Is dementia preventable?

Abstract

Dementía is an important public health problem of increasing magnitude. At present, available therapies provide only minor and temporary relief, and attempts to find a cure have so far failed. Epidemiological studies have identified risk factors for dementía, particularly Alzheimer's disease and vascular dementia. In principle, these findíngs provide an opportunity to intervene and prevent the dementía epidemic. Attention to nongenetic risk factors such as hypertension, hyperlipidemia, smoking, and obesity may thus not only prevent cardiovascular disease but also dementia, although it is difficult to prove the efficacy of these measures for dementía prevention.

The number of dementia victims keeps increasing at a fast rate, reaching pandemic proportions. Because of increased life expectancy, the number of people affected with dementia will double every 20 years and exceed 80 million by the year 2040. Even now the majority of people with dementia live in developing countries, and this proportion is expected to increase in the future. By the year 2040, the number of individuals with dementia in Asian countries (particularly India and China) will increase by more than 200%.¹ The victims are not just the patients themselves; the whole family is always affected. Moreover, there is a huge economic impact on society which will only become larger. A handful of drugs have been developed for the treatment of dementia and particularly Alzheimer's disease (AD). These drugs are approved for this condition, but unfortunately they have only a small effect, and none can offer a cure. Although better solutions will surely be discovered, none seems to become available in the visible future. Moreover, once developed, these therapies are likely to be costly.

The key to the development of new drugs is understanding the mechanism of the disease, or at least identifying (and controlling) the risk factors. Indeed, several important leads have been identified which justify optimism. In this paper, I discuss the recently identified risk factors for dementia, and suggest how preventative measures can delay the onset of dementia. Obviously, it is always better to prevent a disease from occurring altogether.

Dementia is not a disease, but rather a syndrome that encompasses dozens of clinical entities caused by neurodegeneration, trauma, strokes, immunological processes, or infections. The two most common forms of dementia are considered to be AD and vascular dementia (VaD). Conceptually, these are completely different disorders, the first being a result of a primary neurodegenerative process, the other evolving from damage to the brain through ischemic strokes or hemorrhages. However, the distinction between the two entities is blurred. The phenomenology of AD and of VaD are largely overlapping and in older people it is unusual not to find a combination of Alzheimer and vascular pathology at autopsy.^2-4 Although one factor or another may dominate the clinical and pathological picture in individual cases, it would be mistaken to disregard the other. A clear example of an interaction between neurodegeneration and vascular brain disease is the important Nun Study.⁵ Nuns in whom autopsy established a diagnosis of AD had not always been demented clinically. The main difference between women with AD changes who had been demented and those who had not, was not the extent and severity of the Alzheimer pathology, but rather the coexistence of discrete vascular changes, such as basal ganglia lacunar infarcts. These “minor” ischemic changes were sufficient to tip the balance and to make the AD changes manifest clinically as dementia.

Many risk factors for dementia have been identified in recent years, most of which are common, and several are associated with both AD and VaD, as well as with atherosclerosis.^6,7 These include age, hypertension, diabetes mellitus, dyslipidemia, hyperhomocysteinemia, obesity, smoking, coronary artery disease, and low level of education and occupational attainment.^8-11 It is important to note that many of these risk factors seem to exert their critical effects already in midlife.¹² In senescence, the changes mayhave disappeared. Most elderly are not overweight any more, have stopped smoking (if they ever did), and even their cholesterol levels are lower than they have ever been. It is important to realize that an interaction exists between these factors. For example, highly educated people are more likely to follow a healthy lifestyle, eat a healthy diet, not smoke, be involved in stimulating intellectual activities, promote their physical health through more strict attention to hypertension and hypercholesterolemia, etc. This makes it almost impossible to separate individual components potentially contributing to or slowing intellectual decline in old age.

Since many risk factors are common to AD and VaD, the distinction between these two “entities” is not so important from an interventionalist point of view, and attention to the risk factors mentioned above could be effective in controlling various forms of cognitive impairment.

Prevention of dementia is theoretically possible if the risk factors are identified and successfully treated in time.

While early intervention is desirable, it should be recalled that by the time a person develops the first clinical manifestation of AD, brain pathology is already widespread.^{4, 13}

According to accepted estimates, the preclinical stage of AD may be as long as 10 years. Most of the prospective studies that were done, or are being performed at present, in attempt to reduce the incidence of dementia thus actually refer to secondary prevention, ie, assess the appearance of symptoms rather than of the first neuropathologies changes, even if this is not usually acknowledged.

The overlap between AD and VaD probably means that there will never be a single mechanism by which this terrible disease can be prevented. However, attention to risk factors is likely to reduce the incidence of dementia.

