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Impact of DNA Testing for Early-Onset Familial Alzheimer Disease and Frontotemporal Dementia
Ellen J. Steinbart, RN, MA;
Corrine O. Smith, MS;
Parvoneh Poorkaj, PhD;
Thomas D. Bird, MD
Arch Neurol. 2001;58:1828-1831.
ABSTRACT
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Background DNA testing of persons at risk for hereditary,
degenerative neurologic diseases is relatively new. Only anecdotal
reports of such testing in familial Alzheimer disease (FAD) exist, and
little is know about the personal and social impact of such testing.
Methods In a descriptive, observational study, individuals at
50% risk for autosomal dominant, early-onset FAD or frontotemporal
dementia with parkinsonism linked to chromosome 17 underwent DNA
testing for the genetic mutations previously identified in affected
family members. Individuals were followed up for  to 3 years
and were interviewed regarding attitudes toward the testing process and
the impact of the results.
Results Twenty-one (8.4%) of 251 persons at risk for FAD or
frontotemporal dementia requested genetic testing. The most common
reasons for requesting testing were concern about early symptoms of
dementia, financial or family planning, and relief from anxiety. Twelve
individuals had positive DNA test results, and 6 of these had early
symptoms of dementia; 8 had negative results; and 1 has not yet
received results. Of 14 asymptomatic individuals completing testing, 13
believed the testing was beneficial. Two persons reported moderate
anxiety and 1 reported moderate depression. As expected, persons with
negative test results had happier experiences overall, but even they
had to deal with ongoing anxiety and depression. Thus far, there have
been no psychiatric hospitalizations, suicide attempts, or denials of
insurance.
Conclusions Genetic testing in early-onset FAD and
frontotemporal dementia can be completed successfully. Most individuals
demonstrate effective coping skills and find the testing to be
beneficial, but long-term effects remain unknown.
INTRODUCTION
DNA TESTING for genetic diseases is a relatively new and controversial enterprise.
The benefits of relieving anxiety and being better able to plan for the
future must be weighed against the potential risks of emotional
depression, compromise of insurance and employment, and social
isolation.1, 2 Formal evaluation of such testing is largely
available only for breast cancer and Huntington disease (HD).
However, even with these diseases, follow-up is relatively short and
the outcomes are only partially evaluated. There is an urgent need for
additional information in this field.3
The University of Washington Alzheimer Disease Research Center,
Seattle, has ascertained several families with specific mutations
associated with autosomal dominant early-onset familial Alzheimer
disease (FAD) and frontotemporal dementia (FTD) with parkinsonism
linked to chromosome 17. Several individuals in these families
requested detailed genetic counseling and DNA testing. We evaluated the
impact of this testing on their lives.
PARTICIPANTS AND METHODS
In the course of our research on inherited dementia, we
ascertained more than 20 families with specific mutations in the
following genes: amyloid precursor protein, presenilin 1, presenilin 2,
and tau. Many of the pedigrees have been published.4, 5, 6, 7, 8
Lifetime penetrance is known to be greater than 95% in affected
members of these kindreds. A follow-up study of persons at risk for the
disease genes in these families was approved by the University of
Washington Human Subjects Review Committee. Two hundred fifty-one
family members received a letter describing the genetic findings in the
family, discussing the availability of DNA testing, and requesting that
individuals contact the University of Washington Alzheimer Disease
Research Center for further information. Those requesting further
information received a telephone call from one of us (E.J.S.) and a
booklet describing the potential risks and benefits of genetic testing.
This booklet followed the format of a booklet9 about
genetic testing in HD. It was indicated that the DNA testing must be
done in the context of formal genetic counseling according to a
previously published protocol.10, 11 Persons unable to
travel to Seattle (n = 11) had professional genetic
counseling locally. Two of us (E.J.S. and T.D.B.) communicated directly
with the local counselors through all phases of the testing.
