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The
Human Genome
Genetic Testing for Alzheimer's Disease
Pamela S. Board, MS, CGC; Joann N. Bodurtha,
MD, MPH
My mother is getting more forgetful. I want her to have the genetic
test for Alzheimer." This woman's statement raises
questions both about the utility of genetic testing in this situation
and about individual autonomy. Is genetic testing appropriate and,
if so, which test? Who should make the decision about pursuing
testing? Alzheimer disease is the most common form of dementia in
North America and Europe. It is characterized by slowly progressive
dementia
and diffuse cerebral atrophy on neuroimaging studies. Although
a diagnosis of Alzheimer cannot be fully confirmed until autopsy,
it is estimated that a clinical diagnosis of possible or probable
Alzheimer will be correct about 80% to 90% of the time. Establishing
a diagnosis of Alzheimer requires ruling out other, potentially
treatable, forms of dementia including vitamin B12 deficiency and
depression. Most often, Alzheimer appears to be a sporadic condition.
However, familial forms have been identified. The pattern of inheritance
for familial Alzheimer is autosomal dominant. A detailed family
history including information about the ages of onset of dementia
for affected relatives can help differentiate familial Alzheimer
from the sporadic form. Clinically and pathologically, the forms
appear the same.
About 2% of Alzheimer disease can be described
as early-onset familial Alzheimer (frequently defined as before
age 65 years). Three genes
have been identified to date: amyloid precursor protein (APP),
presenilin 1 (PSEN1), and presenilin 2 (PSEN2). It is likely that
there are other genes that have not yet been identified. These
known genes are highly penetrant, meaning that a person receiving
a mutated (changed) copy of the gene will be expected to eventually
develop Alzheimer unless death occurs from some other cause before
the onset of symptoms. Within each of these genes, there are several
possible disease-causing mutations. Mutational analysis is available
on a limited basis commercially and through some research protocols.
The goal of this testing is often to identify a gene change in
the affected individual so that family members may consider presymptomatic
testing. There is no cure for Alzheimer and there is currently
no treatment known to prevent the onset of symptoms among individuals
carrying disease-causing mutations, although research is ongoing.
Therefore, presymptomatic testing should only be pursued under
an established protocol addressing the psychological impact of
the testing, possible changes in family dynamics, financial issues,
and the potential for discrimination in the workforce or in obtaining
life or health insurance. Similar issues arise with other presymptomatic
testing particularly for Huntington disease; therefore, Alzheimer
testing protocols often follow a "Huntington model" involving
specialists from genetics, psychiatry, and neurology.
A more widely
available genetic test for Alzheimer is the variant called APOEe4
of the gene coding for apolipoprotein E. This variant
appears to convey a genetic susceptibility to Alzheimer rather
than to actually cause the condition. The presence of this variant
does not indicate that an individual definitely has Alzheimer
or that he or she will develop it in the future. Conversely, many
individuals with Alzheimer will not have this variant, so its
absence
does not rule out Alzheimer. This testing, therefore, has the
potential to raise anxiety needlessly or to provide false reassurance.
As
such, the American College of Medical Genetics/American Society
of Human Genetics Working Group on APOE and Alzheimer Disease
recommended that this not be used for presymptomatic testing.1
Additionally,
the usefulness of APOE testing in confirming a diagnosis of Alzheimer
may be limited. The presence of the APOEe4 genotype has been noted
in individuals with other forms of dementia
such as Pick disease, so this genotype does not appear entirely
specific for Alzheimer. A tentative diagnosis of Alzheimer in the
presence of clinical symptoms and two copies of the APOEe4 variant
will be accurate about 97% of the time, but it is much more common
for an individual to have only one copy of the variant. Detection
of only one copy will not necessarily result in a significant increase
in diagnostic accuracy as compared with clinical evaluation. Additionally,
the test results would not necessarily change clinical management.
Given these limitations, the determination of one's APOE
status is not likely to be useful for broad population screening
but may be beneficial for some individuals.
The testing may eventually
become more broadly beneficial if therapeutic interventions are
developed in response to one's genetic
make-up (genotype). It is increasingly becoming apparent that a
person's genotype influences responses to medications. Perhaps
there will eventually be treatments geared toward one's APOE
status and/or the presence of one of the highly penetrant mutations
in other genes. Until that time, the benefit of genetic testing
may largely be in determining one's eligibility to participate
in clinical trials.
However, a person with Alzheimer, by definition,
has dementia. Therefore, the provider must not only assess whether
genetic testing
might be appropriate, but must also assess whether the individual
is competent to make an informed decision about testing. In their
position statement entitled "Respect for Autonomy," the
Alzheimer's Association states, "Diagnosis of Alzheimer's
disease alone is not an indication of incompetence." They
also emphasize that competency is task-specific rather than global.
The Association encourages the use of advanced directives so that,
as an individual with Alzheimer becomes more incapacitated, a proxy
may make decisions about medical care and possibly research. In
his recent article, Karlawish discusses in more detail the involvement
of adults with cognitive impairment in research protocols.2
A woman
has stated that her mother is getting more forgetful. The woman
has requested complex testing that may not directly benefit
her mother at this time. An appointment with both individuals present
would be recommended to assess the woman’s reasons for wanting
the testing; her mother's understanding of the risks, benefits,
and limitations of the testing; and whether the daughter, if serving
as a proxy, is acting in her mother's best interest.
Pamela S. Board, MS, CGC, is a research assistant,
and Joann
N. Bodurtha, MD, MPH, is professor of human genetics, pediatrics,
and obstetrics, both in the Department of Human Genetics, Virginia
Commonwealth University,
Richmond.
References
- Statement on use of apolipoprotein E testing for Alzheimer
disease. American College of Medical Genetics/American Society
of Human Genetics Working Group on ApoE and Alzheimer disease.
JAMA. 1995;274(20):1627-1629.
- Karlawish JH. Research involving cognitively impaired adults.
N Engl J Med. 2003;348(14):1389-1392.
Resources
Acknowledgement
This paper was written in memory of Lorna
M. Phelps, MSSW, CGC, friend and colleague. back to top
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