Literature Review

How Do Cognitively Normal Adults Understand Elevated Brain Amyloid Results?

Some participants in an Alzheimer’s disease prevention trial wanted detailed information about the degree of amyloid elevation in relation to the threshold for study entry.


 

Most cognitively normal adults with elevated brain amyloid in an Alzheimer’s disease prevention trial “understood that elevated amyloid conferred an increased but uncertain risk of developing Alzheimer’s disease,” according to research published in the January issue of JAMA Neurology. Some participants, however, “desired clarification of the term ‘elevated’ beyond its being a categorical result enabling trial entry eligibility.”

“Clinicians should be prepared to explain how and why a dimensional biomarker, in this case amyloid-β as measured using PET, is converted to a categorical state … and what the result means in terms of a person’s risk for developing Alzheimer disease dementia,” the researchers said.

Trials in Asymptomatic Populations

Advances in understanding the pathophysiology of Alzheimer’s disease have led to clinical trials in cognitively normal adults with evidence of Alzheimer’s disease biomarkers, but data are limited regarding how cognitively normal adults, comprehend biomarker results. A person’s knowledge of his or her amyloid status “may generate clinical and ethical problems, including the potential for misunderstanding, discrimination, stigma, depression, anxiety, and, in the most extreme cases, suicide in the face of a debilitating disease with no treatment,” the researchers said. “There is no consensus … about whether and how to return Alzheimer’s disease biomarker results to cognitively normal adults, given the prognostic uncertainty and absence of available treatments.”

To determine participants’ comprehension of an elevated amyloid PET biomarker result, Jessica Mozersky, PhD, of the Department of Medical Ethics and Health Policy at Perelman School of Medicine, University of Pennsylvania in Philadelphia, and colleagues conducted the Study of Knowledge and Reactions to Amyloid Testing (SOKRATES).

Jessica Mozersky, PhD

The researchers conducted two semistructured telephone interviews with 80 participants from nine study sites. Fifty of the participants had elevated amyloid PET scan results and 30 had not-elevated amyloid PET scan results. Researchers conducted the interviews about four to 12 weeks after result disclosure and one year later. The present study examined the first interviews of 50 participants with elevated amyloid results.

Of the 50 participants, 49 (98%) were white, 40 (80%) had a family history of Alzheimer’s disease, and 30 (60%) had a postgraduate educational level. Patients were between ages 65 and 85, and half were men. Data were collected between November 5, 2014, and December 10, 2015.

The A4 Study and SOKRATES

SOKRATES is a substudy of the Anti-Amyloid Treatment in Asymptomatic Alzheimer (A4) study, which is testing whether solanezumab, compared with placebo, affects the rate of cognitive decline in cognitively normal adults with elevated amyloid.

Clinicians informed all A4 study participants of their amyloid PET scan result through a disclosure process that was designed to maximize safety and effectiveness. The process included a depression and anxiety prescreen, an educational session, a teach-back exercise to check comprehension, an in-person disclosure by a trained clinician, and a telephone follow-up to assess mood. In addition, a study guide provided information about the amyloid PET scan, its purpose, possible results, and limitations. “The study guide describes ‘preclinical’ or ‘asymptomatic’ Alzheimer’s disease as a new concept in development and explains that elevated amyloid ‘does not necessarily mean you will develop Alzheimer’s disease-related memory loss’ but can be associated with an increased risk, and individual risk estimates are not possible. It further explains that ‘not elevated’ does not mean you will never develop Alzheimer’s disease or ‘elevated amyloid’ in the future,” the researchers said.

A4 trial sites provided participants with materials describing the SOKRATES substudy, and interested participants contacted the SOKRATES researchers at the University of Pennsylvania.

The researchers examined comprehension of an elevated amyloid PET scan result by analyzing participants’ responses to the following questions: “What was the result of your amyloid PET scan?” (followed by “Can you tell me in your own words what that means?” or “How would you explain it to a friend?”), “Was it the result you expected?” and “Did the result teach you anything or clarify anything for you?”

