Is There Hope For The Prevention Of Dementia?

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 often occurs in patients above age 70.

At the 21st Congress of the ECNP 2008 in Barcelona, Dr. Ingmar Skoog, a Swedish researcher in neuroscience from Göteborg University, evaluated the latest findings about the effect of antihypertensive treatment on cognitive function and dementia and highlighted a controversially discussed topic with broad impact on public health in all European countries: is there hope for the prevention of dementia?

Dementia: a growing public health challenge

Characterized by significant decline in memory and other cognitive abilities, dementia is a major cause of disability and mortality, and causes a high burden of suffering for patients and their families. Due to an aging population and the tragic effects of dementia, this age-related disease represents a growing medical, social, and economic problem. 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 immense.

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, 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 investigated.

Dementia is one of the major challenges of the 21st century due to the enormous burden these disorders impose on health care systems.

Dementia: 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, 2003). 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 hypertension. 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.

Dementia: 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 outcomes. 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)
• Syst-Eur: The Systolic Hypertension in Europe Study using a calcium-channel blocker (nitrendipine)
• SCOPE: The Study on Cognition and Prognosis in the Elderly using an angiotensin II type 1 (AT1) receptor blocker (candesartan cilexetil)
• 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. Regarding other 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?

The seemingly 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 results:

• 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 (e.g. 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.
• 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 treatment.
• In order to detect and substantiate an effect of antihypertensive treatment on dementia risk, patients have to be observed for more than 5 years.

Selective attrition should be considered if missed cognitive assessments differ between treatment and placebo groups: SHEP study data e.g. 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 general.

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 essential.

Clinical implications

According to observational studies, antihypertensive treatment is related to a reduced risk of Alzheimer's disease (AD).

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 importance. 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.

References

• Berr C, Wancata J, Ritchie K. Prevalence of dementia in the elderly in Europe. European Neuropsychopharmacology 2005;15:463-471
• Boustani M, Peterson B, Harris R, et al. Screening for Dementia. Systematic Evidence Review No. 20. Rockville, MD: Agency for Healthcare Research and Quality, June 2003
• Jorm AF, Korten AE, Henderson AS. The prevalence of dementia: a quantitative integration of the literature. Acta Psychiatr Scand 1987;76:465-479
• Kawas CH. Early Alzheimer´s disease. N Engl J Med 2003;349:1056-1063
• Skoog I, Gustafson D. Update on hypertension and Alzheimer's Disease. Neurological Research 2006;28:605-611
• Skoog I, Lithell H, Hansson L, Elmfeldt D, Hofman A, Olofsson B, Trenkwalder P, Zanchetti A, for the SCOPE Study Group. Effect of baseline cognitive function on cognitive and cardiovascular outcomes: Study on COgnition and Prognosis in the Elderly (SCOPE) – a randomized double-blind trial. Am J Hypertens. 2005;18:1052-1059