Researchers Grapple With Ethics of Revealing Alzheimer's Risk

Deborah Brauser

July 27, 2012

July 27, 2012 (Vancouver, British Columbia) — New imaging techniques for determining Alzheimer's disease (AD) risk are raising issues for the field, including determining the best risk disclosure methods as well as the ethics of disclosing brain amyloid status to research participants. These topics, and more, were discussed during a Featured Research Session here at the Alzheimer's Association International Conference (AAIC) 2012.

As reported earlier this year by Medscape Medical News, the US Food and Drug Administration approved the brain amyloid imaging agent florbetapir F 18 (Amyvid, Avid Radiopharmaceuticals). It now joins carbon 11–labeled Pittsburgh compound B (C-PiB).

The planned placebo-controlled Anti-Amyloid Treatment of Asymptomatic AD (A4) trial is set to begin assessment of healthy elderly adults to determine whether they are positive for beta amyloid in the summer of 2013. Those with amyloid load will be selected for treatment randomization, and all participants will be informed of their amyloid status.

"We're already developing language for those who are told they're amyloid positive. We don't yet know what that means on an individual level in terms of developing dementia, but that's part of our study," lead author Reisa Sperling, MD, from Harvard Medical School and Brigham and Women's Hospital in Boston, Massachusetts, told Medscape Medical News.

Dr. Reisa Sperling

During the same session, the creation and evaluation of new risk disclosure methods for patients who carry gene mutations associated with AD, including APOE, were discussed.

Investigators from the Risk Evaluation and Education for AD (REVEAL) study, in which individuals with mild cognitive impairment (MCI) will be informed of their APOE genotype status, and investigators from a pilot study in which participants with MCI were given mock PiB amyloid imaging results debated their trials' implications on practice, policy, and research.

"These are really important questions that are just now being addressed. And I think it's important for these researchers to come up with guidelines for clinicians," Ralph Nixon, MD, PhD, chair of the Alzheimer's Association Medical and Scientific Advisory Council, told Medscape Medical News when asked for comment.

Awkward Situation

The A4 study investigators plan to assess an experimental monoclonal antibody vs placebo to decrease amyloid buildup in 1000 individuals who are asymptomatic for AD. The primary outcome measure will be decreasing the rate of decline in cognition and executive function; secondary outcomes include results of structural and functional imaging and spinal fluid assays.

The National Institute on Aging has completed its review of the trial's funding application, and their decision is expected in September. If approved, the investigators plan to begin enrollment next year.

"I think this is our best chance of being able to see whether amyloid really makes a difference or not," said Dr. Sperling.

However, concerns have been raised over whether or not a patient should actually learn his or her amyloid status — especially because it is not yet known whether beta amyloid really is an actual biomarker for later AD development.

"It is incumbent on all those who are advocating that this is an early biomarker to provide some guidance. They are taking on a big responsibility to use that test and then explain to a patient what it means when the field doesn't know what it means yet," said Dr. Nixon.

Dr. Ralph Nixon

"It's an awkward situation for clinicians," he added.

In addition, questions about everything from possible insurance or even employment discrimination to undue patient stress and anxiety over something that might not happen have made the whole topic very thorny.

Insurance Implications?

In fact, Dr. Nixon reported that some of the members of the Alzheimer's Association board of directors were recently discussing the possible impact of these test results on insurance issues.

"If you had a positive scan, insurance would be very interested in knowing about that. And you can be certain that that's going to weigh in to their willingness to give you long-term disability. If it gets into your long-term record, it has to be disclosed," he said.

"I think we need laws that protect people who have biomarkers or evidence of one sort or another so that they're not rejected by insurance."

Dr. Sperling said that although they hope to protect their study participants' anonymity when it comes to insurance disclosures, "we need some public policy work on this."

"I have concerns that if a patient has, for example, an adverse event during the trial, the information could get into their personal record. As well as protecting them as best we can, we need laws just like we have to protect against genetic discrimination. And I hope this is something the Alzheimer's Association will get involved in," she said.

She added that "the vast majority" of A4 participants will be older than 70 years and are under Medicare, which should not use any trial information to discriminate.

"But there will come a time when people who are still working need insurance, and this could become a real issue."

REVEAL Safeguards

The REVEAL study, which was also part of the Featured Research Session, was created to assess what impact, if any, disclosing the probability of developing AD within 3 years (on the basis of having an APOE genotype) has on patients between the ages of 55 and 90 years who have MCI. Follow-ups with both participants and caretakers are being conducted up to 6 months after the risk disclosure.

"We continue to evaluate how well participants understand the Alzheimer's risk assessment. We're [also] monitoring how the people with MCI and their care partners adjust psychologically, and what health-related and behavioral changes they make in response to the new information," explained lead author Robert C. Green, MD, MPH, from Brigham and Women's Hospital and Harvard Medical School, in a release.

"We believe the findings from REVEAL will have important implications for clinicians and policy makers in informing the future practice of educating and treating [these] people," added Dr. Green.

Dr. Sperling reported that her investigative team is currently developing "safeguards" based on the REVEAL study.

"For example, we wouldn't disclose to someone who was overly depressed or anxious. So there's a large screening process. We also plan to include an ethics substudy in the A4 trial to evaluate the short- and long-term impact of learning one's amyloid status," she said.

No Agreement

Finally, investigators led by Jennifer Lingler, PhD, from the University of Pittsburgh, Pennsylvania, completed a pilot study that sought to develop a standardized process for disclosing amyloid imaging results to patients with MCI. This process included scripted dialogue and visual aids based on recommendations from experts in neuroimaging, neuropsychology, and bioethics

So far, 10 sets of participants and caregivers have completed disclosure sessions, which include mock PiB results. Although 19 of the 20 individuals reported that the sessions were easy to follow and all said that the information was "clearly presented," 5 of the participants had questionable comprehension.

"Our study demonstrates that it is possible to provide people with highly comprehensive and acceptable information about their brain imaging results," said Dr. Lingler.

"However, since some of the participants had some difficulty, we recommend that a family member or friend be present and that emotional support be provided," she added.

In a release, William Thies, PhD, chief medical and scientific officer of the Alzheimer's Association, noted that disclosing these types of imaging results "raises some important ethical issues" — especially because there is no agreement yet on how to interpret the findings.

"How will this information be gathered? When, how, and to whom will it be disclosed? How do we disclose it accurately while minimizing any potential negative impact? These are issues that must be addressed," added Dr. Thies.

According to the same release, the Alzheimer's Association and the Society of Nuclear Medicine are now jointly developing guidelines for determining when an amyloid positron emission tomography scan "is appropriate and how it should be interpreted."

Dr. Green's study was funded by the National Human Genome Research Institute. Dr. Lingler's study was funded by the Aging Institute of the University of Pennsylvania Medical Center Senior Services and by the National Institute on Aging. The study authors, Dr. Nixon, and Dr. Thies have disclosed no relevant financial relationships.

Alzheimer's Association International Conference (AAIC) 2012. Abstracts F3-01-1, F3-01-02, and F3-01-03. All presented July 17, 2012.

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