Prevention of dementia I

ittow can I STOP myself getting dementia?' is a question _L _Lcommonly posed to dementia specialists. Until recently, it has not been possible to provide any advice based on reputable research. The situation is rapidly changing, however, and in this and the next chapter I describe the known risk factors for dementia and strategies that may possibly counteract them. One of the features of recent research has been the convergence of identified risk factors for the two most common types of dementia, Alzheimer's disease and vascular dementia. Thus I discuss prevention strategies for dementia as a whole and indicate where particular strategies may be important for specific types of dementia.

Disease prevention

It is important to appreciate that intentional efforts to prevent any disease imply that there is some reasonable understanding of what causes it. The disease process by which the causal factors turn a normal state into a pathological (diseased) state must also be understood. Recognition of 'risk factors' that may facilitate or are associated with the disease process, and 'protective factors' that may suppress the process or are associated with normality, is also crucial. Risk and protective factors may include genetic, medical, biological, environmental, dietary, social and cultural aspects. In the field of dementia, it has only been over the last decade that knowledge has grown sufficiently in these domains for prevention strategies to be mounted.

Historically, of course, many conditions have been prevented unintentionally or by unknown methods. An example is suicide in

Australian men aged between 45 and 75 years, where annual rates have dropped over the last 40 years from around 38 per 100 000 men to 24 per 100 000. No specific suicide prevention strategies were responsible for the change. While it has been hypothesised that the change might be related to improvements in the general health of men in this age group, no one knows for sure what has been responsible, particularly as suicide rates in younger men have increased dramatically during the same period, and those in men aged over 75 years remain very high.

Disease prevention may involve either elimination or postponement of the disease.

Disease elimination

Disease elimination suits diseases with single known causes (pathogens) that can be specifically targeted in a prevention strategy. This has been the model used in infectious diseases such as smallpox, which was eliminated from the community by population vaccination programs, and in other diseases such as measles, rubella, polio and diphtheria, which can be prevented in most individuals by vaccination. This will also be the model used in proposed gene therapies for genetic disorders where a single gene mutation is responsible for the disease. The gene therapy will target the mutation and correct the abnormality before it has had the opportunity to cause irreparable damage. Another method of disease elimination involves DNA testing of a foetus during early pregnancy where a known genetic risk for a disorder, such as Down syndrome, exists leading to a possible termination of the pregnancy.

As most cases of dementia are likely to be multifactorial in origin, disease elimination is not a realistic objective unless the prevention strategy targets a 'final common pathway' of the disease process. Hopes were raised in 1999 by the publication in the prestigious journal Nature of reports of immunotherapy treatment that eliminated beta-amyloid plaques, the major pathological abnormality in the brain in Alzheimer's disease (see Chapter 5). The therapy stimulated the immune system of mice to identify and assault the amyloid plaques. As Alzheimer's disease does not naturally occur in mice, the research involved the transplantation of a rare human Alzheimer's disease gene into the mouse. Immunisation of young transplanted mice with a protein named AN-1792 prevented the development of the beta-amyloid plaques, while immunisation of older mice after they had already developed beta-amyloid plaques halted the further accumulation of beta-amyloid protein and in some cases reversed the process. Later independent studies showed that AN-1792 also improved the performance of these mice on tests designed to measure rodent memory. Once these results hit the media, AN-1792 was quickly dubbed the Alzheimer 'vaccine' (although this is an inaccurate description, 'immunotherapy' being a better term).

These exciting findings quickly led to human trials of AN-1792 with the approval of both the US Food and Drug Administration (FDA) and the UK Medicines Control Agency. Initial trials in 2000 to test its safety in humans (known as Phase I trials) revealed no problems and led to the commencement in 2001 of a small Phase IIA trial in Europe and the United States to begin assessing the drug's effectiveness, to determine the best dosage and to further test safety. The trial enrolled 360 people with mild to moderate Alzheimer's disease. In January 2002, the sponsors, Elan and Wyeth-Ayerst Laboratories, announced suspension of the dosing schedule after four participants who had received multiple doses of AN-1792 developed symptoms of inflammation of the central nervous system. By the end of February 2002, the number of affected participants had increased to fifteen, with several deaths, and the trial was discontinued in March 2002.

