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New Methods Reported for Safely and Accurately Disclosing Alzheimer's Disease Risk based on Newly Approved Tests

VANCOUVER, July 17, 2012 – 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, PhD, 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, PhD, 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, MD, 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, PhD, 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:

"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, MD, 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, MD, 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's care, support and research. Our mission is to eliminate Alzheimer's 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. Visit www.alz.org or call 800-272-3900.

 

AAIC 2012
Tuesday, July 17 Featured Research Session, 8:30-10 AM

Disclosing risk information to individuals at imminent risk of Alzheimer's disease

Biomarkers are seen as critical tools for assessing risk and tracking disease progress in Alzheimer's disease. However, their successful integration into clinical practice (and clinical trials with preclinical populations) will require skilled communications of complex, ambiguous information, as well as better understanding of the psychological and behavioral impact of these communications on patients and family members. This multidisciplinary panel will describe both ongoing and proposed interventions in which biomarker information is disclosed to populations at "imminent" risk (i.e., within the next five years) of developing clinically expressed Alzheimer's.

This session will help attendees consider the challenges and opportunities posed by disclosure of Alzheimer's biomarker information, a topic sure to become increasingly prominent in future clinical trials and dementia care.

F3-01-01
Tuesday, July 17 / AAIC 2012 Featured Research Session, 8:30-10 am

Disclosure of APOE Genotype to Persons with Mild Cognitive Impairment (MCI)

Robert Green1, Scott Roberts2, Jason Karlawish3, Thomas Obisesan4, L. Adrienne Cupples5, Denise Lautenbach6, Margaret Bradbury7, Tolulope Fafowora7, Kristin Harkins3, Wendy Uhlmann8, Elisabeth Wood9
1University of Pittsburgh Schools of Nursing and Medicine, Pittsburgh, Pennsylvania, Untied States; 2University of Michigan School of Public Health, Ann Arbor, Michigan, United States; 3University of Pennsylvania, Philadelphia, Pennsylvania, United States; 4Howard University Hospital, Washington, DC, United States; 5Boston University, Boston, Massachusetts, United States; 6Harvard Medical School, Boston, Massachusetts, United States; 7Howard University, 4Howard University Hospital, Washington, DC, United States; 8University of Michigan Health System Division of Molecular Medicine & Genetics, Tampa, Florida, United States; 9University of Pennsylvania Center for Neurodegenerative Disease Research, Philadelphia, Pennsylvania, United States
Presenting author e-mail: rcgreen@genetics.med.harvard.edu

Background: N/A

Methods: We generated risk estimates using data obtained from a clinical trial involving 769 aMCI patients, which provided three-year conversion data stratified by APOE genotype (Petersen et al. 2005). We used an evidence-based approach in risk communication to develop graphics and language to communicate APOE genotype and a numerical risk estimate. Patients with aMCI are being recruited at 4 university medical centers (Harvard, Univ Michigan, Univ Penn and Howard) and randomized in a 2:1 ratio to either disclosure or non-disclosure arms.  Scales of participant and caregiver distress, health behavior change and insurance/lifestyle change are measured at 6 weeks and 6 months.

Results: Three-year risks for each age-group were: 8.4% for APOE ε4 negative and 42.0% for APOE ε4 positive individuals (ages 55-70), 20.5% for APOE ε4 negative and 47.4% for APOE ε4 positive (ages 71-77), and 30.7% for APOEε4 negative and 57.1% for APOE ε4 positive (age 78 or older). Estimates based on MCI diagnosis and age alone (excluding genotype information) were 25.2% (ages 55-70), 34.0% (ages 71-77) and 43.9% (ages 78 or older). Educational materials were created to describe the possible APOE genotypes, an individual's APOE genotype result and three-year Alzheimer's conversion risk.

Conclusions: An evidence based procedure for risk estimation and an experimental trial of APOE genotype disclosure in aMCI patients has been designed and implemented.  Preliminary results will be presented and discussed.

 

F3-01-02
Tuesday, July 17 / AAIC 2012 Featured Research Session, 8:30-10 am

Development of a Standardized Approach to Disclosing Amyloid Imaging Results in MCI

Jennifer Lingler1, Scott Roberts2, Richard Schulz3, William Klunk3
1University of Pittsburgh, Pennsylvania, United States; 2University of Michigan School of Public Health, Ann Arbor, Michigan, United States; 3University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Presenting author e-mail: linglerj@pitt.edu

Background: Amyloid imaging is increasingly recognized as a powerful tool for predicting clinical outcomes in mild cognitive impairment (MCI).  As this technology moves from the research setting into clinical practice, an emerging concern is that patients with MCI may have difficulty comprehending their test results.  Given the lack of research on disclosing non-genetic biomarker information to cognitively impaired patients, the purpose of this two-phase study is to develop a standardized procedure for effectively communicating amyloid imaging results in the context of MCI. 

Methods: For Phase 1, we convened a panel of experts in neuroimaging, neuropsychology, risk communication, regulatory affairs, and bioethics to determine the content and process for disclosing positive, negative, and inconclusive PiB PET scan results to persons affected by MCI.  The panel critically reviewed a series of outlines and scripted text for results disclosure in an iterative fashion.  Visual aids were subjected to the same process of critique. Phase 2 remains in progress and aims to evaluate MCI patients' and family members' satisfaction with and comprehension of the materials developed in Phase 1. Two out of a proposed sample of ten MCI dyads, including both amnestic and nonamnestic subtypes, have undergone mock (hypothetical) amyloid imaging results disclosure sessions and completed post-disclosure interviews. 

