News about a not-too-distant future of personal genomics is coming at us hard and fast. For example, the New York Times reported on June 1 that the complete DNA sequence of Nobel laureate James C. Watson, of DNA double-helix fame, has been sequenced and handed to him on two DVDs. Watson said he’ll make his entire genome, warts and all, available to researchers to study—with one exception. According to the article, Watson does not want to know which isoform of the ApoE gene he has inherited because it can predispose to Alzheimer disease (AD).
On June 3, the same newspaper ran a story claiming that thousands of people may be able to have their genome sequenced before too long as the cost of this process comes down. This second story paraphrased the president of the Celera Corporation, Craig Venter, as saying that he has already sequenced his own genome and consults his data every time a new announcement of a gene discovery comes out. The story added that Venter last month followed up a newspaper story on a new gene for heart disease and discovered that he indeed carried the high-risk variant.
Amid this heady and perhaps a bit hyperbolic publicity of personal genomics, what is the prudent stance on the concrete example of ApoE testing? What is the evidence-based, and ethical position for doctors, genetic counselors, and lay people as they assess a person’s risk for AD? ApoE testing can add genetic heft to the more classic risk calculations conventionally assembled from family history, gender, age, and ethnicity. But the risks are so significant and so poorly understood that this sort of AD susceptibility testing is not clinically available outside of certain research studies. Robert Green has been heading the REVEAL study, a federally funded, randomized trial to explore ApoE susceptibility testing. Because this issue concerns lay people as much as scientists and medical professionals, the Alzforum has prepared two introductory texts for this discussion.
Robert Green led this Webinar on 15 June 2007. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.
- Lay Introduction by Gabrielle Strobel
- Background Text by Robert Green (see below)
By Robert C. Green
A Decade Later: Is ApoE Genetic Testing Still a Bad Idea? What the REVEAL (Risk Evaluation and Education for Alzheimer's Disease) Study Has Told Us
It’s clear that certain isoforms of the ApoE gene are associated with increased susceptibility for developing Alzheimer disease (AD). Apolipoprotein E is a plasma protein involved in cholesterol transport. It has three common alleles (ε2, ε3, or ε4) that result in six possible genotypes a person can inherit. The ε4 allele is a robust risk factor for sporadic and late-onset familial AD [1-3, AlzGene] The degree of this risk varies depending on whether a person has inherited one or two ε4 alleles. ApoE remains the best-established genetic marker for late-onset AD, although weaker associations of AD with other genes also exist (see Top AlzGene Results, especially reference 4).
But is predictive genetic testing for ApoE to assess a person’s future risk for AD advisable? ApoE was identified as a risk factor for AD in 1993, and in the following years, six separate consensus conferences of experts around the world considered the issue. At each event their answer was: No, ApoE predictive testing ought not to be made clinically available. The statements recommended against disclosing ApoE genotypes largely because information about the future risk of developing AD cannot currently be used to delay or alter the course of the disease [5-10]. However, each of the consensus statements concluded along these lines: “More research is needed on how individuals and families understand complex probabilistic genetic information, as well as on the implications of living one’s life ‘at risk’ for developing AD” . The REVEAL Study has since addressed these questions. In light of these findings, and of the impending development of disease-modifying treatments, these consensus recommendations against susceptibility testing for AD may change.
In 1997, when we began the original REVEAL study, we outlined the potential that ApoE genotyping might hold for devising treatment strategies for AD patients [11,12]. This potential has in recent years begun to be realized with the publication of the first clinical trials to show substantial differences in the response to a given treatment based on a patient’s ApoE genotype [13,14]. I am optimistic that as physician-researchers, we are approaching a new era of AD treatment in which our emphasis will be on interventions that can delay onset or slow progression. If such treatments prove efficacious, they will need to be started early in the course of the disease or even pre-symptomatically. To this extent, genetic testing and other forms of predictive testing are likely to become important in identifying “at risk” asymptomatic individuals for early intervention. As we approach this stage, the available evidence gathered on ApoE predictive testing in the past decade can help inform a reconsideration of its risks and potential benefits.
Our group and others have addressed a range of issues related to genetic testing in AD. They include exploring ways of how best to communicate risk [15-17], studying the differences between predictive testing in HD and in AD [11,12,18,19], establishing a theoretical model of psychological response to knowing one’s genetic status , and even the possibility of selective abortion after fetal testing [21,22]. Surveys indicated that a majority of respondents were interested in predictive testing. The interest varies by individual characteristics, e.g., demographic traits, illness perceptions, as well as factors such as test accuracy, available treatment options, and meaning of test results [11,23,24]. Not until the REVEAL Study has a real-life susceptibility testing paradigm for AD been examined in a research trial. Below follows a summary of the REVEAL study process and its main findings.
