Alzheimer's Disease
Genetics
Contents
Genes play a complex
and not yet fully understood role in all living things. Their
part in Alzheimer's disease (AD) is no exception. The more researchers
learn about AD, the more they become aware of the important function
genes play in the development of AD. Recent excitement has centered
around the discovery of the relationship between the apolipoprotein
E (apoE) gene and AD.
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.
Graphical
Representation -- Anatomy of Genes
[Illustration] Anatomy
of Genes -- Shows a cell, mitochondria, the cell membrane, a
chromosome, the DNA double helix, DNA chains, linked sequence
pairs of bases, paired bases, and the four bases (cytosine,
adenine, quanine, and thymine). 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. AD, on the other hand, is not a single-gene
disorder. More than one gene mutation can cause AD, 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 AD are familial and sporadic. Familial AD (FAD) is a rare
form of AD, affecting less than 10 percent of AD 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 AD if 1 of their
parents had it. FAD occurs in younger people (usually before
age 60) than sporadic AD does.
ApoE in Sporadic
Alzheimer's Disease
Sporadic AD 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
AD. That is, having the E4 allele is a risk factor for AD. But,
it does not mean that AD is certain. Having one or two E4 alleles
of the apoE gene increases a person's risk of AD, 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 AD 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 AD 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, AD 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 AD, 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 AD 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
AD 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 AD. 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 AD 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 AD are available.
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 insurance premiums could be affected.
Little is known about
how stigma associated with an increased risk for AD may affect
people's families and their lives.
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 AD. 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 AD 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
AD 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 AD, 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 AD 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
233 Canterbury Drive
Wallingford, PA 19086-6617
610-872-1192 (fax)
mailto:"beansgc@aol.com"(e-mail)
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 AD risk can benefit people.
Among the issues are privacy and confidentiality policies related
to genetic information and AD, and the small number of genetic
counselors now trained in neurodegenerative disorders.
Learning more about
the role of apoE in the development of AD may help scientists
identify who would benefit from prevention and treatment efforts.
Age, still the most important known risk factor for AD, 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 AD 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 AD researchers
are studying the genetics of AD. In addition, researchers, ethicists,
and health care providers are developing policies about the
appropriate use of genetic testing and counseling for AD.
Accurate, current information
about AD 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 AD. Staff respond to telephone and written
requests and make referrals to national- and State-level resources.
The ADEAR Center
distributes two other free fact sheets about apoE and
heredity:
- Alzheimer's
Disease and Apolipoprotein E
From the University of California, San Diego Alzheimer's Disease
Research Center. Describes the relationship between AD and
apoE.
- Alzheimer's
Disease and Heredity
From the Alzheimer Society of Canada. Discusses current knowledge
about family history and AD, FAD, sporadic AD, and apoE4;
and what scientists are doing to learn more about each.
For more information
about genetics and AD, contact:
ADEAR
Center
PO Box 8250
Silver Spring, MD 20907-8250
800-438-4380 (toll-free)
301-495-3334 (fax)
mailto:"adear@alzheimers.org" (e-mail)
http://www.alzheimers.org/adear
- Alleles
Alternate forms of the same gene. Two or more alleles can
shape each human trait. Each person receives two alleles,
one from each parent. This combination is one factor among
many that influences a variety of processes in the body. On
chromosome 19, the apolipoprotein E (apoE) gene has three
common forms or alleles: E2, E3, and E4. Thus, the possible
combinations in one person are E2/2, E2/3, E2/4, E3/3, E3/4,
or E4/4.
- ApoE Gene
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 AD and appears to influence the
age of onset of the disease. However, it is not the sole cause
of AD. No cause and effect relationship exists between a person's
apoE status and the development of AD.
- Chromosomes
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.
- Genes
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.
- Genetic Mutations
Permanent changes to genes. Once such change occurs, it can
be passed on to children. The relatively rare, early-onset
familial AD is associated with mutations in genes on chromosomes
1, 14, and 21.
- Proteins
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.
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
National Institutes of Health
National Institute on Aging
Published
in August 1997
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