To assess the effects of DNA testing, 11 persons completed a 5-page
questionnaire that provided demographic information and included
questions about attitudes toward the testing and the impact of the
results on their lives. The Impact of Event Scale (IES) and the
Hospital Anxiety and Depression Scale were also administered. The latter contains 14 questions, 7 relating to anxiety and 7
relating to depression.12 The sum of the individual scores
indicates an overall anxiety (range, 0-21) and depression (range, 0-21)
score. A score of 8 or 9 on either subscale is an indication of
borderline anxiety or depression, and a score of 10 or higher in either
subscale is an indication of definite anxiety or depression. The
validity and reliability of the Hospital Anxiety and Depression Scale
have been demonstrated previously.13, 14 The IES classifies
stress into 2 major categories: intrusion and avoidance.15
Intrusion refers to constantly experienced ideas, images, feelings, or
dreams. Avoidance refers to conscious denial of certain ideas,
feelings, or situations. The IES is a reliable self-report scale that
can be anchored to any specific life event, such as DNA testing for a
neurogenetic disease. Seven items form the intrusion subscale, with a
maximum score of 21, and 8 items form the avoidance subscale, with a
maximum score of 24. The items are scored by choosing 1 of 4 indicators
of occurrence of the specified event (never, seldom, often, and
continuously). The IES is especially useful in determining
how much a person worries about a disease process and the degree of
denial concerning the disease that is experienced by the individual.
This test has been particularly useful in assessing the distress
experienced by individuals undergoing DNA testing for
HD.13, 14
The small number of participants in this study and the subjectivity of
the data did not warrant statistical analysis. DNA mutation screening
for presenilin 1, presenilin 2, and tau were performed by previously
described methods.16, 17, 18 A positive test result indicates
that the individual carries the disease gene mutation and has a greater
than 95% chance of developing the condition at some point in their
lifetime.
RESULTS
The 251 mailed letters prompted 58 specific inquires about
DNA testing (23.1%); 21 persons (8.4%) decided to proceed with
genetic counseling and testing. Of this group, 16 persons from 9
families were at risk for FAD (10 with presenilin 2 and 6 with
presenilin 1 mutations) and 5 persons from 2 families were at risk for
FTD with parkinsonism linked to chromosome 17 tau mutations. The mean
age of disease onset in these families was 51.8 years (range, 30-75
years). There were 11 women and 10 men, with an average age
of 42.5 years and an average of 14 years of education. All persons had
an affected parent and were at 50% risk for inheriting the disease
gene. Additional demographic data are shown in Table
1.
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Table 1. Genetic Testing for Familial Dementia*
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Six persons requesting DNA testing were considered by their
families and physicians to probably be in the early stages of dementia. DNA testing was preformed in
collaboration with the physicians, and all 6 individuals had a positive
test result. In all 6 cases the results were considered useful in
helping to explain the cause of the early dementia and in allowing the
family and health care providers to tailor the diagnostic evaluation
and plan for the future. The mean ± SD age of the
symptomatic individuals was 48.0 ± 8.2 years.
The mean ± SD age of the 15 asymptomatic
individuals was 40.3 ± 11.3 years. Posttest follow-up
ranged from to 3 years. One of these persons received
genetic counseling and completed a questionnaire but decided to
postpone testing for 1 year; the testing process has not yet been
completed. Two persons received genetic counseling and had a blood
sample taken but postponed receiving their results for 2 years. Of 14
individuals receiving results, 8 had negative results and 6 had
positive results.
In the 12 asymptomatic persons completing a questionnaire, the 3
most common reasons for requesting DNA testing were financial planning
(n = 10), family planning (n = 8), and
relief from worry and anxiety (n = 9). Other
less frequently given reasons included travel or retirement planning,
career planning, possible effect on family relationships, and possible
eligibility for future treatment trials.