The Impact of Genetic Risk Assessment with ApoE Disclosure
The goal of the REVEAL Study in its first funding cycle (REVEAL I, 1999-2003) was to assemble a multi-disciplinary team of genetic, medical, and social scientists to determine what kind of person would choose to obtain susceptibility genotyping for Alzheimer disease and what the consequences of genotype disclosure would be for them. The heart of this project was a randomized clinical trial (RCT) comparing the impact of an overall genetic risk disclosure with and without an ApoE genetic component. Since there was no clinical experience in disclosing ApoE status to asymptomatic individuals, a number of steps were necessary prior to conducting this trial.
The REVEAL team includes experienced clinicians and investigators in AD (Drs. Robert Green, Norman Relkin, Peter Whitehouse, Thomas Obisesan, and Ron Petersen), researchers on the genetics and biology of ApoE genotyping (Drs. Lindsay Farrer, Green, Relkin, and Deborah Blacker), clinical geneticists and genetic counselors (Drs. Farrer, Dessa Sadovnick, Charmaine Royal, Blacker, Barb Biesecker, and Kimberly Quaid), a senior neuropsychologist (Dr. Robert Stern), health psychologists (Drs. Scott Roberts and Theresa Marteau), experts in genetic risk communication (Drs. Marteau, Deb Roter, and Biesecker), nurse-researchers (Drs. Ann Hurley and Cathy Read) and some of the most recognized figures in bioethics (Drs. Post, Juengst, Annas, Quaid, Karlawish, and Whitehouse). The REVEAL Study has been conducted at five sites: Boston University; Cornell University, New York; Case Western University, Cleveland, Ohio; Howard University in Washington, D.C.; and most recently at University of Michigan in Ann Arbor. At each site a board-certified or board-eligible genetic counselor serves as the site coordinator. The REVEAL Study team is supported by an independent External Advisory Board, led by Dr. Robert Cook-Deegan, Director of the Duke Institute for Genome Sciences and Policy.
Prior to the start of funding, REVEAL Study investigators performed surveys to explore whether there was public interest in receiving genetic risk information for AD [11,23,25]. During the first portion of the funding period, these surveys were expanded. A surprising number of individuals (between 30-50 percent) have reported that they are interested in receiving genetic risk assessment. There are distinct differences in the perceptions of African Americans versus European Americans in their perspective on genetic testing for AD in that African Americans were less interested in genetic testing but anticipated fewer negative reactions to such testing results [26,27].
In REVEAL I, we also explored why people might seek genetic risk assessment by asking participants to rate the importance of 12 possible reasons. Commonly endorsed reasons included: 1) to arrange personal affairs (87.4 percent), 2) the hope that effective treatment will be developed (86.8 percent), 3) to arrange long-term care (81.4 percent), 4) to prepare the family for the possibility of my illness (77.8 percent), 5) to do things sooner than planned (75 percent), and 6) relief if I learned I was at lower risk (69.6 percent). Women strongly endorsed more reasons for seeking testing than did men (.05 our data suggested that at-risk individuals are interested in ad susceptibility testing for a variety of mostly non-medical reasons even the absence of effective treatments. We gauged interest in risk assessment by following two groups of participants from initial contact to their enrollment in the RCT. They were people who were systematically contacted through research registries (n = 196), and others who self-referred (n = 179), i.e., heard about the trial and contacted the investigators. Forty-seven of the systematically contacted participants (24 percent) decided to proceed from initial contact to enrollment; they were more likely to be younger than 60 (adjusted OR = 3.83, and college educated; 3.48 percent of self-referred participants progressed from initial contact to enrollment. Most had an education and were female; these findings suggest that susceptibility testing for ad may be of particular interest to women, college-educated persons below age. Our uptake rates sufficiently high merit concern, future test demand outstrip available counseling resources. Early in the course of REVEAL I, we used data from prior epidemiological studies [30,31] to estimate risk curves that we would use in the disclosure of genetic risk assessment to first-degree relatives of patients with AD. The assumptions and methods used for the creation of these curves are fully described elsewhere . We also developed a standardized method of presenting these risk curves in order to examine differences in risk disclosure protocols either including or excluding ApoE disclosure. With these preparations, the team conducted an RCT in which 162 asymptomatic first-degree relatives of patients with AD were randomized to receive risk assessment using family history only versus risk assessment using family history and ApoE genotype. In all cases, the education about risk assessment, and risk disclosure, were performed using genetic counselors (GCs). Standardized scales of depression and anxiety served as primary outcome measures.
