NEWS FROM THE ALZHEIMER'S ASSOCIATION INTERNATIONAL CONFERENCE: Risky Business: How to Disclose Risk for Alzheimer's Disease Responsibly

Neurology Today
4 October 2012; Volume 12(19); p 30–32

Bain, Lisa J.

Investigators test the effectiveness of strategies to disclose genetic risk for Alzheimer's disease.

DR. ROBERT C. GREEN: “With these data we can start to assuage the concerns of people who have felt that disclosing APOE status is a bad idea. So far, in the first 30 or so subjects, we have not been able to demonstrate any anxiety, depression, or distress among either the subjects or their partners when they received e4 information despite having mild cognitive impairment.”

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VANCOUVER, BC—As investigators gear up for three large prevention trials in Alzheimer's disease, they are focusing on identifying subjects who are close to developing the disease and selecting interventions that may prevent or delay onset. Meanwhile, another group of researchers is conducting trials where risk information itself is the intervention. These trials aim to determine how to disclose this information effectively and responsibly while limiting misunderstanding, distress, depression, and anxiety.

“We have seen a move in the field towards trying to use biomarkers to identify so-called pre-clinical populations,” particularly for research studies, said Scott Roberts, PhD, associate professor of health behavior and health education at the University of Michigan School of Public Health, who chaired a research session on disclosing risk information to individuals at imminent risk of Alzheimer's disease (AD) at the Alzheimer's Association International Conference here in July.

“But what do you do with them once they reach a point where they actually attain utility in terms of clinical practice?” This move from research to clinical application is already starting to occur, he said.

In May, he noted, the FDA approved the use florbetapir F18 injection for imaging amyloid in adults, and commercially available tests of biomarkers in blood and cerebrospinal fluid are not far behind. Indeed, OPKO Health, Inc. presented data at the meeting here from recent studies of a serum test for diagnosing AD, which they have licensed to Laboratory Corporation of America Holdings (LabCorp) for commercialization.

Neurologist and medical geneticist Robert C. Green, MD, MPH, associate director of medicine in the Division of Genetics from the Brigham and Women's Hospital and Harvard Medical School, presented preliminary data from the most recent trial in the Risk Evaluation and Education for Alzheimer's Disease (REVEAL) Study.

REVEAL-IV is testing a protocol for disclosing apolipoprotein (APOE) genotype risk to individuals with mild cognitive impairment (MCI). Earlier studies (REVEAL I-III) tested variations of the disclosure protocol in cognitively normal adult children of people with AD and showed that risk information could be communicated effectively without causing undue anxiety in this population.

The APOEe4 allele is the most powerful genetic factor identified for late onset AD, substantially increasing the risk of developing the disease. The REVEAL-IV protocol is based on risk estimates derived from a clinical trial involving 769 amnestic MCI patients, which provided three-year conversion estimates based on age and APOE genotype. This study showed that if you have MCI and carry the APOEe4 allele, your risk of converting to AD within three years ranged from 42 percent for individuals age 55–70 to 57.1 percent for those over age 78. Excluding genotype information, the three-year conversion rates for these two age groups were 25.2 percent and 43.9 percent, respectively. The REVEAL risk disclosure session used visual aids, such as risk curves based on age, gender, and APOE genotype, as well as printed take-home materials. The session was followed by a phone call and subsequent data gathering six weeks and six months later. Study participants were randomized in a 2-to-1 ratio to either disclosure or non-disclosure arms. Participant and caregiver distress, health behavior change, and insurance/lifestyle change were assessed.

Preliminary analysis of the first 12 control, 10 APOEe4-positive, and 14 APOEe4-negative subjects revealed no significant difference in any of the assessments. Scores on the Impact of Events Scale (IES), a widely used measure of stress to traumatic events, were well below clinical significance for all participants. Scores on the Geriatric Depression Rating Scale (GDRS) and Mini-STAI, a state-trait anxiety inventory, were also similar.

Dr. Green called this preliminary analysis a “safety check” for REVEAL-IV since these data have not been fully analyzed. “With these data we can start to assuage the concerns of people who have felt that disclosing APOE status is a bad idea,” he said. “So far, in the first 30 or so subjects, we have not been able to demonstrate any anxiety, depression, or distress among either the subjects or their partners when they received e4 information despite having mild cognitive impairment.”

Susan E. Hahn, a genetics counselor and assistant director of communications, compliance and ethics at the John P. Hussman Institute for Human Genomics at the University of Miami Miller School of Medicine, was not surprised that individuals with MCI took the information in stride.

