The n e w e ng l a n d j o u r na l of m e dic i n e
edi t or i a l s
Effect of Genetic Testing for Risk of Alzheimer’s Disease
Rosalie A. Kane, Ph.D., and Robert L. Kane, M.D.
Genetic testing can be considered a complex vari-
ant of diagnostic testing. If the results are not ac-
tionable, the findings may lead to anxiety or even
life-disrupting actions with little offsetting bene-
fit. Even if the results are actionable, the anxiety or
actions resulting from disclosure may outweigh
any benefit. Because the benefits of genetic testing
are often modest, and the tests themselves are
often imprecise in identifying risk, consideration
must be given to potential harm in revealing the
test results. A test that discloses an elevated risk
of Alzheimer’s disease — a fearsome condition
involving memory loss, personality change, and
physical dependency — warrants extra caution.
In this issue of the Journal, Green et al.1 de-
scribe the results of a randomized, controlled
trial of genotype disclosure on the level of psy-
chological distress of adult children of persons
with Alzheimer’s disease; positive genotyping for
the apolipoprotein E (APOE) ε4 allele is associated
with an increased risk of Alzheimer’s disease.
The purpose of the study was to determine
whether substantial harm was caused by this
testing of offspring and disclosure of the results.
As part of the study, genetic counseling was pro-
vided to all subjects before phlebotomy, which was
followed by random assignment to receive the re-
sults of APOE genotyping or not to receive the
results. The counselors also interpreted the re-
sults of testing. Subjects in the disclosure group
did not have significantly more depression or
anxiety than those in the nondisclosure group
either immediately after receiving the genotyping
results or 1 year later, regardless of whether
they were in a subgroup of subjects carrying the
high-risk APOE ε4 allele.
The study by Green et al. is a rare and wel-
come trial of a process that might inform ethics
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guidelines. But how reassured should we be that
testing and disclosure would not be harmful?
None of the subjects had high anxiety or depres-
sion scores at baseline, which would have exclud-
ed them from the study. Presumably, subjects
who agreed to participate were sufficiently in-
different to the potential test results to accept
randomization and thus are not representative
of those who have a strong perceived need to
know or need not to know. It seems possible that
some subjects were unable to interpret the data.
Despite the rhetoric of a new patient-centered,
evidence-based society, we remain largely innu-
merate2 and poorly equipped to comprehend sta-
tistical probabilities. Consumer-based informa-
tion on the quality of health care has had little
effect on subsequent consumer decisions about
care.3-6 Perhaps many subjects understood that
a negative result conferred no immunity from
Alzheimer’s disease and that a positive result in-
troduced too many layers of uncertainty to jus-
tify personal planning or psychological distress.
There are two levels of uncertainty with re-
spect to Alzheimer’s disease: whether and when
the disease might develop and, if so, the likely
experience with the disease. Alzheimer’s disease
can have a trajectory of more than a decade and
is famously variable in its course. As Green et al.
acknowledge, without such genetic counseling,
subjects might not have understood the uncer-
tainties of risk they might have and therefore
responded differently. A similar caveat concerns
the fact that subjects had at least one parent with
Alzheimer’s disease. The investigators do not pre­
sent data on the course of the parents’ disease or
on the nature and extent of the relationship be-
tween the subjects and their affected parent,
factors that may influence how a person reacts to
 editorials
learning the results of genotyping. Approximately
three quarters of the subjects reported being a
caregiver for a relative with Alzheimer’s disease,
but the term “caregiver” was not defined and
could connote various types of involvement with
varying intensity and duration.
Fryback and Thornbury7 proposed a six-part
framework for analyzing the value of diagnostic
tests, including technical accuracy, diagnostic ac-
curacy, effect on diagnosis, effect on treatment,
patient outcomes, and effect on society. Knowl-
edge of the results of APOE genotyping has no
effect on treatment, although in this area, the
science is rapidly evolving, as discussed by Caselli
et al.8 in their report in this issue of the Journal
on the temporal effect of APOE ε4 on cognition.
However, the study by Green et al. prompts
thought about patient outcomes and the effect
on society.
On an individual level, the value of diagnos-
tic testing lies in its ability to produce benefits
that outweigh the risks. In this regard, how much
solace does the study by Green et al. provide?
The investigators measured negative psychologi-
cal outcomes, but not negative and positive social
and financial outcomes. Some APOE ε4 carriers
might have responded to the disclosure of their
increased risk by acting precipitously and unnec-
essarily on the information to get their affairs
in order, fashion advance directives, avoid major
residential or occupational changes, and save
money or, conversely, spend it rapidly. They might
have become ineligible for certain types of in-
surance; the Genetic Information Nondiscrimina-
tion Act of 2008 specifically prohibits the consid-
eration of genetic-testing results for employment
or health insurance but does not prohibit com-
panies from considering such results for long-
term care, disability, or life insurance. Moreover,
APOE ε4 carriers might have risked losing vari-
ous social opportunities and relationships if their
heightened risk of Alzheimer’s disease had be-
come known.
Green et al. followed the subjects for a year,
but persons who tested positive for the risk allele
(or who simply received disclosure) might react
years later, perhaps when they first forget a name
or observe distress in a relative with dementia.
Green et al. point out that larger studies with
longer follow-up are needed to detect effects
such as “delayed emotional repercussions and
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injudicious life decisions.” Also, the subjects were
a well-educated group with a mean age in the
early 50s; the results of the trial may have limited
relevance to younger or less educated subjects.
Could any societal good or harm result from
widespread, on-demand genetic testing for APOE
ε4? Societal benefit seems unlikely, given that it
is not possible to prevent Alzheimer’s disease,
and available treatments have at best a modest
effect on disease progression. Societal harm from
testing remains possible, given that Alzheimer’s
disease is widely regarded as being singularly
horrific,9,10 although persons with Alzheimer’s
disease can retain their sense of humor, experi-
ence existential joy, and overcome the sum total
of so-called negative behaviors that are typically
measured in care settings. One hopes that the
subjects in this study had experiences with their
affected family members that were consistent
with this observation. With an increasing public
familiarity with Alzheimer’s disease and improv-
ing choices in community care for those with
the disease, perhaps the social effects of genetic
testing will be less worrisome by the time a
clinical rationale for the test becomes apparent.
Dr. Robert Kane reports receiving consulting fees from SCAN
Health Plan, United Health Group, and Medtronic. No other
potential conflict of interest relevant to this article was reported.
From the School of Public Health and Center on Aging (R.A.K.,
R.L.K.) and the Center for Biomedical Ethics (R.A.K.) — all at
the University of Minnesota, Minneapolis.
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Copyright © 2009 Massachusetts Medical Society.
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