When asked, "Would you advise other persons in your situation to have
such testing?" 4 individuals with negative results and 1 with
positive results replied yes. All others said that they would give no
specific advice and that it would "be up to the individual." No
person answered the question no. However, as noted later herein, 1
individual with positive test results refused all further follow-up
evaluations.
All 8 persons receiving negative results expressed relief or
gratefulness. As expected, individuals with positive results were
disappointed, but they expressed the following feelings: this was an
"important and necessary life decision," "glad I know result for
planning," "ambivalent but glad to have knowledge," and "gives
me clear choices for the future." One person stated that the positive
test results "confirmed what I thought."
Three individuals scored moderately high on the anxiety subscale of the
Hospital Anxiety and Depression Scale (1 with positive and 2 with
negative DNA test results) (Table
2). Only 1 person had a
moderately high score on the depression subscale. This person had a
negative DNA test result but a past history of depression.
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Table 2. Impact of Genetic Testing
on 14 Asymptomatic Persons*
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On the IES, 5 persons had relatively high intrusion scores, suggesting
frequent daily thoughts about the disease. Four of these 5 persons had
negative DNA test results, 1 of whom still cares for an affected
mother.
Four persons had relatively high scores on the avoidance subscale of
the IES, suggesting a strong tendency to avoid thinking about the
disease. Two of these persons had a positive DNA test. The 2
individuals with the highest avoidance scores include one who postponed
receiving results for 2 years and another who has not yet received
results after a 1-year postponement.
Thus far, no asymptomatic person with a positive DNA test result has
lost employment or been denied insurance, to our knowledge. There have
been no psychiatric hospitalizations and no suicide attempts.
The testing affected the marriages of 3 persons. An individual
with positive test results separated from his or her spouse. A person
with negative test results proceeded with a divorce, and another with
negative results proceeded with plans for a second marriage. All 3
persons stated that the test results were a factor in these decisions.
The testing affected family planning in 3 individuals. A woman with
positive test results proceeded to have a first child. Another person
with positive test results had 1 child and decided not to have
additional children. Another person had a first child during a 2-year
hiatus between having the blood sample drawn and deciding to receive
the test information.
Two years after receiving a negative test result for FAD, 1 person had
high anxiety and intrusion scores on the IES. These scores were
associated with ongoing concerns and worries about AD in the family,
which had affected the father, a deceased brother, and a living
brother.
One individual who had positive test results for a tau mutation
was distressed with the result and requested no further evaluation or
contact from study personnel.
One individual had counseling and a blood sample drawn and then
postponed receiving the results for 2 years while "emotionally
preparing." When the result proved to be negative he or she stated,
"I was so convinced I carried the (abnormal) gene that I have to
retrain my mind to think differently . . . Now I have a future—I
take less of my anti-anxiety pills—my closest friends cried with
happiness."
A 57-year-old woman who had negative test results for FAD subsequently
wrote a one-woman play about her life that has been publicly performed
on several occasions. A major theme of this play is her family history
of AD and the impact of genetic testing on her life.
COMMENT
Detailed information about the psychosocial impact of genetic
testing is primarily available for only 2 diseases, namely, HD and
breast cancer.3 Testing for inherited forms of breast
cancer is different from testing for either HD or dementia. Treatment
and prevention options are available for persons with positive test
results for a BRCA (breast cancer gene) mutation, and breast
cancer does not cause degenerative brain disease. A large worldwide
follow-up study19 of persons undergoing genetic testing for
HD showed that persons generally coped reasonably well with the
results. However, in persons with positive test results for HD there
was a 2% frequency in approximately 2 years of serious psychiatric
distress, such as depression requiring hospitalization or a suicide
attempt.19, 20 These adverse events usually did not occur
immediately after testing but rather at a later date, when the
individual began to experience early symptoms of the disease.