Even if these concerns about the safety of AN-1792 are resolved, there are other concerns. A hypothetical concern is the possibility that in provoking an immune reaction to one of the body's own proteins AN-1792 could stimulate an autoimmune reaction in which the body mobilises an indiscriminate onslaught on its own tissues. Also, more recent studies in mice have found an increased risk of cerebral haemorrhage (stroke) in vaccinated mice. Apart from safety, possibly the most important question is whether dissolution of amyloid plaques will actually result in improvement of mental function. Many Alzheimer's experts have expressed doubts about this. There is even doubt about the capacity of AN-1792 to generate a strong enough immune response in humans to have a therapeutic effect. The participants are still being followed up, and in October 2002 it was reported that those who received the vaccine did develop antibodies to beta-amyloid and that there did not appear to be any correlation between an individual's antibody levels and the risk of developing brain inflammation. There is not yet any indication of any effects on trial participants' memory or thinking abilities.1 In March 2003, the autopsy findings of one of the AN-1792 subjects were reported in Nature. They indicated a very large reduction of beta-amyloid plaques in the brain, the desired outome.2

So, while there are tantalising suggestions that immunotherapy might provide a therapeutic opportunity to eliminate Alzheimer's disease, it is clearly not going to happen just yet. I explore this theme further in Chapter 13.

Disease postponement

In complex or chronic diseases associated with ageing, such as dementia, disease postponement may be an adequate prevention measure for the foreseeable future. While postponement does not prevent disease, the period of time involved may still have a dramatic effect. Delaying the onset of dementia could allow a person to enjoy a longer period of healthy life, before succumbing to some other condition perhaps before dementia developed, or when their dementia was still relatively mild. In the United States, it has been estimated that if the onset of Alzheimer's disease were delayed by two years, the prevalence of around 2.9 million cases in 2007 would be reduced by around 600 000! Disease postponement is largely about modifying known risk factors of dementia.3

Public health model of prevention

The public health model of prevention identifies three types of strategy to prevent disease. Universal strategies apply to the whole population, selective strategies to individuals at high risk and indicated strategies to individuals with early symptoms or indications of disease. These different types of strategy can be applied to dementia prevention. The rest of this chapter outlines some universal strategies; the next chapter covers selective and indicated strategies of dementia prevention.

Universal dementia prevention strategies

Universal strategies for disease prevention are applied to everybody in a population because all the population is at potential risk of harm from the targeted risk factor. Common examples include water purification to eliminate waterborne infectious diseases in the water supply, hand washing before food handling to prevent bacterial food contamination and treatment of sewage before disposal to prevent bacterial contamination of waterways. Although universal strategies may seem to have only a limited effect for the individual, when applied across a whole population the effect is magnified considerably. A number of dementia risk factors apply to the whole population, so universal strategies are applicable.

Age and the role of antioxidants

Increasing age is the most established risk factor for dementia, though there is still debate about whether the risk continues to increase after the age of 90. Some authorities believe that there may be a reduction of the risk; others suggest that the rate of dementia in centenarians may be at least 70 per cent. It also remains unclear whether the increased rates of dementia in old age are caused by the ageing process itself or by other diseases or events that are themselves age-related. Obviously we do not want to prevent a person from getting older, but a better understanding of the ageing process and of factors that enhance its effects may lead to some useful prevention strategies.4

One particular strategy involving the ingestion of antioxidants may already be informally in place. Antioxidants potentially have a role in preventing dementia. As the brain ages, its capacity to remove certain harmful small molecules known as 'free radicals' is reduced, resulting in cell death and increased susceptibility of nerve cells to other factors that cause damage. The brain cells' natural defences against this damage include manufacturing antioxidants that mop up free radicals, but with age some of these protective mechanisms decline.

Curcumin (from the herb turmeric), alpha-lipoic acid, flavonoids, vitamin B6, vitamin C, vitamin E and vitamin A are just a few of the many antioxidants available on the shelves in health food stores. A number of these substances have been examined for their ability to prevent Alzheimer's disease, vascular dementia or cognitive impairment, but the results so far are equivocal.

Vitamins C and E

There is modest evidence that vitamins C and E may have a protective role against dementia. The Honolulu-Asia Aging Study found that older men who took supplements of vitamins C and E had lower rates of vascular dementia and cognitive impairment but not Alzheimer's disease. An epidemiological study published in the influential Journal of the American Medical Association (JAMA) in June 2002 suggested that eating foods rich in antioxidants (such as fibres, grains, fish, green vegetables), especially vitamin E (but not vitamin E supplements), may help lower the risk of developing Alzheimer's disease.5 A second study published in the Archives of Neurology in July 2002 found vitamin E to be protective against memory decline.6

An editorial in JAMA concluded that while the studies were not conclusive as to whether antioxidant vitamins are truly protective against Alzheimer's disease (because of weaknesses in their design), they supported the view that dietary antioxidant vitamins may prevent the development of Alzheimer's disease.7 The optimal dose of vitamin E is not known. Many doctors recommend 500 international units (IU) twice daily; this level is safe for most individuals and should have the antioxidant effect desired in the brain. However, people taking anticoagulants such as warfarin may not be able to take vitamin E, and should be monitored closely by their doctor.