Our data suggest that risk assessment and genotype disclosure did not adversely affect the psychological well-being of participants [33,34]. We compared results among three study groups: Control Arm participants; Intervention Arm participants who tested positive for the ε4 allele (ε4-positive group); and Intervention Arm participants who tested negative for the ε4 allele (ε4-negative group). There were no significant post-test group differences in depression or anxiety symptoms, and all group means were well below clinical cut-off scores at all three time points (6 weeks, 6 months, and 1 year following risk disclosure). A few participants experienced significant increases in depression or anxiety symptoms following risk disclosure, but interviews with study GCs indicated that these changes were primarily due to external stressors (e.g., death in the family).
To gauge the impact of providing a “negative” genetic test result for AD, we conducted a sub-analysis of 66 women, all of whom received a cumulative lifetime AD risk estimate of 29 percent. Compared to the controls, and despite having received an identical numerical lifetime risk estimate, the ε3/ε3 carriers perceived their risk as lower. They reported testing as having a more positive impact on them, they believed less strongly that they might develop AD, and they reported a greater reduction in their anxiety about AD . Related analyses suggest that perceptions of risk are influenced by including genetic tests in risk assessments for AD in those receiving ε4-negative but not those receiving ε4-positive results . These findings highlight the powerful effects that genotype information can have on participants, even when delivered by trained genetic counselors as part of a larger multivariable risk assessment . REVEAL also analyzed how well participants understood and retained risk information. The data showed that participants had good recall of their genotype (whether or not they were told they had the risk allele), and good recall of their approximate (within 5 percentage points) cumulative risk figure. 
We examined insurance changes that participants reported having made in the 12 months following risk disclosure. Relatively few participants reported changes regarding health (8 percent), life (5 percent), or disability insurance (4 percent), with no group differences in these domains. The ε4+ group, however, was more likely to report changes in long-term care insurance than the controls or the ε4- group (17 percent vs. 4 percent vs. 2 percent, .05 respectively) should susceptibility testing for ad enter clinical practice. These results suggest that policymakers will need to address issues of adverse selection and genetic discrimination in the long-term care insurance market. Participants self-reported changes in health behavior following risk disclosure will be the topic of a forthcoming paper. Our preliminary analyses suggest that participants found to be at higher risk for AD were more likely to report having engaged in activities to prevent AD (e.g., adding vitamin E, making changes in diet or exercise) .
Some REVEAL investigators conducted and transcribed open-ended interviews with a subset of 60 REVEAL participants. This component of the study will assist with interpretation of quantitative findings, and provide added details regarding issues such as participants’ motivations for pursing risk assessment and their response to risk information . We conducted related analyses on the impact of risk disclosure on participants’ anxiety about developing AD. On the Impact of Event Scale, a measure of test-related distress, the ε4- group scored lower than the ε4+ group or controls at all time points, with all group mean scores below clinical cut-offs. Following risk disclosure, nearly 90 percent of all participants reported the same or lower anxiety about developing AD as compared to baseline, with the ε4- group particularly likely to report lower anxiety. These findings suggest that most participants experienced the same or lower levels of anxiety about AD after risk disclosure than they had felt going into the study.
The Impact of a “Condensed,” Clinically Feasible Risk Assessment Protocol
The education, disclosure, and counseling protocol tested in REVEAL I is too extensive for general clinical use. In the second funding period of the REVEAL study (2003-2006), we created and tested a more clinically feasible condensed protocol that could be delivered in a more cost-effective manner than our original protocol. Our more conventional extended protocol required three visits totaling about 3.5 hours, the condensed protocol involved two 30-minute visits. This was implemented by creating a mail-out brochure to replace our educational efforts. REVEAL II randomized a new set of participants into the condensed or extended protocol in a ratio of 2:1. People in the latter group received disclosure from the genetic counselor; in the former group, half received disclosure from a genetic counselor and half received disclosure from the study physician.
The team also created customized risk curves and risk estimates for African American participants. We enrolled African Americans into the REVEAL II (successfully enrolling more than 20 percent). To increase diversity in our sample, Howard University was added as a study site, led by site director Dr. Charmaine Royal, genetic counselor Grace Fasaye, and geriatrician Dr. Thomas Obisesan.
This trial has been completed with over 350 subjects enrolled. Preliminary results to be reported at the upcoming AD Prevention Meeting in Washington DC again support the notion that risk assessment with ApoE disclosure can be safely conducted, even with a condensed, clinically feasible protocol.
Special Challenges in the Disclosure of Genetic Susceptibility Information
The evaluation of risk using genetic markers has a special impact because (a) it carries an almost mythical connotation of determinism, (b) it is not typically attached to voluntary modifiable behaviors, i.e., people can’t do much to prevent the predicted disease, and (c) there may be a long time delay between the testing and the clinical manifestations of the disease. Genetic information not only is full of symbolic meaning, it also can affect the entire family [41,42]. Moreover, it can be difficult for medical professionals to interpret and communicate because of its probabilistic nature [43-46].
