ALZHEIMER’S DISEASE: SOME ANSWERS AT LAST?

Introduction

Alzheimer’s disease (AD) is set to reach epidemic proportions over the next few decades. By 2050, dementia sufferers could increase from 700,000 to 1.7 million. This increase will place an immense burden on family and professional carers and the financial impact on health economy will be substantial, to say the least.

Alzheimer’s disease is characterised by the accumulation of protein plaques around the neurons. Neurons die prematurely due to increasing amounts of beta amyloid (or Abeta peptide), a toxic chemical produced in greater amounts in sufferers.

The length of time we can expect to live has increased markedly since the 1930’s with overall improvement of health and medical interventions. However, this has also resulted in an increase in years of dependency and ill health and poor quality of life in the latter part of life. Possibly the worst scenario is to cheat the grim reaper to find oneself a victim of AD.

At last, however, research is discovering new ways both of increasing independence in old age, and of preventing or alleviating AD and other chronic diseases.

Pharmaceutical Approaches

Donepezil (Aricept), rivastigmine (Exelon) and galantamine (Reminyl) ( all approved by NICE in early Alzheimer’s) are AChE inhibitors. AChE is the enzyme which breaks down acetylcholine. Clinical trials show that these drugs can stabilise or improve cognition, global assessment scores, mood and behaviour in people with Alzheimer’s disease.

Unfortunately, as the disease progresses, there are fewer and fewer cholinergic neurones and so there is less potential for the drugs to work. Thus the drugs only slow the symptomatic progression of the disease, and don’t alter the underlying disease process.

Sadly the drugs do not benefit everyone with AD and sooner or later everyone will stop responding.

Memantine (Ebixa) which acts by blocking the neurotransmitter glutamate has been developed for patients with severe Alzheimer’s. Glutamate is believed to play a role in the disease by over stimulating nerve cells which subsequently die. Memantine has been found to slow the progress of symptoms in patients with more severe disease.

These new drugs have been a great breakthrough in management of the disease, but their limitations mean that there is a continuing pressure to find new and more effective ways of treatment or prevention.

Recent research projects from all parts of the globe have been focusing on a number of promising alternatives.

Genetic Approaches

Most cases of Alzheimer’s are sporadic. It tends not to run in families, although there are genetic components to the risk of developing the disease.

There are three rare genetic syndromes which can cause the disease, but development in these cases is at an earlier age, before 60. These forms of the illness are caused by mutations in the APP, PS1 and PS2 genes. If the gene mutations are present in a parent, the child will have a 50% chance of developing the illness.

These genes are called predictive genes as there is no way to avert this genetic inheritance.

By contrast, susceptibility genes place their bearers at increased risk, but with care, development of the disease can be delayed, avoided or reduced in intensity. The gene which increases risk in this way is the e4 form of the APOE gene. Adverse environmental effects need to combine with genetic effects for the disease to manifest in these cases.

Over half the people carrying this gene will not develop Alzheimer’s. This raises the possibility that if environmental factors such as diet, exercise, hormones and mental stimulation can be maximised, the disease may be held at bay. Professor Ralph Martins and his team in Perth, Western Australia, are presently running trials to see how effective this approach might be.

Eventually there might be good, ethical reasons for genetic testing and life style counselling in these cases.

Androgens and Alzheimer’s Disease

Oxidative stress has been implicated in AD pathogenesis as well as in other illnesses such as atherosclerosis and Parkinson’s. Many studies show that oestrogen, progesterone, testosterone and luteinizing hormone have a neuroprotective role. Changes in the levels of these hormones during aging are thought to increase risk of AD as a result of reduced protection against oxidation (Hogervorst, 2004).

Overproduction of Abeta peptide is believed to be a key factor in the development of AD. It is neurotoxic probably due to its capacity to cause oxidative stress.

The reproductive hormones help to reduce the damaging effects of Abeta (Barron et al 2006).

Testosterone depletion is a normal consequence of aging in men. One consequence of this is an increased risk for the development of AD (Pike et al, 2006, Rosario 2004). Testosterone plays a role in regulating toxic beta-amyloid (Abeta) levels but also has both neurotrophic and neuroprotective functions.

