Alzheimer's Research Trust

GJ Livanos House, Granhams Road Cambridge CB2 5LQ
Tel: (01223) 843899 Fax: (01223) 843325 e-mail:azt@btinternet.com

Alzheimer's facts

 

What is Alzheimer's Disease?

The symptoms of Alzheimer's disease

Who is at risk from Alzheimer's disease?

What causes Alzheimer's disease?

Is there a cure?

What more do we need to know?

What drugs are available?

Read the diary of an Alzheimer's Scientist

Hope Through Research

 

 

 

 

 

 

What is Alzheimer's Disease?

Alzheimer's Disease is a form of dementia, which means a serious deterioration in several mental functions, such as memory, language, orientation and judgement. Dementia is a major cause of ill-health, with approximately 6 million sufferers in the European Union and 800,000 in the UK.

Alzheimer's Disease is the commonest cause of dementia, accounting for about 65% of dementia in the elderly. Dementia due to narrowing of the brain's blood vessels (vascular dementia) and Lewy body dementia make up most of the remainder. Rarely, dementia can be reversed, for example if it is due to thyroid hormone deficiency or deficiency of vitamin B-12 or folic acid. It is therefore important that all patients with dementia are screened for these treatable causes.

In some cases of Alzheimer's disease, mental decline may occur relatively rapidly whilst in others the loss of cognitive ability may be more gradual. Alzheimer's disease shortens the life span and, although patients may live for as many as 15 years after diagnosis, the average period to death (usually from an infection) is about 8 years.

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The symptoms of Alzheimer's disease

Loss of memory is the first and most characteristic symptom; often, early childhood memories are preserved whereas recognition of a loved one, work colleague or sense of daily routine is lost. As the disease progresses, language difficulties in co-ordination, depression, paranoia, aggressive outbursts, delusions and hallucinations may take hold. Self-neglect, incontinence, wandering and disorientation necessitates constant supervision.

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Who is at risk from Alzheimer's disease?

Alzheimer's disease observes no social, cultural or geographical boundaries. Very rarely may it occur across generations as an inherited disease affecting 50% of family members within which the age of onset is predictable, but more commonly it occurs without a strong family history of the disease.

Research has shown that the clinical symptoms may be caused by more than one factor. One of these factors involves a protein called beta-amyloid. The gene responsible for this amyloid protein is located on chromosome 21. Individuals suffering from Down's syndrome, who have more than the normal two copies of this amyloid gene, or people who have a mutation in one of their two amyloid genes are at high risk. Others at risk are those people who have mutations in the presenilin genes which appear to interact with amyloid. Two such genes have been identified so far - one located on chromosome 14 and another on chromosome 1. Many different mutations usually lead to dementia before the age of 60.

Dominantly inherited forms of the disease have become the focus of research. However, they represent only about 1 per cent of Alzheimer's disease cases worldwide. The identification of genetic mutations in affected individuals means that the inheritance of the disease can be determined with accuracy across each generation. Genetic testing to determine who will suffer from the disease within these families is technically possible, but until a treatment is available this is being discouraged.

Another form of 'risk' can be likened to the everyday risks we take in our lives, such as travelling: we know that it is more risky to travel by bicycle than on foot, in other words, a cyclist has a higher susceptibility to injury than a pedestrian. In the same way, there are certain genes and certain environmental factors that increase our susceptibility to develop Alzheimer's disease. Having these genes, or being exposed to these environmental factors, does not mean that we will inevitably get the disease any more than cycling inevitably means that we will get injured - it just increases the chances that we will.

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What causes Alzheimer's disease?
Alzheimer's disease is not an inevitable part of normal ageing, nor even an acceleration of ageing; it is a true disease. But it is a disease, like heart disease and cancer which is increasingly common as we age. The incidence of Alzheimer's disease approximately doubles for every 5 years of age over the age of 60, so that about 25% of those over 80 years old have the disease.

The symptoms of Alzheimer's disease are caused by a loss of nerve cells in certain regions of the brain, principally the cerebral cortex, the part that controls our higher mental functions and which makes us unique as humans. The degeneration of these nerve cells leads to a loss of millions of the connections (synapses) between nerve cells; it is the loss of connections in the part of the brain dealing with memory (medial temporal lobe; see diagram) that causes the first symptoms. The disease progresses and spreads throughout the cerebral cortex, gradually affecting those parts of the cortex that deal with almost all our other higher cognitive functions and our behaviour. Certain parts of the cortex are spared: for example, the processing of vision and the control of normal movement are not affected.

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What more do we need to know?

What causes the death of the nerve cells?

Why are only certain nerve cells affected?

What triggers the whole process?