Many different voices have eloquently articulated the concerns over the ethical and psychological dangers of general genetic testing. The dangers include the possibility of psychological distress, family discord, inadvertent transfer of risk information to other family members who do not wish to know it, social stigmatization, and insurance or employment bias [43,47-50]. Despite these dangers, there has been an acceleration of progress in the identification of both deterministic and susceptibility genes. Concurrently, investment by industry in patenting and marketing such tests and popular interest in such tests are all increasing at an unprecedented rate. At present, ApoE is licensed for CNS use exclusively to Athena Diagnostics. As Nancy Wexler's sister Alice has noted in her book, “Human genetics inhabits a volatile space at the intersection of medicine, biology, corporate profits, law, government funding of science, state health programs, private insurance companies, genetic counseling services, schools, and popular culture” .
Many additional factors intensify the debate over the use of genetic tests. One is the recognition that recipients of risk information may respond with controversial actions such as suicide or prenatal testing and subsequent termination of pregnancy. There is disagreement among health care professionals, as well as in the general population, over the value of disclosing risk information to otherwise healthy people, particularly in the absence of interventions that could prevent or delay the onset or improve the prognosis of the condition in question . That genetic testing can offer risk information years or even decades before recognizable symptoms are due to appear, particularly in degenerative and late-onset chronic diseases, makes accurate validation of these tests difficult. This delay of a decade, or decades, challenges the wisdom of saddling an asymptomatic person with many years of possibly inaccurate expectation.
The debate is particularly heated when the risk information is based upon susceptibility genes rather than deterministic genes (for a discussion of those, see Early-onset Familial AD: Genetic Testing and Counseling). Genotyping to identify susceptibility genes provides estimations of risk that are, by definition, influenced by other genes and non-genetic environmental exposures. This type of information, though technically “genetic,” does not carry nearly the same degree of certainty as genotyping deterministic genes, where the presence or absence of specific mutations can be unequivocally associated with the future manifestation (or not) of a specific disease. Moreover, susceptibility genes are likely to be far more common than deterministic genes, particularly in the late-onset diseases. Thus, susceptibility genotyping is much closer to the kind of information already available to patients on the basis of family history, environmental exposures and health-related behaviors.
Many individuals express a desire to be tested for genetic markers that will offer them personal risk information, both for diseases in which there are prevention/treatment possibilities as well as for diseases in which these are not yet available. In recent decades, there has been a steady evolution in the activism of the patient and in the patient’s “right to know,” as well as an increasing interest in risk factors with emphasis on disease prediction and prevention. As research on susceptibility testing for cancer demonstrates, genetic testing for risk assessment clearly provides information that some individuals wish to know. Such markers can often be measured with relative ease once identified, and the initiatives of motivated individuals and the power of market forces may make it difficult to limit or prevent the widespread use of susceptibility genotyping in the future. Our responsibility as experts may be to understand how to use them wisely, and to articulate publicly whether and under what circumstances they should be used. As physician and bioethicist Michael Grodin at Boston University has noted, “good ethics begin with good facts” . Thus, just as new medications are evaluated for benefits and adverse effects, clinical trials are imperative to determine the effects of disclosing risk information from susceptibility genotyping. In the REVEAL Study, we are carrying out such trials, using susceptibility genotyping for ApoE polymorphisms as a model.
The REVEAL Study has been renewed for a third clinical trial (REVEAL III) that will examine the impact of disclosing their ApoE genotype to persons who do not have a family history of AD. REVEAL III will also look at disclosing pleiotropic information, since ApoE has been linked to cardiovascular disease risk as well as AD risk.
For this discussion, I suggest these topics:
- In 2007, do we know enough to reconvene a new consensus group for a review of the previous recommendation?
- What other studies and trials should be done until it is time?
- In 2007, what should doctors tell their patients who express interest in ApoE genotyping because of a family history?
- Overall, the REVEAL data look reassuring. On an anecdotal basis, however, have there been bad outcomes of people who learned they carry ApoE4? Depression, suicide, hopelessness, loss of job, divorce, etc.?
- Can clinicians ever recommend testing if even a small fraction has severe complications?
- Which current clinical trials are assessing drug response as a function of ApoE genotype?
- On probabilistic risk interpretation, for example, what is a 48-year-old person to make of a 40 percent remaining lifetime risk of developing AD? How does the clinician explain that?
- What did REVEAL II say about the need for trained genetic counselors?
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