Genetics and Alzheimer's Disease
Genes play a complex and not yet fully understood role in all living things. Their part in Alzheimer's Disease is no exception. The more researchers learn about Alzheimers Disease, the more they become aware of the important function genes play in the development of Alzheimers Disease. Recent excitement has centered around the discovery of the relationship between the apolipoprotein E (apoE) gene and Alzheimers Disease.
Like recipes, genes provide instructions about how to make something, indicating what ingredients go in and in what order. But, the environment (things outside the body like food, the air we breathe, or chemicals we are exposed to) and processes inside the body determine which ingredients are available and in what forms and quantities.
Along with environmental influences, genes and processes inside the body combine to do more than just determine eye and hair color and other traits inherited from our parents. For example, genes ensure that we have two hands and can use them to do things, like play the piano. In almost every case, nature (genes) and nurture (including the physical and chemical environment) work together to shape all living things.
Genes alone are not all-powerful. Most genes can do little until spurred on by other substances. Although they are necessary in their own right, genes basically wait inside the cell's nucleus (control center) for other molecules to come along and read their messages.
Each of these messages is used to build a certain protein. Genes may build a protein correctly or incorrectly, depending on the content of the DNA (deoxyribonucleic acid) message. A gene can produce a faulty protein if it has one or more mutations (defects) in its DNA. Faulty proteins can lead to cell malfunction, disease, and death.
Within the nucleus of every human cell, two long, thread-like DNA strands encode the instructions for making all proteins needed for life. Each cell holds more than 50,000 different genes found on 46 chromosomes of tightly coiled DNA. Each DNA strand bears four types of coding molecules or bases. The sequence of bases in a gene is the code for making a protein.
Alzheimer's Disease: Not a Single-Gene Disorder
Diseases such as cystic fibrosis, muscular dystrophy, and Huntington's Disease are single-gene disorders. If a person inherits the gene that causes one of these disorders, he or she surely will get the disease, unless it is prevented by other means. Alzheimers Disease, on the other hand, is not a single-gene disorder. More than one gene mutation can cause Alzheimers Disease , and genes on multiple chromosomes are involved. Sometimes, two genes--one from each parent--are needed for a person to get the disorder.
The two basic types of Alzheimers Disease are familial and sporadic. Familial Alzheimers Disease (FAD) is a rare form of Alzheimers Disease, affecting less than 10 percent of Alzheimers Disease patients. It is associated with gene mutations on chromosomes 1, 14, and 21. FAD is the result of a certain inheritance pattern called autosomal dominant. In this pattern, all offspring in the same generation have a 50/50 chance of developing Alzheimers Disease if 1 of their parents had it. FAD occurs in younger people (usually before age 60) than sporadic Alzheimers Disease does.
ApoE in Sporadic Alzheimer's Disease
Sporadic Alzheimers Disease usually occurs later in life, is far more common than FAD, and appears to be related to the apoE gene found on chromosome 19. ApoE comes in several different forms or alleles, but three occur most frequently. People inherit one allele (apoE2, apoE3, or apoE4) of the apoE gene from each parent. People with both apoE3 and apoE4 alleles (E3/E4) are affected by both alleles.
Having one or two copies of the E4 allele increases a person's risk of getting Alzheimers Disease. That is, having the E4 allele is a risk factor for Alzheimers Disease. But, it does not mean that Alzheimers Disease is certain. Having one or two E4 alleles of the apoE gene increases a person's risk of Alzheimers Disease, but not to 100 percent. Some people with two copies of the E4 allele (the highest risk group) have not developed the disease, and others with no E4s have. Scientists have yet to determine the exact degree of risk of Alzheimers Disease for any given person based on apoE status.
Medical tests are designed for various purposes. Some tests can indicate susceptibility (the risk or likelihood of getting a disease); some help confirm diagnoses, and others assist in planning or monitoring treatment. In an effort to prevent disease, physicians test some people without symptoms to predict who might develop a given medical problem. For people with Alzheimers Disease symptoms, doctors try to rule out other disorders and determine, as accurately as possible, what is causing the symptoms. If no other cause is found, Alzheimers Disease is diagnosed.
A blood test is available to identify which apoE alleles a person has, because apolipoprotein also is associated with an already well-studied condition, heart disease. However, this blood test cannot tell people whether they will develop Alzheimers Disease, or when. Instead of a yes or no answer, the best information a person can get from this genetic assessment for apoE is maybe or maybe not. Although some people want to know whether they will get Alzheimers Disease later in life, this type of prediction is not yet possible. In fact, some researchers believe that apoE tests or other screening measures may never be able to predict Alzheimers Disease with 100 percent accuracy.
In the research setting, apoE testing is a tool that can identify study volunteers who may be at risk of getting Alzheimers Disease. In this way, researchers can look for early brain changes. This test also helps researchers compare the effectiveness of treatments for patients with different apoE statuses. Several researchers believe that the apoE test is most useful for studying Alzheimers Disease risk in large groups of people and not for determining one person's individual risk. Predictive screening in otherwise healthy people will be useful when effective ways to treat or prevent Alzheimers Disease are available.
