Alzheimer's Disease and Genetics: The role of genes in Alzheimer's disease
What is Alzheimer's disease?
Alzheimer's disease is the most common of a large group of disorders known as "dementias." It is an irreversible disease of the brain in which the progressive degeneration of brain cells causes thinking ability and memory to deteriorate. Alzheimer's disease also affects behaviour, mood and emotions, and the ability to perform daily living activities.
There is currently no cure for Alzheimer's disease, but there are treatment options and lifestyle choices that can slow its progression and, within the next five years, treatments are expected that may well stop the disease in its tracks! Also, the pursuit of new research strategies should one day help restore some lost function and memory.
Alzheimer's disease progresses through early, middle and late stages before reaching the final end of life stage. However, identifying the transition from one stage to another is often difficult. Not only does the disease usually progress slowly, but the symptoms related to each stage tend to overlap and the order in which they appear and how long they last varies from person to person.
The duration following diagnosis is usually seven to ten years. However, when the diagnosis is delayed, as it may be if the affected person fails to see a doctor early on, the disease duration is shorter than this. Conversely, as the ability to diagnose Alzheimer's disease improves and people become more willing to be assessed, survival times following diagnosis are lengthening.
"Related dementias" resemble Alzheimer's disease in that they also involve a progressive degeneration of brain cells that is currently irreversible. They include the dementia associated with Vascular Dementia (the second most common dementia after Alzheimer's disease), Frontotemporal Dementia, Creutzfeldt-Jakob Disease, Lewy body Dementia, Parkinson's disease, and Huntington disease.
Family History and Genetics
Familial Alzheimer's disease (FAD)
A very small percentage of people with Alzheimer's disease (5-7%) have Familial Alzheimer's disease or FAD (formerly known as "early onset Alzheimer's disease"). At some point in their family history certain genes mutated and developed the abnormal characteristics that cause FAD. These inherited genes have a powerful influence: if one parent has FAD, each child has a 50 % chance of inheriting the disease, and with two parents with FAD, all their children will go on to develop Alzheimer's disease in adulthood. These inherited genes differentiate FAD from the more common sporadic form of Alzheimer's disease, but the disease itself is identical.
Sporadic Alzheimer's disease
The sporadic form of Alzheimer's disease (which used to be called "late onset Alzheimer's disease"), was formerly assumed to have no family linkages. However, it's now known that a person with a direct relative (parent or sibling) with Alzheimer's disease has a three times greater chance of developing the disease than someone who does not .1 The risk increases further if both parents have the disease. So aside from the FAD-related genes there are Alzheimer's disease-related genetic factors shared by family members.
New research is revealing more and more genetic risk factors for the sporadic form of Alzheimer's disease. That means that these genes are found to a greater extent among those with the disease, though they are also found in people without Alzheimer's disease. People with these genetic risk factors are not in the same high-risk category as people who have the mutated genes responsible for FAD. In fact, the risk associated with any one of these newly discovered genetic risk factors is lower than the risk associated with having a parent with the sporadic form of the disease (with the exception of the apoE4 gene discussed below).
ApoE4 Gene
This gene is the most important genetic risk factor for the sporadic form of Alzheimer's disease. ApoE genes regulate the production of a protein that helps carry cholesterol and other fats in the blood to the cells of the body. Of the three variants of the apoE gene (apoE2, apoE3 and apoE4), the apoE4 variant is associated with an increased risk of Alzheimer's disease.
In our cells (except ova and sperm) all genes are paired, one being contributed by the father and one by the mother. If a person's pair of apoE genes includes one apoE4 gene, they have three times the normal risk of developing Alzheimer's disease. If a person carries two apoE4 genes, half of all of them will develop Alzheimer's disease at age 65. Unlike the genes responsible for FAD, the 3 variants of the apoE gene are not regarded as full mutations but only as minor variations that have developed over time. People with no apoE4 genes can still get Alzheimer's disease and people with two apoE4 genes will not necessarily get the disease.
Genes are not the complete answer
Although one's genes are present from birth, they can't cause the disease on their own. Alzheimer's disease seems to develop when the combined effects of the various risk factors cross a certain threshold and overwhelm the natural self-repair mechanisms in the brain that normally help to maintain nerve cells in a healthy state. The most important risk factor is aging. Even in FAD a minimum age needs to be reached for Alzheimer's disease to develop (family members do not get the disease in their teenage years or even in their 20s). It is well-established that aging can impair the body's self-repair mechanisms. And of course, many of the risk factors increase as one ages, such as blood pressure, stress, and obesity.
For more information on risk factors, please refer to Alzheimer's Disease and Risk Factors.
Alzheimer's disease and genetic testing
Predictive genetic testing can sometimes help identify whether a person has a high or low chance of developing Alzheimer's disease. In particular, the presence of the apoE4 gene gives an indication of susceptibility for developing Alzheimer's disease in the sporadic form. However, there is presently no reliable genetic test for the common sporadic form of Alzheimer's disease. Therefore, for the vast majority of families, predictive testing is not a recommended option for a variety of reasons, the most important perhaps being that at best it can only point to susceptibility; the testing can never predict whether a person will or will not get Alzheimer's disease.
For the small number of people for whom there are clear indications that the disease is transmitted through the family, predictive testing is often recommended though entirely at the discretion of the person concerned. In these instances it is important that an experienced clinical geneticist* is involved in the required medical assessment. The aim here is always to identify families in which Familial Alzheimer's Disease (FAD) can be reliably assessed.
If the person suspected to have had Alzheimer's disease is no longer living, a retrospective diagnosis can often be proposed following a careful review of autopsy reports and medical records, if they are available.
*Contact your local Alzheimer Society, the Canadian Association of Genetic Counsellors or your family physician for information about the availability of genetics clinics in your area. It is important to note that at present, genetic risk assessment for Alzheimer's disease can be performed in Canadian clinics but this would only be done after discussion between the clinic and the doctor requesting the assessment.
What
are the implications of testing for genetic factors?
The decision to participate in genetic testing is a personal one. Prior to consenting to genetic assessment or testing, it is important to consider the psychological, legal, social and ethical implications of genetic testing. If the decision is made that genetic testing is appropriate, the person should:
- give
informed consent to the testing
- receive
counselling from a trained professional
- be
guaranteed that the test results will remain confidential
Need
further information?
For
more information on the ethical questions raised by testing,
refer to Genetic Testing and Alzheimer's Disease, part
of the Alzheimer Society of Canada's Ethical
Guidelines. Copies can also be obtained from your local
Alzheimer Society.
Families
with a history of Alzheimer's disease can inquire about participating
in research through the Familial Alzheimer Disease Registry,
Centre for Research in Neurodegenerative Diseases, Tanz
Neuroscience Building, University of Toronto, 6 Queen's
Park Crescent West, Toronto, ON M5S 3H2; www.utoronto.ca/crnd;
e-mail: crnd.info@utoronto.ca or telephone 416-978-6912.
Footnotes
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Here is a useful way of looking at the relative risk: of 100 people with no defined genetic risk factor, 5 will get Alzheimer’s disease at age 65 (and 95 will not). Of 100 people, each with a parent with Alzheimer’s disease, 15 will get Alzheimer’s disease at age 65 (and 85 will not).
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