There are several similarities among early-onset FAD, FTD, and
HD. All 3 are inherited, autosomal dominant, progressive, degenerative
neurologic diseases for which there are no dramatically effective
treatments. However, there are important differences that could affect
the perspective of family members toward these diseases. Huntington
disease has been known to be a genetic disease for more than 100 years,
and the potential risks and benefits of genetic testing have been
discussed in the HD community for at least 25 years. Specific genetic
knowledge about FAD and FTD is much more recent. Huntington disease has
a prominent movement disorder, is usually not associated with early
dementia, and has an average disease duration of approximately 15
years. Familial Alzheimer disease and FTD do not commonly have a
movement disorder, always begin as a dementing or aberrant personality
disorder, and typically have a shorter disease duration than HD. Also,
AD is a heterogeneous disease such that everyone in the general
population has a risk of eventually developing the disorder even if he
or she has negative test results for a specific FAD mutation. This is a
confounding variable not present in the genetic counseling of families
with HD. For all of
these reasons, attitudes toward genetic testing
in FAD and FTD cannot be assumed to be identical to or even similar to
those in HD.
Although the potential for genetic testing of asymptomatic persons in
families with FAD has been discussed,21 only 2 anecdotal
studies actually reported such testing. In a family from Sweden, a
person with positive test results for an amyloid precursor protein
mutation experienced more than 6 months of severe
depression.22 In an American family with an amyloid
precursor protein mutation, 2 siblings had negative and 1 had positive
test results.23 The individual with the positive test
result wrote a personal statement describing her anxiety and difficulty
coping with the results.24
Results of the present study should be considered preliminary because
of the small number of participants and the relatively short follow-up.
However, the following observations can be made:
- A relatively small number of persons at risk decide to actually
pursue DNA testing (8% in this study). This is similar to
recent experience with HD testing.25, 26 Thus, persons who
pursue genetic testing are a highly self-selected group, possibly
biased toward those most able to deal with the process and
results.27
- DNA testing can be of diagnostic benefit in evaluating persons at
risk for early-onset FAD who are in the initial stages of memory loss
and dementia and are from families with known autosomal dominant
mutations.
- Persons with negative DNA test results experience considerable
relief and have an affirmative attitude toward the testing. However,
even persons with negative test results might continue to experience
anxiety, depression, or both because of previous personal history or
ongoing involvement with the disease in the family. Negative test
results can affect future behavior.
- Persons with a positive test result often display strong
coping abilities, are able to carry on with their lives, and might
express affirmative attitudes toward the testing. However, there is no
doubt that the testing can have a major personal impact, especially on
marriage and family planning. The long-term effect of a positive test
result is unknown, including its effect on the recognition of or
concern about possible early symptoms of dementia.
- Deciding to proceed with genetic testing can be associated
with considerable ambivalence, and individuals may postpone receiving
test results at the last minute.
In summary, we conclude that DNA testing in autosomal dominant
early-onset FAD and FTD with parkinsonism linked to chromosome 17 can
be successfully accomplished in appropriate families in the context of
formal genetic counseling with ongoing follow-up and monitoring. The
testing has benefits and risks for persons with positive or negative
results. The overall impact of such testing, especially on marriage and
family planning, should not be underestimated, and further longitudinal
studies are required to fully appreciate the long-term effects of
genetic testing.
AUTHOR INFORMATION
Accepted for publication June 26, 2001.
This work was supported by grant NIA/AG05136 from the National
Institutes of Health, Bethesda, Md; grant H133B980008 from the National
Institute for Disability and Rehabilitation Research; and VA Research
Funds.
We thank the many members of the families who participated in this
study.
From the Departments of Neurology and Medicine,
University of Washington Medical School (Mss Steinbart and Smith and Dr
Bird), and the Geriatrics Research, Education, and Clinical Center (Drs
Poorkaj and Bird), VA Puget Sound Health Care System, Seattle,
Wash.
Corresponding author and reprints: Thomas D. Bird, MD, Geriatrics
Research 182, VA Medical Center, 1660 S Columbian Way, Seattle, WA
98108 (e-mail: tomnroz{at}u.washington.edu).
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