These findings have led to trials evaluating androgen-based therapies for the prevention and treatment of AD (Lim et al, 2003, Tan R., 2003). Initial findings suggest that testosterone could indeed improve cognition, including visual-spatial skills in mild to moderate Alzheimer’s disease.

Testosterone replacement has continued to be viewed as a controversial treatment for a number of reasons. Definition of the normal pattern of blood levels has remained a stumbling block as many patients exhibiting symptoms of androgen deficiency have apparently normal levels of blood testosterone.

However, it is now generally recognised that three factors undermine the use of total testosterone as an indicator of hormonal sufficiency.

Firstly, the level of available and usable testosterone is reduced increasingly with age by the accumulation of sex hormone binding globuline (SHBG) which inactivates the hormone. Other proteins also have a binding effect. To overcome this difficulty, Calculated Free Testosterone is now used as a more accurate alternative (Vermuelen, 1971, 1998).

Secondly, Recent papers have revealed the extreme difficulty of obtaining accurate measure of both testosterone and oestrogen using current laboratory techniques. There are large inter-laboratory and inter-method discrepancies which render results unreliable.

Another factor which can influence results is the state of the patient at the time of testing. A heavy drinking bout the night before can lower testosterone. If the patient is fasting, the level will be raised.

Finally, variations in the androgen receptor also radically affect the effective use of the hormone in the tissues.

The androgen receptor is the most mutated receptor in the body. CAG  repeat polymorphism can dramatically change the body’s reactions to testosterone. Short chain repeats increase the effects of the hormone, long chain repeats require higher levels to trigger a reaction in the tissues.

Hence, an apparently normal level of testosterone in the blood may be ineffective for those with a mutated CAG repeat chain.

In fact, AD is associated with androgen receptor CAG polymorphism (Lehmann et al, 2003) so this is a relevant risk for the illness.

An increasing number of studies have demonstrated the positive effects of testosterone supplementation upon cognitive function in older men (Cherrier, 2005,2006, Moffat, 2005, Beauchet, 2006)

Links with Metabolic Syndrome

Recent work has discovered a link between AD, metabolic syndrome and insulin resistance (Razay et al 2007). The link here may be the androgen deficiency shared by these conditions in many cases.

Kapoor et al (2006) found that testosterone replacement reduces insulin resistance and improves glycaemic control in hypogonadal men with type 2 diabetes.

In addition to the possibility of androgen replacement, an Australian initiative at the Edith Cowan University near Perth, is undertaking a series of studies to look at the effects of controlling diet, exercise and physical activity under the guidance of Professor Ralph Martins. Already there is evidence that these interventions may help in preventing, delaying or alleviating AD.

Dietary Approaches

Generally speaking vitamin B deficiency, obesity and central adiposity together with high levels of homocysteine are associated with a higher risk of Alzheimer’s disease. A diet delivering antioxidants, folic acid and omega-3 fatty acids tends to reduce incidence.

Homocysteine is an amino acid which is considered to be a risk factor in a number of conditions including cardiovascular disease and osteoporosis as well as Alzheimer’s.

A homocysteine level above 14µmol/L plasma increases the risk of Alzheimer’s by 150%.

In order to prevent or reverse this risk factor, it is necessary to avoid foods which are rich in methionine (which is converted to homocysteine), such as fish and to eat more of foods rich in folic acid, B6 and B12 which help to break down the homocysteine.

These include green leafy vegetables (spinach, savoy cabbage, curly kale, Brussels sprouts, broccoli, asparagus), citrus fruits (particularly oranges and grapefruit), pulses (such as black eyed beans and chickpeas) and wholegrain cereals.

It is not enough to simply add supplements to the diet. It is important that the required food elements are delivered as part of a general healthy diet. This enables other factors in the diet to interact with them. The Mediterannean diet is regarded as a good example of a diet likely to be helpful.

Higher folate intake and Vitamins B6 and B12 lower levels of homocysteine (HCY) sand so decrease the incidence of the illness. (Lucksinger et al, 2007).