At least five clinical trials are currently underway specifically to examine the role of vitamins C and E and other antioxidants in preventing memory decline and Alzheimer's disease; until the results of these trials are available, it is unknown whether vitamin supplements will prevent Alzheimer's disease.

Alcohol (red wine)

It is well established that excessive alcohol intake, usually in combination with thiamine deficiency, can cause brain damage. One well-known type of brain damage is the Wernicke-Korsakoff syndrome, in which profound short-term memory impairment occurs. Unlike dementia, this is not a progressive condition but it is irreversible, leaving the sufferer severely impaired even when alcohol consumption ceases. More controversially, alcohol has long been regarded as a cause of dementia, although precise brain pathology has not been established.

Epidemiological studies have not demonstrated that alcohol is a risk factor for dementia. Indeed, as demonstrated in the Rotterdam Study, light to moderate drinking (one to three drinks per day) was significantly associated with a lower risk of any dementia, and vascular dementia in particular, in individuals aged 55 years or older. The effect seemed to be unchanged by the source of alcohol.8 However, some studies have suggested that red wine may have particular benefit. The flavonoids in wine— powerful antioxidant substances also contained in tea, fruits and vegetables—have been thought to offer protection. One study has found that the intake of antioxidant flavonoids was inversely related to the risk of dementia.9 While these findings may give some encouragement to drink alcohol in old age, a few words of caution are required. For some individuals there may be a fine line between a potentially beneficial amount of alcohol and a deleterious amount. Further, women experience the deleterious effects of alcohol at much lower amounts than men. Until prospective controlled studies of light to moderate alcohol intake are undertaken, it remains an unproven preventive strategy. In those who have established dementia, relatively small amounts of alcohol can cause increased confusion and behavioural changes.

The lack of strong evidence for the effectiveness of antioxidants in the prevention of dementia should not be viewed too negatively. The lack of evidence does not mean that they are ineffective—it is just that to determine whether a particular antioxidant may be effective requires very large, randomised, placebo-controlled studies, such as the trials underway in the United States involving thousands of subjects monitored over many years.

Education, intelligence and brain reserve

Low levels of formal education have been found to be associated with higher levels of cognitive impairment, dementia in general and Alzheimer's disease in particular. Another way of looking at it is that people with higher levels of education are less likely to develop dementia. In one Canadian study, people with more than ten years of education were four and a half times less likely to have dementia than those with less than six years of education. Pooled data from European studies, however, has suggested that the effects of education may only occur in women.10

The mechanism of this relationship between education and dementia is unclear but there are a number of possibilities. One possibility is that a low level of education may be a proxy for deleterious environmental influences. Another is that a high level of education may be a proxy for intelligence, as more intelligent people are likely to obtain more formal education. The evidence that low intelligence may be linked with the development of dementia is quite varied. Lower premorbid intelligence has been found to predict the development of dementia in elderly people. More generally, lower premorbid intelligence predicts a worse cognitive outcome following head injury. Possibly the most intriguing evidence, however, is the Nun Study, in which a cohort of elderly Roman Catholic nuns were assessed, with a number having their brains studied post-mortem. Diary entries written in their late teenage years were examined for linguistic ability. Low linguistic ability during the teenage years was associated with Alzheimer's disease brain pathology at autopsy. One interpretation of these findings has been that incipient Alzheimer's disease was already present in the teenage nuns; certainly, it has been shown that the pathological changes of Alzheimer's disease may be present for 30 to 50 years before its clinical onset. Another interpretation is that the linguistic ability was a proxy for intelligence.11

