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March 22, 2009

Genes and Alzheimer's disease

Alzheimer's disease is the most common form of dementia. Medical research has identified four genes that influence disease development. Three of these genes affect younger people, and one affects older people. Early onset Alzheimer's disease. The three genes that have a major effect on risk of Alzheimer's disease are the amyloid precursor protein (APP) gene and two presenilin genes (PSEN-1 and PSEN-2). People with any of these genes tend to develop the disease in their 30s or 40s, and come from families in which several members also have early onset Alzheimer's disease.
The prevalence of these genes is as follows:
A small number of families worldwide have a genetic fault on chromosome 21 in the APP gene, which affects production of the protein amyloid.
Amyloid build-up in the brain has been linked to Alzheimer's disease.
A slightly larger number of families carry a fault on chromosome 14 (PSEN-1) causing early onset familial Alzheimer's disease. A very small group of families (mainly in the United States) has a fault on chromosome 1 (PSEN-2), causing early onset familial Alzheimer's disease. The important thing to remember is that all of these risk genes are very rare in the population. Indeed, they account for less than one in 1000 cases of Alzheimer's disease.
On average, half of the children of a person with one of these rare genetic defects will inherit the disease. Probably all those who inherit the genetic defect develop Alzheimer's disease at a comparatively early age. People who do not inherit the disease cannot pass it on.If you have two or more close relatives (a close relative is defined as a parent, brother or sister) who developed Alzheimer's disease before the age of 60, your GP could advise you about genetic counselling and testing and refer you to a geneticist, if appropriate.
Late onset Alzheimer's disease occurs over the age of 65 and is the most common form of Alzheimer's disease, accounting for over 99 per cent of cases. Currently, only one gene is known to influence disease development: apolipoprotein E (APOE). The effects of the APOE gene appear more subtle than the genes affecting early onset Alzheimer's, and even individuals with two copies of the risky form of the gene are not certain to develop Alzheimer's disease. This gene comes in three forms: APOE2, APOE3, APOE4. We all have two copies of the gene, and these may be the same as each other or different.
APOE4 is associated with a higher risk of Alzheimer's. About a quarter of the population inherits one copy of the APOE4 gene. This increases their risk of developing Alzheimer's disease by up to four times. • Two per cent (2%) of the population gets a 'double dose' of the APOE4 gene -one from each parent, which increases the risk of developing Alzheimer's disease by about ten times. • Sixty per cent (60%) of the population has a 'double dose' of the APOE3 gene and is at 'average risk'. About half of this group develops Alzheimer's disease by their late 80s.
The APOE2 form of the gene is mildly protective against the development of Alzheimer's disease. Eleven per cent of the population has one copy of APOE2 together with a copy of APOE3, and one in 200 has two copies of APOE2. Some researchers think that APOE4 does not affect whether a person will get the disease but when they get it. This means that people with APOE4 develop the disease before people with APOE2.
There are more genes influencing the risk of developing Alzheimer's disease that still remain to be found. Recent scientific developments allow researchers to test every gene in the human genome for a relationship with Alzheimer's disease. We anticipate new discoveries of susceptibility genes in the next few years.
Vascular dementia is the second most common form of dementia. There are a number of very rare forms of the disease that are caused by genetic mutations. For example, mutations in a gene called Notch3 result in a form of vascular dementia known as cerebral automsomal dominant arteriopathy with subcortical infarcts and leukoencephalopahth (CADASIL). Variation in the APP gene, which also contains variants responsible for rare cases of Alzheimer's disease, leads to a form of vascular dementia called heritable cerebral haemorrhage with amyloidosis (HCHWA). However, it is important to remember that these forms of the disease are very rare. There are no established direct genetic causes for the more common forms of vascular dementia, but the APOE gene (described above) is a risk factor for vascular dementia as well as for Alzheimer's disease. There are known genes that contribute to some of the risk factors for vascular dementia, such as high cholesterol levels, high blood pressure and diabetes. People with Down's syndrome are at particular risk of developing Alzheimer's disease. Different studies have suggested different rates of dementia among people with Down's syndrome, but it could be as high as 50 per cent of people with Down's syndrome in their 60s.
Huntington's disease is a progressive hereditary disease caused by a particular gene. The course of the disease varies for each person, and dementia can occur at any stage. Some other forms of dementia can be inherited. Some people with fronto-temporal dementia (such as Pick's disease), or with Creutzfeldt-Jakob disease and similar conditions have a very strong family history of the disease. In some of these cases the genetic link has been found. For example, some families with inherited fronto-temporal dementia have one of a number of faults on the tau gene. However, these inherited forms of dementia are rare.
Genetic testing - either for family members or for whole populations - is not a straight forward issue. Individuals need to think carefully before deciding to take a genetic test. The experience might be very difficult emotionally, may not provide conclusive results either way, and may cause practical difficulties. On the positive side, genetic testing might: identify people who might benefit from drugs used to treat Alzheimer's disease; help genetic researchers understand the disease better and so lead to improved treatment; help people to plan for the future.
However, it may create problems, for the following reasons: A genetic defect cannot be repaired, and effective treatment is not yet generally available, so a test might raise anxiety without offering a clear course of action; the genetic test for a higher risk of late onset Alzheimer's disease (APOE4) cannot accurately predict who will develop the disease. Testing positive does not mean a person will definitely develop the disease, while testing negative does not guarantee that they will not. People testing positive could face discrimination affecting their ability to buy property, get insurance or plan financially for their old age, although there is a moratorium on the use of genetic information by insurance companies
Gene 'has key schizophrenia role'
Two studies have pinpointed a single gene as key to the development and treatment of schizophrenia. A US team from the Howard Hughes Medical Institute found that a mutated version of the DISC1 gene disrupts the growth and development of brain cells. And a team from the University of Edinburgh showed that the gene affects how patients respond to treatment.
DISC1 Gene. Linked in the early 1990s to mental illnesses prevalent in a large Scottish family. Over five generations many family members had developed schizophrenia, bipolar disorder, and other mood disorders. Each family member diagnosed with mental illness also carried a mutated copy of DISC1. The condition is a common form of mental illness, affecting up to 1% of adults worldwide. Several researchers showed that DISC1 plays a key role in normal brain development and the growth of individual neurons. However, carrying the wrong version of the gene can make this process go awry. Working on mice, they showed that DISC1 was active, both in cells taken from embryos and in brain stem cells taken from adult mice. When DISC1 levels were reduced in adult mice their brain cells failed to divide, and the animals developed symptoms mimicking schizophrenia in humans.
Further tests showed that DISC1 acts like lithium, a drug commonly prescribed as mood stabiliser to patients with mental illness, inhibiting the action of a key chemical in the brain. When mice with depressed levels of DISC1 were treated with this chemical, their symptoms began to improve.

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