Results: Disclosure scripts for positive, negative, and inconclusive results, with accompanying visual aids, were developed.  Each script was sequenced to review the purpose of amyloid imaging, disclose a hypothetical result, and interpret that result in terms of dementia risk and recommendations for clinical follow up.  Scripts ranged from 245 to 300 words long with Flesch-Kincaid reading levels of 8th to 9th grade.  All four participants agreed or strongly agreed with statements indicating that the session was "easy to follow," "included just about the right level of detail," and was "just about right" in length.  All four rated the information as "clearly presented," and adequately restated, in their own words, the results that were disclosed.

Conclusions: These preliminary findings support the feasibility of presenting amyloid imaging results in a manner that is satisfying to, comprehended by, patients with MCI and their families.

 

F3-01-03
Tuesday, July 17 / AAIC 2012 Featured Research Session, 8:30-10 am

Disclosure of amyloid status in secondary prevention trials for Alzheimer's disease

Reisa Sperling1, Scott Roberts2
1Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States; 2University of Michigan School of Public Health, Ann Arbor, Michigan, United States

Background: As the field moves towards early intervention, there is increased reliance on biomarker evidence of preclinical Alzheimer's disease (Alzheimer's) for inclusion into studies. There are a number of secondary prevention trial initiatives in the planning stages that will be conducted in asymptomatic individuals at-risk for Alzheimer's on the basis of genetic and/or biomarker positivity.  The disclosure of biomarker results with uncertain clinical implications in clinically normal older individuals raises important ethical issues.

Methods: PET amyloid imaging and/or cerebrospinal fluid markers of amyloid-b accumulation will be used to select eligible participants for the Anti-Amyloid treatment of Asymptomatic Alzheimer's disease (A4) trial being proposed by the Alzheimer's Disease Cooperative Study.  This placebo-controlled trial will treat clinically normal amyloid-positive older subjects with a biologically active immunotherapeutic agent for 3 years to test the hypothesis that decreasing "upstream" amyloid accumulation will slow "downstream" neurodegeneration and rate of cognitive decline. Participants will be informed of their amyloid status, as only amyloid-positive individuals will be randomized to receive treatment or placebo, but a group of of amyloid-negative individuals will participate in a natural history arm.

Results: Although converging evidence suggests that high amyloid burden is associated with an increased risk of cognitive decline, the impact of amyloid-positivity on the likelihood and timing of clinical progression to Alzheimer's dementia on an individual basis remains unknown. 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 imbed an ethics substudy in the A4 trial to evaluate the short and long-term impact of learning one's amyloid status (positive or negative). Alternative designs being considered by other prevention trial initiatives in genetic-risk subjects include randomizing non-mutation carriers to receive placebo only.

Conclusions: The advent of secondary prevention trials in preclinical Alzheimer's populations requires careful consideration of the issues of revealing biomarker results in asymptomatic populations.  These trials provide an important research opportunity to evaluate the impact of learning one's amyloid status in the setting of incomplete knowledge regarding the future clinical implications, and the factors that influence the response to this information.

 

F3-01-04
Tuesday, July 17 / AAIC 2012 Featured Research Session, 8:30-10 am

Disclosing amyloid imaging results

Jason Karlawish
University of Pennsylvania, Philadelphia, Pennsylvania, United States
Presenting author e-mail: jason.karlawish@uphs.upenn.edu

Background: Progress in Alzheimer's disease diagnostics has revolutionized how clinicians and investigators define the disease. Central to this revolution are biomarkers, measures of pathophysiology that will allow investigators and clinicians to "see" Alzheimer's disease prior to the onset of dementia. As promising as this revolution is, before clinicians can apply "preclinical Alzheimer's disease" to diagnose and treat persons prior to disabling functional losses, investigators need to perform clinical trials. These investigators need best practices to safely, effectively and efficiently use amyloid imaging in clinical trials designed to prevent cognitive decline in cognitively normal older adults. The A4 Trial is an excellent opportunity to develop and test these practices.

Methods:  Literature review and structured Delphi interviews with experts in the fields of genetic testing and amyloid imaging, and analysis of the planned NIA supported A4 Trial.

Results: Methods developed in the fields of genetic testing provide a template for how to disclose amyloid imaging results to asymptomatic older adults. Investigators need to develop methods to assess psychosocial wellbeing prior to testing and monitor this after disclosure. Disclosure materials need to convey the uncertainty of both a positive and negative amyloid imaging scan. The A4 trial offers the first opportunity to roll out amyloid imaging in a real world context and to gather data to inform how best to translate amyloid imaging into clinical care.

Conclusions:  Successful recruitment and retention to clinical trials in persons with pre-clinical Alzheimer's disease brings novel challenges related to participant informed consent and safety. The A4 Trial is an excellent opportunity to better understand how older adults make sense of biomarker results and how the results impact on health and well-being.


Contact:

Alzheimer's Association
Media line: 312.335.4078
E-mail: media@alz.org

 

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