So how might intelligence reduce the risk of dementia? One hypothesis, proposed by Peter Schofield from the University of Newcastle, Australia, is that more intelligent people have a larger 'brain reserve'. The concept of brain reserve is based on the fact that our brains carry redundant neurons that act as a type of back-up in times of need. In this hypothesis, when the brain is damaged, for example by a stroke or through the gradual development of Alzheimer's disease, the brain reserve comes into play to replace or cover for the damaged cells. If the brain reserve is inadequate to cover for the damage, the threshold of the disease is reached and the person becomes symptomatic. Thus the larger the brain reserve, the greater the damage that can be sustained before symptoms occur. Whether this effect is due to there being 'further to fall' before reaching disease threshold, or whether the large brain reserve in some way resists the neuropathological changes, for example through greater cognitive flexibility, is unclear. Whatever the model, a person with a large brain reserve may have incipient Alzheimer's disease for many years and be asymptomatic (see Figure 2.1). In this situation, intelligence is delaying the onset of dementia.12

Other important factors contribute to brain reserve. Any physical damage to the brain may reduce the reserve. This ties in with the finding that head injuries causing loss of consciousness for at least fifteen minutes may increase the risk of Alzheimer's disease up to twofold, though the studies are inconsistent and possibly the most methodologically sound prospective study had a negative result. Boxers may develop 'dementia pugilistica' due to repeated blows to the head and recently Jeff Astle, a former England soccer international, was found to have died from a degenerative brain disease caused by 'heading' the soccer ball,

Figure 2.1 Brain reserve: Two models (Schofield, 1999)

'Further to fall'

Figure 2.1 Brain reserve: Two models (Schofield, 1999)

'Further to fall'

Brain pathology over tim

o 'Resistance to change'

o 'Resistance to change'

Brain pathology over time

a skill for which he was famous. Other types of previous brain damage, including strokes, and mental retardation may also increase the likelihood of dementia occurring.

Brain size is another factor—the larger the brain, the larger the brain reserve. This may be linked with intelligence, as more intelligent people tend to have larger brains. People with larger brains, as measured by CT scans, MRI scans or head circumference, are less likely to develop the symptoms of Alzheimer's disease, even if they have the features of the disease in their brains at autopsy.

Mental activity also influences brain reserve. It is possible that mental activity enhances neuronal integrity through the action of better cerebral blood flow in reducing levels of stress and improving DNA repair. More tantalisingly, it may also enhance brain growth. A number of studies have shown that engaging in various forms of intellectual activity through life, even in the sixth and seventh decades, may protect against cognitive decline and enhance memory function. In a study published in JAMA in 2002, investigators from Rush Presbyterian St Luke's Medical Centre in Chicago followed 801 older Catholic nuns, priests and brothers for almost five years, tracking their everyday activities: reading the newspaper, listening to the radio, playing games such as chess, or watching television. They found that those clergy who did three or more of these things at least several times a week were almost 50 per cent less likely to develop Alzheimer's disease than those who read, listened to the radio and played games only a few times a month.13

It may not just be the quantity of mental activity that is important. Deciding to stimulate your brain through a series of repetitive, boring mental exercises, or putting pressure on yourself by taking on an intellectual pursuit that is well beyond your capacity, may both be detrimental. Authors of memory books often recommend mental exercises that include 'pegging' numbers to words for easier recall, visualising pictures with numbers and words, crossword puzzles, logic and graph puzzles, and exercises to improve the recall of word lists. Unless you enjoy doing these things they are unlikely to be of much benefit. Put simply, the mental activity should be fun!

The implications of these findings are that early life events may influence the development of dementia and that participating in varied mental and physical activities through life may impart a protective role.

Cerebral blood flow

The Chinese herb Ginkgo biloba is thought to increase circulation to the brain. In Europe and some Asian countries, standardised extracts from ginkgo leaves are taken to treat a wide range of symptoms, including dizziness, inflammation and reduced blood flow to the brain and other areas of impaired circulation. It is routinely prescribed in Europe for memory problems and although there is some evidence that it may be beneficial, the studies are not strong. The US National Institute on Aging helped fund a trial in which 2000 older adults at risk of dementia took daily doses of ginkgo or a placebo; the results, released in August 2002, were negative. One of the problems with existing studies is that many different strengths and types of ginkgo preparations have been used, and it is unclear if there is an optimal and safe dosing regime. However, Germany recently approved ginkgo extracts (240 mg a day) to treat Alzheimer's disease and this may give some guide. Too often it is incorrectly presumed that all herbal remedies are safe, and it should be noted that ginkgo can cause stomach bleeding, especially when taken with aspirin.14

Physical exercise can increase cerebral blood flow, which may in turn be beneficial for mental function. There are certainly studies that demonstrate that exercise can improve memory and mood, though none have specifically shown that exercise prevents dementia. There are many valid reasons for embracing physical exercise; it would not be surprising if it turns out that dementia prevention is another benefit.