Increasing folic acid in the diet in the USA and Canada has resulted in 31,000 less deaths due to stroke and 12,800 less deaths due to heart attacks.  Reduction of homocysteine levels has also been shown to improve cognitive performance in the elderly.

It is important to follow a diet which will help to reduce any excess weight carried. (Domini et al, 2007)

Hartman et al (2006) found that pomegranate juice, being high in antioxidant polyphenolic substances which are shown to be neuroprotective, decreases the amyloid load and improves behaviour, at least in animal studies.

Physical Exercise

Physical exercise, or lack of it, is another factor which contributes to loss of brain power.

Larson (1998) and his colleagues from the Group HealthCooperative in Seattle, tracked 1,740 people, free of Alzheimer’s and over 65 years old over a 9 year period. At the end of the study, the 77% of the group who were still free of dementia were those who reported exercising three or more times a week.

Walking is especially good for the brain as it increases blood circulation so that more oxygen and glucose reach the brain. Senior citizens who walk regularly show significant improvement in memory skills, learning ability, concentration and abstract reasoning. This after as little as 20 minutes a day.

The University of California, Los Angeles measured brain function in nearly 6000 women over an eight year period. In the high energy groups there was much less cognitive decline but of the women who walked least (less than half a mile a week) 25% had significant decline in their test scores. Only 17% of the active women showed a decline.

For every extra mile walked, the risk of cognitive decline was reduced by 13%. The protective effect can amount to as much as 40%.

A five-year study at Laval University in Quebec also suggested that the more a person exercises, the greater the protective benefits. Inactive individuals were twice as likely to develop Alzheimer’s but even light or moderate exercisers cut their risk significantly for AD and cognitive decline.

Physical exercise has also been shown to have an antidepressant effect as effective as medication in treating major depression (Blumenthal et al, (2002, 2007) Duke University Medical Centre).

Cognitive Training and Mental Stimulation

There is also some evidence that mental activity can help support continuing cognitive function.

Sandra Bond Chapman (2004) found that patients taking Aricept who also took part in weekly sessions of mental training, including reading and writing, retained more communication skills and functional ability and experienced greater emotional well-being and quality of life than those who did not attend sessions.

Aricept together with mental stimulation slowed the decline of Alzheimer’s Disease.

Reading habits prior to the age of 18 are a key predictor of later cognitive function. Dr. David Bennet (2006) of Chicago’s Rush University maintains that challenging the brain in early life is crucial in building up a greater ‘cognitive reserve’ to counter brain damaging disease later in life.

One very large study headed by Dr. Michael Valenzuela (2006) from the University of New South Wales, found that staying mentally active reduces the risk of Alzheimer’s disease and other forms of dementia by 48%. The protective was present even in later life providing the individuals were taking part in mentally stimulating activities.

As Venezuela puts it, ‘If you increase your brain reserve over your lifetime, you seem to lessen the risk of AD and other neurodegenerative diseases’.

And, in addition, an unpublished study by a British psychologist is said to have demonstrated that when elderly people regularly played Bingo, it helped to minimize memory loss and improved hand-eye coordination. Bingo helped players of all ages to remain mentally sharp!

Dr. Amir Soas (2001), of the Western Reserve Medical School, encourages his patients to read, do crossword puzzles, learn a foreign language, start a new hobby – anything to stimulate the brain. This advice is supported by a study from the NIH in America. The Director of the study, Richard Hodes (2006) stated, ‘This large trial found that community dwelling seniors who received cognitive training had less of a decline in certain thinking skills than their peers who did not. The study addresses a very important hypothesis – that interventions can be designed to maintain cognitive function. The challenge now is to further examine these interventions and others to see how they can be employed in real-world settings’.

Conclusions

In addition to the recognised, orthodox, tried and tested approaches to the treatment of Alzheimer’s (Alexopoulos et al, 2005) there are now a whole series of research studies which point the way to other interventions which may offer more lasting solutions to the illness, either by prevention or by delaying or alleviating symptoms.

Should they prove successful, most of these techniques will require less financial input by the caring services and most likely give rise to fewer side effects.

In addition, they may offer protection against other major illnesses and have the capacity to improve quality of life, not only for the patient, but also for their families.