Many of the nerve cells that are destined to die show abnormal deposits of a protein called tau, which is assumed to be toxic to nerves. Another insoluble protein is beta-amyloid, which is deposited in the spaces around nerve cells; this protein is also toxic to nerve cells. In the rare genetically-determined cases of the disease it seems likely that the mutant genes lead to the excessive accumulation of amyloid. In the common forms of the disease there is no clear evidence whether it is the accumulation of amyloid or of tau that leads to the death of nerve cells. Many researchers think that there can be many different causes of nerve cell death and that Alzheimer's disease is like other common diseases and is 'multifactorial' in causation. Some of these causative factors are called susceptibility genes, which are relatively common genetic variants found in the population that for some reason predispose us to Alzheimer's disease. The best established susceptibility gene is a variant (E4) of the gene for apolipoprotein E that occurs in about 15% of the population. Having the E4 variant does not determine that we will get the disease but, if other factors are present, it makes the disease occur earlier than in people who do not have this variant.

A big search is on for the other, non-genetic, factors that might increase our risk of developing Alzheimer’s. These studies compare the incidence of a factor in subjects with Alzheimer’s with its incidence in well-matched people without the disease. Such studies can only show possible associations between a factor and Alzheimer’s; they cannot demonstrate causation. In order to do that, it will be necessary to modify the exposure of a large number of people to the possible risk factor and see whether the modification influences their likelihood of getting the disease. Proposed risk factors that are being investigated include: head injury, low oestrogen levels in women, deficiencies of certain vitamins, diabetes, smoking and other risk factors for heart disease, such as high blood pressure.

Suggestive evidence of potentially modifiable environmental factors is that Alzheimer’s disease is more common amongst Japanese living in Hawaii than those living in Japan.

The bottom line is that the commonest form of Alzheimer’s disease is caused both by genetic and by non genetic factors and that several of these factors need to be present in an individual to develop the disease.

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Is there a cure?

Because Alzheimer’s is a progressive degenerative disease of the nervous system, we cannot expect a 'cure' in the sense that one can cure an infectious disease. The idea of transplanting healthy nerve cells into the brain to replace those that have died in order to 'cure' Alzheimer’s is not realistic because many different types of nerve cell are affected in the disease, each with specific connections to other nerve cells.

Two approaches are being tried. First, treatments are being developed either to alleviate some of the symptoms or to slow down the process of nerve degeneration. Second, as with heart disease and stroke, the search is on for measures that might prevent the disease from developing.

One group of nerve cells that degenerate in Alzheimer’s disease makes the chemical acetylcholine, which acts as a transmitter of information between nerve cells. The only drugs so far proved for use in the UK are designed to inhibit the enzyme that normally breaks down acetylcholine. The cholinesterase inhibitors (see below) increase the levels of acetylcholine in the cerebral cortex and give some improvement in the memory problems early on in Al disease. However, cholinesterase inhibitors do not prevent nerve cells from dying and so they do not influence the development of the disease. Drugs under development include chemicals that inhibit the formation of the protein beta-amyloid and it is hoped that these drugs, if given early enough, might slow down the disease process. This class of drug is unlikely to be available for several years.

A few clinical trials are in progress, or planned, to see whether modifying risk factors might slow the development of the disease. Large doses of vitamin E are being tested to see if the anti-oxidant properties of this vitamin might prevent some nerve cells from dying and slow down the decline in cognitive abilities. Anti-inflammatory drugs are being tested because Alzheimer’s disease appears to be less common in those who regularly take these drugs. Trials of blood pressure lowering drugs are in progress, since these might reduce the development of vascular dementia (due to narrowing of the arteries in the brain) but also possible Alzheimer’s disease. The unexpected finding that Alzheimer’s is associated with several of the established risk factors of heart disease and stroke raises the possibility of preventing Alzheimer’s disease by dietary modification and by changes in life-style, which have been so successful in the diseases of the vascular system. Much research needs to be done to test this and other hypotheses about risk factors, but the rewards are potentially great.

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What drugs are available?

Apart from the use of established drugs to modify the behavioural problems and depression in Alzheimer’s disease, there are only two drugs licenced in the UK for the treatment of dementia itself.

Donepezil (Aricept) - licenced in 1997 for the treatment of Alzheimer’s disease; a cholinesterase inhibitor. Improves short-term memory and so helps patients manage themselves better. Appears to work only for a short time and quite early on in the disease in about one third of patients. Unlikely to be of benefit in advanced cases.

Rivastigmine (Exelon) - licensed in 1998 for the treatment of Alzheimer’s disease; a cholinesterase inhibitor. Improves short term memory and so helps patients manage themselves better. Has been in use for too short a time to assess, but likely to have a similar effectiveness to donepezil. Possibly has more side effects.

No other drugs are currently licensed for use in Alzheimer’s disease in the UK. Clinical trials are underway with several cholinesterase inhibitors, with drugs that mimic the effect of acetylcholine, with drugs that help nerve cells to grow, with anti-oxidant drugs and with a variety of drugs whose basis of action is not properly understood, such as extracts of Gingko biloba.

It is not likely that any drugs that markedly slow down progression of the disease will become available within the next 10 years. The trials of preventative treatments, such as vitamins, anti-inflammatory drugs, or oestrogen hormone replacement therapy, will take several years to complete before any advice can be given about prevention.