Nutrition

Vitamin B12, Vitamin B6 and folate—the role of homocysteine

Vitamin B12 (cobalamin), vitamin B6 (pyridoxine) and folate play vital roles in effective DNA synthesis and normal brain metabolism. These B-group vitamins act as catalysts in chemical reactions in which homocysteine is converted to methionine, and dietary deficiencies can result in a build-up of serum homo-cysteine. High levels of homocysteine have been linked with Alzheimer's disease, vascular dementia, cerebrovascular disease and cognitive impairment in general. In addition, vitamin B12, vitamin B6 and folate deficiencies are known to cause depression and other neurological syndromes. What is unclear at present is whether these associations reflect a causal mechanism between high levels of homocysteine and dementia. There is some evidence that high levels may exacerbate cognitive impairment after acute stroke, so there may be an additive effect. Certainly, homocysteine provides another link between Alzheimer's disease and cerebrovascular disease, but the extent to which it may be responsible for either condition is not known.15

Probably the most important issue is that there is a simple treatment for preventing high levels of homocysteine. A diet rich in green leafy vegetables, low-fat dairy products, citrus fruits and juices, wholewheat bread and dry beans can significantly lower levels of homocysteine. Since 1998, the US Food and Drug Administration (FDA) has required the addition of folic acid to enrich breads, cereals, flours, corn meals, pastas, rice and other grain products, but it is too soon to know whether this will reduce the rate of dementia. In Australia, where folate enhancement of grain products does not routinely occur, folate supplements could be considered. In individuals with normal folate levels but elevated homocysteine levels, low dose folate supplementation (50 micrograms daily) should suffice, while individuals with folate deficiency may require up to 5 milligrams daily until the deficiency is overcome before reverting to a lower dose. Of course, vitamin B12 replacement is required if that vitamin is deficient.

Unfortunately there have been no randomised controlled studies of folate supplementation for the prevention of dementia. While it is speculative to suggest it as a reasonable prevention strategy, it is unlikely to be of harm and may have other cardiovascular benefits. Folate supplementation could be regarded as a universal preventive measure suitable for the entire population.

Fish

A recent French study has reported that the consumption of fish at least once a week reduces the risk of dementia by one-third over a seven-year period. This protective effect may be explained by the omega-3 polyunsaturated fatty acids contained in fish oils, which have a protective effect against cardiovascular disease and hence on the vascular risk factors implied in vascular dementia and Alzheimer's disease. They could also have a specific effect on brain development and neuroprotection, though this is unproven. Another factor may be education; this was found to exert an independent effect, with more highly educated older people eating more fish.16

Caffeine

Whether or not this is the best place to deal with caffeine is debatable—while for some of us caffeine is a major nutrient, there may be argument about it! There has long been evidence in the test tube that caffeine may have a potential role in treating Alzheimer's disease. Caffeine belongs to a family of chemicals that includes drugs such as propentofylline, currently in the final pre-licensing stages by the USFDA as a treatment for Alzheimer's disease. Propentofylline acts by modulating the activity of glial cells in the brain. Caffeine itself has been shown to stimulate nerve cells to take in more choline, the building block for acetylcholine, the most important neurotransmitter for memory function. Caffeine also blocks receptors for adenosine, another neurotransmitter, a function thought to be of potential therapeutic benefit in Alzheimer's disease.

In July 2002, the first clinical evidence that caffeine consumption might be associated with lower rates of Alzheimer's disease was published in a case control study. The study has numerous weaknesses but does point to the need for larger, prospective studies. At this stage, however, there is insufficient evidence to recommend the use of caffeine to prevent Alzheimer's disease.17 It should be remembered that caffeine can have adverse effects on sleep and on the heart, and can increase anxiety.

Summary

Traditional strategies to prevent disease have focused upon disease elimination. In the case of dementia, a delay in the onset of the disease may have a preventive effect as potential victims may die of other disorders before they develop dementia. An understanding of risk and protective factors for dementia is required before any preventive strategies can be undertaken. Universal prevention strategies are those that can be applied to the whole population.

Table 2.1 summarises the various universal dementia prevention strategies and comments on the strength of evidence and potential tolerability. Most universal strategies are easy to apply, have a wide range of health benefits and few, if any, drawbacks. Examples include dietary changes to improve antioxidants in our food, continuing physical exercise and continuing education. The extent to which these strategies may reduce the risk of dementia is unclear, but they are unlikely to harm.

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