there hope for the future?
scanty findings from these trials could give rise to pessimism regarding
the possibilities for dementia prevention. However, there are several
methodological shortcomings that might explain some of the results and
need to be considered in subsequent trials in order to achieve sound
- Changes in cognitive function may better be detected when the
majority of patients does not score close to the maximum in cognitive
tests (exclude 'ceiling effect');
- Generally, studies should include patients with a higher short-term
risk of developing dementia (eg old patients, patients with other risk
factors, patients with poor cognitive performance at study entry);
- Sufficient test-sensitivity should be ensured to detect
cognitive changes over time; and
- Follow-up has to be at least 5 years to detect an effect of
antihypertensive treatment on Alzheimer's disease. All hypertension
trials so far have only measured short-term effects of antihypertensive
In order to detect and substantiate an effect of antihypertensive
treatment on dementia risk, patients have to be observed for more than 5
- Selective attrition should be considered if missed cognitive
assessments differ between treatment and placebo groups: SHEP study data
eg revealed that the placebo group had more missed assessments than
the treatment group. In addition, patients with missed assessments had
more cardiovascular events during the study period. Thus an assumption
was made that 20–30% of those with missed assessments were cognitively
impaired, and consequently antihypertensive treatment was shown to
reduce the risk of cognitive impairment.
- Dementia prevention should also be investigated in younger
patients: Even if risk factors are treated, it might be too late to
achieve a prevention effect in those ages in which trials have been
conducted so far.
Strikingly, consistent associations between low blood
pressure and Alzheimer’s disease (AD) have been reported, with
decreasing blood pressure in the years preceding AD onset. Thus patients
with high blood pressure enrolled in hypertension trials might in fact
have a decreased short-term risk for dementia, and those who develop
dementia in these trials may have other characteristics than dementia in
The influence of dementia risk factors has to be clarified with
regard to their roles in early, mid and late life, and relative to
disease onset. In any case, early treatment of hypertension is
- According to observational studies,
antihypertensive treatment is related to a reduced risk of Alzheimer’s
- Primary prevention trials published so far have yielded
first hints for the prevention of dementia by antihypertensive
treatment. Due to these findings the following clinical considerations
should be taken into account:
- Most of the individuals with
hypertension or dementia are not detected.
- For the prevention of
cardiovascular disease the detection and treatment of hypertension,
irrespective of whether it prevents dementia or not, is of eminent
- Convincing study data clearly show that antihypertensive
treatment reduces the cardiovascular risk, even among very old people.
- Furthermore, it is vital to diagnose cognitive impairment in individuals
with hypertension as it may have implications for patient compliance.
Detection and treatment of hypertension in patients with dementia
including Alzheimer's disease (AD) is important, as prevention of stroke
and silent cerebrovascular disease may slow down the course of cognitive
decline in AD.
This article was written for the 21st Congress
of the European College of Neuropsychopharmacology, 2008, in Barcelona,
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