Cognitively Healthy Individuals Want to Know Their Risk for Alzheimer’s Disease: What Should We Do?

INTRODUCTION

In this issue of the Journal of Alzheimer’s Disease, Richard Milne and colleagues present the results of a focus group study to discover the attitudes and concerns research participants and their supporters hold toward learning biomarker test results [1]. Their results were intended to inform the development of the risk disclosure process for recruitment into clinical trials [2, 3]. Their findings also foreshadow ethical and pragmatic challenges of translating advances in Alzheimer’s disease (AD) diagnostics into routine clinical care.

Disclosure of AD biomarker results to cognitively unimpaired individuals is not currently recommended in routine clinical practice [4, 5]. The rationale for this is the lack of individualized risk estimates, concerns for harmful psychosocial outcomes, lack of therapeutic options, and concerns that testing could result in over-diagnosis of a stage of AD that is not yet validated. AD biomarkers are being disclosed to unimpaired or mildly impaired individuals enrolled in research particularly AD prevention trials. At least six trials are currently underway testing drugs in cognitively unimpaired persons who have either an AD gene or biomarker (e.g., a copy of the ApoE4 gene or “elevated amyloid”). In the U.S., the goal of these studies will be to achieve a national plan to discover an effective treatment by 2025 [6]. Whether by 2025 or later, if this approach succeeds, AD biomarker testing will move from research into routine clinical practice. In this new model of care, clinicians will use gene and biomarker tests to diagnose AD before a person has cognitive impairment and then prescribe interventions to prevent or delay the onset of these problems.

Milne and colleagues found that participant’s curiosity may be a common reason to support disclosing biomarker results in the research setting. Although some participants may feel as a matter of autonomy a strong desire to learn their biomarker result, this reason is alone not sufficient. More compelling is the suggestion by Milne and colleagues that disclosure is justified when the goal of the clinical trial is prevention-based because the participant is positive for an AD biomarker. Their study and others [7, 8] show another reason to disclose biomarker results in research. Research emphasizes safety and uses rigorous and standardized procedures to gather data to discover how learning this information affects study participants’ and their study partners’ health and well-being. What is discovered in the context of clinical trials will guide the safe and effective use of disclosure in the research setting and in routine clinical practice.

The authors reported that participants’ primary reason to learn an AD biomarker result was the personal utility of the result. This describes the expectation that the knowledge will have some value, positive or negative, that is independent of clinical or health outcomes. However, participants expressed strong expectations that at least part of the utility would be access to risk reduction strategies and follow-up care. These expectations are understandable, but they raise ethical and pragmatic problems—both for research and routine clinical practice.

The evidence supporting interventions to reduce the risk of developing AD is weak at best [9, 10]. This leads to an untenable situation. Individuals are informed of a biomarker result that conveys an elevated risk of a disease yet do not have access to ways to reduce or manage that risk. The absence of effective risk reduction strategies is an omission that could leave individuals disappointed and as well susceptible to exploitation by programs that lack evidence, and vulnerable to other negative outcomes, like stigma, depression and anxiety. We need the results of studies that will develop these strategies.

An important opportunity to conduct these studies is the disclosure of AD risk information occurring in prevention trials. To adequately provide risk reduction strategies to individuals who learn they have a “positive” or “elevated” result, it is key to understand how they may be interpreting this risk. Little is known about how individuals understand results of AD biomarker tests or the “risk” of AD conveyed by them. What is known is largely from studies where individuals learned they had genetic markers of disease. Biomarker tests are distinct from genetic tests. They convey information about the probability a person will develop AD dementia and they are dynamic. They are likely to change over time because they depict active underlying pathology as opposed to susceptibility.

Risk reduction strategies must be developed to mitigate the gamut of issues associated with an elevated AD biomarker. Because an AD biomarker result depicts a probability of future disease, notions about lowering this “risk” often center on delaying the onset of clinical symptoms. However, being “at risk” for AD also includes being vulnerable to other types of problems, like financial mishaps and abuse, the failure to adequately plan for end-of-life, and stigma. In addition to interventional studies that develop clear evidenced-based options for reducing disease risk, research is needed to develop methods to address these problems. This might include strategies that help individuals to plan for the future, implement financial safeguards, and reduce stigma [10]. Moreover, individuals suggest there is personal utility in learning a biomarker result. Learning a biomarker result might encourage individuals to seek out strategies. Studies to understand how individuals do or do not self-initiate activities to manage AD risk may help inform development of risk reduction strategies.

Suicide has long been a concern in deciding to disclose AD risk information to trial participants. Although studies have shown that suicide after disclosure may be rare [11], it remains crucial to screen for its risk factors [12]. This is particularly important for deciding whether learning AD risk information could compromise one’s present safety. It is also important for being able to anticipate how one’s future safety might be impacted if and when the person begins to experience cognitive decline, which can elevate the risk of suicide. Research with preclinical Huntingon’s disease suggests the need for professional counselling and well-designed protocols to adequately address suicide risk [13]. Moreover, individuals found to be at risk for AD but disqualified for a trial for other reasons, such as an abnormal laboratory result, are excluded from the benefits of the group identity offered by trial participation [11]. This could exacerbate risks for suicide. Enrollment into an alternate research study or clinical follow-up may help minimize suicide risk and other poor outcomes.

Patients expect and want follow-up after learning a positive AD biomarker result. This presents novel challenges for clinical practice. AD care currently focuses on the management of symptoms. Memory evaluation centers and primary care practices are not equipped to monitor potentially large numbers of unimpaired individuals. Research is needed to understand how to design systems and procedures to do this. Short- and long-term follow-up are essential for understanding how disclosure of risk information may or may not impact a person. Follow-up studies can also help answer questions about how to implement systems that monitor cognitive decline—such as when to transition a person from passive to active monitoring or from monitoring to clinical care—and how to effectively deploy and maintain these systems.

Appropriate procedures for follow-up and monitoring need to be established within the research context in order to understand these issues and develop solutions. These procedures may also help meet the immediate needs being expressed by study patients and study partners; however, incorporating these procedures surrounding risk in research may pose challenges. Engaging study patients and study partners in risk reduction, follow-up, and other pragmatic issues might be outside the scope of the primary research question, especially after the study has ended and the data are collected.

CONCLUSION

Milne and colleagues’ study moves the field closer to processes for disclosing AD biomarker results. Careful attention is needed to develop evidence-based guidelines that meet the needs of persons learning these results. This includes attending to what information should and should not be included in the disclosure process and when and how this information should be communicated to patients and their supporters [7]. More research is needed to inform the development of these guidelines. How individuals understand and are affected by learning AD biomarker data remains largely unknown. How healthcare delivery needs to adapt to meet their needs—via strategies for ongoing monitoring or practices that aid long-term and financial planning—is not yet known.

DISCLOSURE STATEMENT

Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/17-1089r2).