New Methods Reported For Safely And Accurately Disclosing Alzheimer's Disease Risk Based On Newly Approved Tests

VANCOUVER, British Columbia, July 17, 2012 /PRNewswire-USNewswire/ -- With FDA approval of a brain amyloid imaging compound in early 2012 and the expected start in 2012 and 2013 of three clinical trials in people with pre-symptomatic Alzheimer's disease, issues around disclosure of dementia risk status are becoming more urgent. Several research efforts reported today at the Alzheimer's Association International Conference® 2012 (AAIC® 2012) describe the creation and evaluation of new risk disclosure methods, and the examination of related ethical issues.

Alzheimer's is a devastating, progressive, and fatal illness. There is a movement in the Alzheimer's research field to detect and treat the disease earlier – even before there are outward symptoms – so that people do not have to suffer from the debilitating memory and thinking problems that lead to loss of normal daily activities and independence, and eventually death.

A number of Alzheimer's prevention trials are in the planning stages. They will be conducted in people without memory or thinking symptoms who are considered at-risk for Alzheimer's on the basis of genetic and/or biomarker* positivity.

* A biomarker is something in the body that can be measured as an indicator of normal biological processes, disease processes, or changes in response to therapy. For example, cholesterol levels are a biomarker for heart disease. A variety of imaging and fluid biomarkers are under investigation in Alzheimer's disease. Biomarkers allow investigators and clinicians to detect Alzheimer's-related changes in the brain and other body systems prior to the onset of dementia symptoms due to Alzheimer's.

"Biomarkers are being increasingly used in clinical practice and research trials to provide risk information for Alzheimer's. The goal is to develop evidence-based methods for communicating this risk in effective and supportive ways," said J. Scott Roberts, Ph.D., of the University of Michigan, School of Public Health. Dr. Roberts is chair of an AAIC 2012 featured research session where new research on disclosing risk information will be reported and discussed.

One of the most promising biomarkers is brain imaging using positron emission tomography (PET) scans that can show whether a person has deposits of an abnormal protein called beta amyloid, which is one of the hallmarks of Alzheimer's disease. There also are well-established genetic risk factors, such as the APOE Alzheimer's risk gene.**

** Based on current knowledge, APOE-e4 is the gene with strongest impact on Alzheimer's risk. APOE-e4 is one of three forms of the APOE gene; the others are APOE-e2 and APOE-e3. Everyone inherits a copy of APOE from each parent. Those who inherit one copy of APOE-e4 have an increased risk of developing Alzheimer's. Those who inherit two copies have an even higher risk, but not a certainty. Scientists estimate that APOE-e4 is implicated in about 20 to 25 percent of Alzheimer's cases. APOE-e2 may provide some protection against Alzheimer's.

Until recently, the presence of brain amyloid could only be confirmed by autopsy. Now it is possible to look for the protein in living brains using a special type of dye during a PET scan. These PET scans may help determine whether or not a person who is experiencing memory loss has Alzheimer's disease.

"People with memory loss who test negative on a PET scan using the newly-approved dye do not have Alzheimer's disease," said William Thies, Ph.D., Alzheimer's Association® Chief Medical and Scientific Officer. "Their symptoms are caused by something else. If they test positive, the cause is likely Alzheimer's, but that is not 100% certain because the presence of amyloid can be detected in other diseases besides Alzheimer's. We do not yet know what the test means in people without symptoms. The predictive value of the test is uncertain."

"The disclosure of test results to cognitively normal older people raises some important ethical issues because researchers and clinicians do not yet know how to interpret them. How will this biomarker 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 by the research and healthcare communities, with crucial input from Alzheimer's families and other stakeholders," Thies added.

The Alzheimer's Association currently is working with the Society of Nuclear Medicine to develop guidelines for when an amyloid PET scan is appropriate and how it should be interpreted.

Disclosing Alzheimer's disease genetic risk to people with MCI
The Risk Evaluation and Education for Alzheimer's Disease Study (REVEAL) is a multi-center randomized clinical trial enrolling people with mild cognitive impairment (MCI) to investigate the impact of disclosing "imminent" Alzheimer's disease risk information – specifically, the probability of progressing to Alzheimer's within the next three years. The trial tests different methods for disclosing this information, including a method where genetic testing is used to refine the risk estimates given to study participants.

"We hope to learn how people with MCI and their study partners respond to health education and learning risk information," said Robert C. Green, M.D., MPH, of Brigham and Women's Hospital and Harvard Medical School. "We continue to evaluate how well participants understand the Alzheimer's risk assessment and what they do with the information. We're 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."

Green and colleagues designed and are implementing an evidence-based procedure for risk estimation and an experimental trial of APOE genotype disclosure in people age 55 to 90 with MCI and their study partners recruited at four university medical centers (Harvard, Univ. of Michigan, Univ. of Pennsylvania, and Howard). Participants receive risk estimates for their chance of progressing to Alzheimer's disease that are based on their age, MCI diagnosis and APOE genotype (intervention arm) or age and MCI diagnosis alone (control arm). Risks disclosed to participants range from 8-57% in the intervention arm and 25-44% in the control arm.