The best supportive data on the importance of these risk factors that we have come from observations like the CAIDE study in Finland,¹² in which the incidence of dementia was estimated over a period of 20 years. Similar data were derived from several expensive studies extending for decades. However, in such studies the control group is not randomized, and in any case the results that demonstrate an association can only suggest causation, not prove it. It has been more difficult to accumulate prospective data on whether treatment of these risk factors can delay the onset of dementia. For example, onlymeager data exist to support the idea that treatment of hypertension, one of the most common risk factors, is efficacious in reducing the incidence of dementia. An important example is the SystEur study, in which elderlysubjects with systolic hypertension were treated with either nitrendipine or placebo. After only 2 years, the treatment was successful in reducing end point events, including the occurrence of dementia. Interestingly, the reduction included cases diagnosed clinically as having AD as well as VaD.¹⁴ Retrospective analysis also confirms that treatment with statins reduces the occurrence of dementia in patients with hypercholesterolemia,^15,16 and prospective data support this conclusion.¹⁷ However, it is unknown whether the results can be extrapolated to people with cholesterol levels in the ”normal“ range.

Several studies in different populations have suggested that late-life depression is another important risk factor for dementia. The underlying mechanisms are complex and still unclear, but the existence of cerebral white matter damage in depressed individuals¹⁸ suggest vascular changes as one mechanism. Therefore, depressed individuals must be treated intensively and aggressively if they have vascular disease such as hypertension, or changes likely to lead to these changes, such as hyperlipidemia and possibly hyperhomocysteinemia, among others. Such therapy should continue and be monitored even after the depression remits. Another presumed connection between depression and dementia is hypercortisolism, frequently found in depression. At high concentrations, Cortisol is toxic to the brain and particularly to the hippocampus which has a high concentration of steroid receptors. At present, treatment of depressed individuals targets behavioral end points, such as affect and sleep disturbances. However, it is possible that patients may have persistent hypercortisolemia even after remission of the clinical manifestations. If this is the case, monitoring and normalization of Cortisol levels may be important.¹⁹

The degenerative brain disease involves a complex inflammatory response consisting of cytokine release and microglial activation, among others. Interestingly, several epidemiological studies have suggested that nonsteroidal anti-inflammatory drugs, including aspirin, may attenuate the neurodegeneration and delay or prevent the onset of dementia.^20-22 These conclusions were the result of retrospective analysis of people treated by different drugs at various levels, for varying periods of time, so that exact information is not available.

A popular hypothesis suggests that oxidative stress is involved in neurodegenerative processes. While this theory is unsubstantiated, it has not been refuted so far. Moreover, several prospective data demonstrate an association between consumption of dietary antioxidants and reduced incidence of dementia. The data do not point to a single antioxidant but rather to a diet such as the Mediterranean diet, which is low in saturated fats and rich in fish, olive oil, and vegetables, particularly leafy ones which contain vitamin E. Other sources of data confirm that dietary vitamin E,but not supplements, are key to this beneficial effect.²³

Another important source of antioxidants can be red wine, and although several studies confirm the beneficial effect of wine if consumed in moderation (approximately 1 glass per day), no study has demonstrated an advantage of red wine over other alcoholic drinks.

One important caveat is the fact that all the abovementioned risk factors (Table I) act during midlife, rather than at an advanced age. This establishes a “window of opportunity” during which the interventions must be used. Apparently once the pathological process is fullyactive, interventions might not be effective any more.

Table I. Midlife factors associated with development of dementia in old age.

- Smoking

- High bloob pressure

- Diabetes mellitus

- Dietary unsaturated fat

- Serum cholesterol

Why is it so difficult to accumulate supporting evidence on the protective effects of antihypertensive or choles terol-lowering drugs against dementia? Firstly, it is unethical to perform placebo-controlled studies on the treatment of these disorders in people who are hypertensive or hypercholesterolemia Syst-Eur was possible only because at the time there was no consensus as to whether systolic hypertension per se should be treated in the elderly. In addition, such studies are long and costly, and thus not appealing to investigators and financing agencies. Strictly speaking, the results of Syst-Eur only applyto treatment of systolic hypertension in the elderly where we are allowed to assume that it will result in reduced incidence of dementia. Although it is logical to extrapolate these results to younger people, or those with more severe forms of hypertension, technically an effect in these situations has not been proven.

Obesity has also been associated with the occurrence of dementia.¹⁰ Of course, no randomized studies can ever be performed to establish whether prevention (or treatment) of obesity can reduce the incidence of dementia. Similarly, no class I evidence will ever demonstrate whether physical or intellectual activities, wine drinking or cessation of smoking in midlife can either singly or in combination affect the incidence of dementia several decades later.

Nevertheless, nobody is likely to contest the idea that overweight or smoking are bad for health in general, and therefore attempts to reduce obesity and to stop smoking are promoted by physicians even without referring to the cognitive aspects.

It is with this view that we have to approach the other risk factors mentioned above. It should be stressed again that most of these risk factors predispose to the occurrence of dementia several decades later. Low level of education and head trauma are examples of such delayed effects, but this is also true for hypertension, diabetes, hyperlipidemia, and more, where it is their midlife occurrence which is associated with the development of dementia in senescence.

Not all the factors mentioned here are equally important (and data are missing on several), and some may be redundant to others. It is difficult to envisage that we shall ever be able to definitely confirm that manipulation of these risk factors can reduce the risk of dementia, and what is their quantitative effect singly or in different combinations. Nevertheless, it is more than reasonable to promote physical health in order to prevent dementia. Since the prevalence of dementia doubles every 5 years after age 65, delaying the onset of dementia by 10 years could markedly reduce age-specific prevalence, particularly in people who are still in critical productive years by 75%. This is probably achievable.