Concerns About Confidentiality
ApoE testing, and indeed all genetic testing, raises ethical, legal, and social questions for which we have few answers. ApoE information gathered for research purposes generally can be protected by confidentiality laws. On the other hand, information obtained in apoE testing may not be protected as confidential once it is part of a person's medical records. Thereafter, employers, insurance companies, and other health care organizations could gain access to this information; and discrimination could result. For example, employment opportunities or health or long-term care insurance premiums could be affected. Little is known about how stigma associated with an increased risk for Alzheimers Disease may affect people's families and their lives.
Public Policy on ApoE Testing
Scientists, ethicists, and other health professionals joined together in October of 1995 to write a public policy statement about the appropriateness of apoE testing and the role of genetic counseling for Alzheimers Disease. Discussions leading to the statement took place at a conference in Chicago, Illinois, sponsored by the National Institute on Aging (NIA) and the Alzheimer's Association.
The public policy statement supports the use of apoE testing for diagnostic purposes only in conjunction with other tests during medical evaluations of patients who show Alzheimers Disease symptoms. It recommends not using apoE testing as a patient screening (predictive) method. Conference participants said that further research and agreement about confidentiality are needed before they will recommend routine apoE testing.
Depending on the study, research volunteers may have the opportunity, during genetic counseling, to learn the results of their apoE testing. The meaning of these results is complex. Since the results of apoE testing can be hard to understand, and more importantly, devastating to those tested, the NIA and the Alzheimer's Association recommend that research volunteers and their families receive genetic counseling before and after testing.
People who learn through testing that they have an increased risk of getting Alzheimers Disease may experience emotional distress and depression about the future because there is no effective way to prevent or cure the disease.
Through counseling, families can learn about the genetics of Alzheimers Disease, the tests themselves, and possible meanings of the results. Due to privacy, emotional, and health care issues, the primary goal of genetic counseling is to help people with Alzheimers Disease and their families explore and cope with the consequences of such knowledge.
For the free fact sheet, Genetic Counseling: Valuable Information for You and Your Family, you may write, fax, or e-mail the National Society for Genetic Counselors (NSGC). Their address is:
NSGC, Executive Office
The NSGC does not provide information about specific genetic disorders.
Many questions remain about the usefulness of apoE testing in non-research settings. Some researchers believe that the best use of apoE testing will be as one in a combination of methods for assessing patients (including family history, neurological tests, needs assessments, etc.) to help doctors make informed treatment recommendations.
Experts still do not know how limited information about Alzheimers Disease risk can benefit people. Among the issues are privacy and confidentiality policies related to genetic information and Alzheimers Disease, and the small number of genetic counselors now trained in neurodegenerative disorders.
Learning more about the role of apoE in the development of Alzheimers Disease may help scientists identify who would benefit from prevention and treatment efforts. Age, still the most important known risk factor for Alzheimers Disease, continues to be associated with the disease even when no known genetic factors are present. Research focusing on advancing age may help explain the role that other genes play in most Alzheimers Disease cases. For example, recent research suggests that certain alleles of other as yet unidentified genes also may increase risk in late-onset cases.
Scores of Alzheimers Disease researchers are studying the genetics of Alzheimers Disease. In addition, researchers, ethicists, and health care providers are developing policies about the appropriate use of genetic testing and counseling for Alzheimers Disease.
For More Information
Accurate, current information about Alzheimers Disease and its risk factors is important to patients and their families, health professionals, and the public. The Alzheimer's Disease Education and Referral (ADEAR) Center is a service of the NIA and is funded by the Federal Government. The ADEAR Center offers information and publications about diagnosis, treatment, patient care, caregiver needs, long-term care, education and training, and research related to Alzheimers Disease. Staff respond to telephone and written requests and make referrals to national- and State-level resources.
The ADEAR Center distributes two free fact sheets about apoE and heredity:
From the University of California, San Diego Alzheimer's Disease Research Center. Describes the relationship between Alzheimers Disease and apoE.
From the Alzheimer Society of Canada. Discusses current knowledge about family history and Alzheimers Disease, FAD, sporadic Alzheimers Disease, and apoE4; and what scientists are doing to learn more about each.
For more information about genetics and Alzheimers Disease, contact:
A gene on chromosome 19 involved in making apoE, a substance that helps carry cholesterol in the bloodstream. ApoE is considered a "susceptibility" gene for Alzheimers Disease and appears to influence the age of onset of the disease. However, it is not the sole cause of Alzheimers Disease. No cause and effect relationship exists between a person's apoE status and the development of Alzheimers Disease.
Rod-like structures in every cell of the human body. Chromosomes carry genes. All healthy people have 46 chromosomes in 23 pairs. Usually, people receive one chromosome in each pair from each parent.
Basic units of heredity that direct almost every aspect of the construction, operation, and repair of living organisms. Every human cell has from 50,000 to 100,000 genes arranged like beads on a string (chromosome). Each gene is a set of biochemical instructions that tells a cell how to assemble one of many different proteins. Each protein has its own highly specialized role to play in the body.
Permanent changes to genes. Once such change occurs, it can be passed on to children. The relatively rare, early-onset familial Alzheimers Disease is associated with mutations in genes on chromosomes 1, 14, and 21.
Cells translate genetic information into specific proteins. Proteins determine the physical and chemical characteristics of cells and therefore organisms. Proteins are essential to all life processes.
Source: National Institute on Aging, August 1997
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