The research team developed graphics and language to facilitate communication of APOE genotype and numerical risk estimate. Both participants with MCI and their study partners are followed up to 6 months following risk disclosure to determine its impact on caregiver distress, health behavior, and insurance/lifestyle changes. To inform further development of educational materials, researchers will also evaluate how well participants understood the information that was provided to them.

"This is the first study to examine the impact of disclosing Alzheimer's genetic risk information to individuals with MCI," Green said. "We believe the findings from REVEAL will have important implications for clinicians and policy makers in informing the future practice of educating and treating people at risk for Alzheimer's."

Disclosing brain amyloid imaging results to people with MCI and their families
Brain amyloid imaging is increasingly recognized as a powerful tool for predicting whether people with MCI will transition to Alzheimer's disease.  As this technology moves from the research setting into clinical practice, an emerging concern is that people with MCI may have difficulty comprehending their test results.

Given the lack of research on disclosing this information to people with cognitive impairments, Jennifer Lingler, Ph.D., of the University of Pittsburgh, Pennsylvania, and colleagues conducted a study to develop a standardized procedure for effectively communicating amyloid imaging results in the context of MCI, which is often described as an intermediate state between normal cognitive aging and Alzheimer's.

Based on previous research and insights from a panel of experts in neuroimaging, neuropsychology, risk communication, regulatory affairs, and bioethics, Lingler developed scripts and visual aids that guide clinical researchers in disclosing positive, negative, or inconclusive amyloid scan results. Ten people with MCI and 10 of their family members participated in mock results disclosure sessions and provided feedback on the procedure.

The researchers found that:

• The great majority of participants reported that the session was "easy to follow," (19 of 20) "included just about the right level of detail," (17 of 20) and was "just about right" in length (17 of 20).
• All 20 participants rated the information as "clearly presented."
• Eight of the 10 family members and seven of the 10 people with MCI correctly repeated their mock results back to an interviewer after the session.
• Analysis of interview data from the five participants with questionable comprehension suggested that (a) cognitive factors may explain problems with comprehension among those with MCI, while (b) emotional factors may underlie problems with comprehension among family members.

"Our study demonstrates that it is possible to provide people with MCI and family members with highly comprehensible and acceptable information about their brain imaging results of Alzheimer's risk," Lingler said.  "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, when imaging results are discussed."

Risk disclosure in the Anti-Amyloid treatment of Asymptomatic Alzheimer's disease (A4) trial
Although evidence suggests that amyloid deposits (or "plaques") in the brain are associated with an increased risk of cognitive decline, the impact of being "amyloid positive" on the likelihood and timing of progressing to Alzheimer's dementia on an individual basis remains unknown. The beginning of secondary prevention trials in people with presymptomatic Alzheimer's provides an important research opportunity to evaluate the impact of learning one's amyloid status.

One such trial is the Anti-Amyloid treatment of Asymptomatic Alzheimer's disease (A4) trial being proposed by the Alzheimer's Disease Cooperative Study.  PET amyloid imaging and/or cerebrospinal fluid markers of beta amyloid accumulation will be used to select participants for the trial, which will test an experimental treatment in older adults who are cognitively normal and amyloid-positive for three years. The goal is to test the hypothesis that decreasing "upstream" amyloid accumulation will slow "downstream" brain cell death and cognitive decline.

A4 participants will be informed of their amyloid status, as only amyloid-positive individuals will be randomized to receive treatment or placebo.

"People whose amyloid imaging results meet the research criteria for pre-clinical Alzheimer's face an unusual risk, namely, that the knowledge of the results can itself be harmful, particularly the label of being 'amyloid positive,'" said Jason Karlawish, M.D., of the University of Pennsylvania, Philadelphia. "The predictive value of the information remains uncertain. Indeed, part of the goal of the Alzheimer's prevention trials is to establish this value. Such uncertainty can create misunderstandings on the part of the participants over what it means to be 'amyloid positive.'"

Study leader Reisa Sperling, M.D., of Harvard Medical School and Brigham and Women's Hospital, Boston, said, "We are developing safeguards based on the REVEAL study and consent language to convey the uncertainty of the clinical implications of amyloid-status in asymptomatic individuals. 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."

About AAIC
The Alzheimer's Association International Conference (AAIC) is the world's largest conference of its kind, bringing together researchers from around the world to report and discuss groundbreaking research and information on the cause, diagnosis, treatment and prevention of Alzheimer's disease and related disorders.  As a part of the Alzheimer's Association's research program, AAIC serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community.

About the Alzheimer's Association
The Alzheimer's Association is the world's leading voluntary health organization in Alzheimer care, support and research. Our mission is to eliminate Alzheimer's disease through the advancement of research, to provide and enhance care and support for all affected, and to reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer's. For more information, visit www.alz.org or call 800-272-3900.

SOURCE Alzheimer's Association