Understanding Risk

When asked, “What was your result,” 64% used the word “amyloid” or “amyloids,” and the remaining participants primarily referred to the presence of “plaques” or to the result being “positive.” Two answers suggested misunderstanding. Six participants used the word “elevated” to describe their amyloid result, while most participants used other words (eg, “increased,” “higher levels,” or “excessive”). Nineteen participants described the result in terms of qualifying for the A4 study (eg, “enough amyloid buildup to qualify for the study”).

More than half of the participants (54%) expected their elevated result due to a family history of Alzheimer’s disease or subjective memory problems. Fifteen participants (30%) were unsure what result they had expected or were prepared for either result. Eight participants (16%) expected not to have elevated amyloid because they had led a healthy lifestyle, had no family history of Alzheimer’s disease, and had no subjective memory concerns.

When asked about the meaning of the result, 94% responded with their understanding of the risk of developing Alzheimer’s disease conferred by elevated amyloid. Thirty-one participants (62%) interpreted the result as signaling an increased risk of developing Alzheimer’s disease, while 10 participants (20%) perceived the risk conferred by elevated amyloid to be equivocal. Six participants (12%) perceived elevated amyloid to mean that Alzheimer’s disease was imminent or that it was diagnostic of Alzheimer’s disease.

Twenty participants (40%) were dissatisfied “with the lack of specificity regarding the meaning of ‘elevated,’” the researchers said. Some wanted “a granular result describing the degree of amyloid elevation … and how close they were to the threshold for study entry,” and some participants expressed frustration at the lack of detail.

Implications

The results suggest that some people who are cognitively normal but have subjective memory concerns “will use an Alzheimer’s disease biomarker test to explain their memory concerns, potentially pathologizing normal and nondisease-related cognitive aging,” the researchers said. In addition, people without a family history of Alzheimer’s disease or subjective memory concerns “may be unprepared to receive their biomarker results.”

A desire for more specific and detailed information about the results may be especially relevant to cognitively normal adults. “Such specific information is likely less relevant for symptomatic individuals who receive a binary result that either confirms or rules out a diagnosis that explains their history of cognitive decline,” the researchers said.

Because most participants were highly educated and had a family history of Alzheimer’s disease, the applicability of the results to other populations is limited. In future studies, the researchers plan to assess how elevated versus not-elevated brain amyloid results influenced SOKRATES participants’ sense of self, social relationships, and behaviors.

Potential Interventions and Ethical Concerns

The long prodromal period of Alzheimer’s disease “represents our greatest hope for effective therapeutic intervention as well as a domain of serious ethical concern,” said Winston Chiong, MD, PhD, of the Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, in an accompanying editorial. “Prevailing appropriate use criteria advise against clinical use of amyloid imaging in asymptomatic individuals, citing ‘a significant potential for patients and families to make inaccurate assumptions about risk and future outcomes on the basis of amyloid PET results.’” The A4 trial, however, “not only requires that amyloid imaging be performed but also effectively requires that the results of such imaging be disclosed to participants.”

Qualitative research may elicit unanticipated beliefs or concerns, and in SOKRATES, “a sizable proportion of participants … expressed dissatisfaction with the categorical characterization of results.”

“Overall, the findings of Mozersky and colleagues are broadly reassuring regarding research participants’ ability to understand the prognostic uncertainty of amyloid imaging. But as the authors note, caution is needed in generalizing their results,” Dr. Chiong said. “These participants represent a selected subpopulation of an already rarified group: prospective participants in the A4 study were provided with study materials for this substudy, and interested participants themselves contacted the study investigators. These participants were thus likely to be particularly supportive of the Alzheimer’s disease research enterprise, and given their family histories and high educational attainment may have been better positioned to interpret information about the limitations and ambiguities of testing than other groups.”

Suggested Reading

Chiong W. Challenges in communicating and understanding predictive biomarker imaging for Alzheimer disease. JAMA Neurol. 2018;75(1):18-19.

Mozersky J, Sankar P, Harkins K, et al. Comprehension of an elevated amyloid positron emission tomography biomarker result by cognitively normal older adults. JAMA Neurol. 2018;75(1):44-50.

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