“Testing somebody who is symptomatic is considerably less controversial than testing an unaffected person because if you're already showing signs of dementia, whether it's Alzheimer's disease or not, and someone tells you that you have a gene that puts you at risk for dementia, it's not going to have the same impact. That said, adult children of someone identified to carry the e4 allele may suffer increased anxiety and risk for discrimination since it indirectly says something about their e4 status.”

The greatest concern with disclosure, she said, is for people who have no family history and no signs of cognitive impairment who are essentially blindsided by the information.

This will become even more of an issue in the era of personalized medicine, as individual genome sequencing becomes readily available, added Dr. Green.

“Our ability to study this has some implications for what it means when the world gets its genotype information just as readily as we all get our blood pressure information today,” he said. “We have to ask questions like, do we want our teenage children participating in football and soccer and other things that bang their heads, even if they are e4-positive?”

What about all the direct-to-consumer testing being done for Alzheimer's disease? Neurology Today previously interviewed neurogeneticists and genetics counselors about how to best advise patients about the results of these tests: http://bit.ly/S3Vn4H .

In another pilot study, investigators developed different scripts for disclosing results from amyloid imaging to people with MCI. “There is a sense of urgency to consider whether, when, and how we might disclose amyloid imaging results in the context of clinical research studies,” said Jennifer Lingler, PhD, a certified nurse practitioner from the University of Pittsburgh Schools of Nursing and Medicine, who described the trial findings. While this may become a clinical issue in the near future with the increasing popularity and pending commercial availability of amyloid imaging, the research setting offers an opportunity to examine carefully the psychological and behavioral impact of receiving biomarker information, she said.

Dr. Lingler worked with a multidisciplinary expert panel to develop a protocol for disclosing results, and then tested the protocol by delivering “mock” results to 10 pairs of individuals with MCI and their care partners. Anyone who had actually undergone amyloid imaging testing was excluded to eliminate confusion about whether the results were real. “We were attempting to avoid the emotional overlay that may come with actual results disclosure because our interest at this early stage was to determine whether the information was clear, comprehensible, and acceptable to the stakeholders of interest,” she said.

Scripts were developed to convey positive, negative, and inconclusive results. All three scripts started by explaining that amyloid is often found in patients with AD, that many scientists believe it builds up over many years before memory impairment begins, and that PET imaging now is able to reveal how much amyloid build-up an individual has. The positive script went on to explain that a positive scan confers a 50–50 risk of developing symptoms of AD within the next three years. The message for the negative script was that a negative scan means a lower chance of developing AD within the next three years; and the inconclusive script noted that it is not possible to know how significant it is. All scripts then described the results of each type of scan in more detail and gave recommendations to follow up with their physician.

The study used both surveys and open-ended questions and was analyzed both quantitatively and qualitatively. Among the 20 participants, all 20 rated the information as “clearly presented,” 19 rated it “easy to follow”, and 17 described it as having “just about the right level of detail” and “just about right” in length. Interview data suggested among five participants who did not seem to fully comprehend the information, cognitive factors in those with MCI and emotional factors in family members were involved.

Overall, this analysis indicated that most patients and caregivers were satisfied with the disclosure session and were able to understand and apply the information provided, suggesting that information can be standardized. However, said Dr. Lingler, “there is a clear need to be flexible and responsive to patients and family members.”

—Lisa J. Bain

The Anti-Amyloid treatment of Asymptomatic Alzheimer's Disease (A4) trial, proposed by the Alzheimer's Disease Cooperative Study, will offer a real world test of how to disclose results of amyloid testing to people who are cognitively normal, and the experience of learning the results. In this secondary prevention trial, cognitively “normal” older adults with a positive amyloid scan will be randomly treated with placebo or a biologically active anti-amyloid compound (still to be identified) for three years. Participation in the trial thus requires individuals to know their amyloid status.

Experts in human amyloid imaging, genetic testing, genetic counseling, and medical communications have been enlisted to identify topics that should be discussed before and after imaging as well as effective means of delivering the information. The result of this process will be a script that study site investigators will use when disclosing amyloid imaging results in the trial. The script will then be tested using outcome measures that assess both effectiveness and safety: Does the script provide understandable information, and how does it affect mood, depression, and anxiety among participants after receiving amyloid imaging?

The A4 trial thus will provide a test not only of a prevention strategy and the amyloid hypothesis, but of the impact of disclosure as well. “We essentially have a kind of case-control longitudinal cohort study to assess the impact of being amyloid positive or amyloid negative, which over the course of the study will allow us to measure how people understand and appreciate their risk of developing Alzheimer's disease,” said Jason Karlawish, MD, associate professor of medicine and a senior fellow of the Center for Bioethics and of the Leonard Davis Institute of Health Economics at the University of Pennsylvania Perelman School of Medicine.

—Lisa J. Bain