Study partners should be required in preclinical Alzheimer’s disease trials

To minimize cost, maximize efficiency, and understand the clinical impact of knowledge of AD gene or biomarker results, most preclinical AD trials use a “transparent” enrollment design [15]. In transparent designs, the investigator discloses AD genetic or biomarker test results to the subject [16]. Standardized approaches to do this and to monitor participant health and safety after disclosure have been developed [17, 18]. Prospective safety data remain limited, however, as many of the first transparent design studies are ongoing. To date (September 2017), no study has reported a safety concern related to the impact of learning gene or biomarker results.

Data are available from two studies that have investigated the safety of disclosing amyloid positron emission tomography (PET) AD biomarker information to cognitively normal participants [19, 20]. In their randomized preclinical AD trial of physical exercise, Burns and colleagues required disclosure as part of enrollment after excluding participants demonstrating either depression or anxiety [20]. The investigative team disclosed results at a unique study visit, describing the outcome of PET imaging as demonstrating elevated or not elevated amyloid levels. Lim and colleagues made qualitative PET results (described as positive or negative) available to participants’ neurologists as an ancillary study to a preclinical AD trial enrolling older participants with both a family history of AD and subjective memory complaints [19]. Participants had the option to learn their results through their physician. Both studies were relatively small (27 and 4 amyloid-positive individuals in the Burns and Lim studies, respectively) and found that disclosure was largely safe; low rates of psychological adverse events were observed through standardized outcome measures. In both studies, however, participants learning positive amyloid PET results experienced elevations in distress and anxiety at the time of disclosure, which were deemed not clinically significant. In the Burns study [20], participants were required to enroll with a study partner. In the Lim study [19], all participants indicated that they had shared their results with family or friends and reported satisfaction with their support network.

Similar findings of test-related distress exist for the disclosure of AD genetic results. The Risk Evaluation and Education in AD (REVEAL) studies have examined the safety of disclosing apolipoprotein E (APOE) ε4 allele genotypes to cognitively normal middle-aged adults with a first-degree family history of AD. Learning AD genetic risk did not cause clinical anxiety or depression, but individuals who learned that they were ε4 carriers experienced transient test-related distress [21]. Although participants were not required to enroll with a study partner, discussing test results with others was associated with reduced scores on depression and anxiety measures 1 year after APOE disclosure [22]. APOE test results were most commonly shared with spouses or other family members [23].

These data suggest that study partners may play a key role in how participants in preclinical AD trials cope with anxiety and distress, and that enrolling participants who lack a support network could exacerbate the psychological harms of AD risk disclosure. Surveys of the public and of registries of individuals willing to participate in AD research find that 10–12% of individuals wish to gain access to biomarker and/or genetic risk information to instruct suicide planning [24‐26]. One of these studies found that suicide planning was associated with feelings of non-support and being single [24]. Investigators are ethically bound to minimize risk, maximize benefit, and ensure the safety of those enrolling in trials; enrolling only participants with a satisfactory support network, including at least one individual who can serve as study partner, is a sensible means to achieving this ethical obligation.

Preclinical AD trials use objective cognitive tests as primary outcomes. Key secondary outcomes, however, assess subjective cognitive and functional performance. It is unclear whether subjects or their informants provide the more accurate assessment of these constructs. Traditional measures of global or functional performance, such as the Clinical Dementia Rating (CDR) scale [27], are being used in preclinical AD trials. These rely on study partner reports. Other scales, such as those developed in the AD Cooperative Study Prevention Instrument (ADCS PI) study [28], include participant and study partner versions, enabling direct comparisons to determine which is optimal for preclinical AD trials.

The ADCS Activities of Daily Living Prevention Instrument (ADCS-ADL-PI) scale [29] examines 15 instrumental ADLs and 5 physical functions. In the ADCS PI study, the participant version demonstrated greater sensitivity to age effects, but also showed an apparent racial bias [29]. Both versions showed modest sensitivity for identifying global and cognitive decline, though only 12-month follow-up data have been reported (the duration of the study was 48 months) [29]. Both versions are used in the Anti-Amyloid treatment in Asymptomatic AD (A4) study [30], and study partners are being asked additional questions about the frequency of functional tasks and the time to complete those tasks. The decision to rely on study partners for these additional items is supported by observations that in mild cognitive impairment (MCI), study partner reporting of functional impairment is more strongly predictive of conversion to dementia than is self-reporting [31].

The Cognitive Function Instrument (CFI) was also developed in the ADCS PI study [32]. The CFI incorporates 14 subjective items assessing cognitive performance and has been proposed as a potential functional outcome measure for preclinical AD trials [33]. In the ADCS PI study, participant self-ratings were more closely related to objective cognitive testing performance than were study partner ratings at baseline. Study partner ratings were better correlated at 48 months [33]. The combination of participant and partner reports was more strongly correlated with cognitive test performance than either report alone [33]. Similar results were observed in the National Alzheimer’s Coordinating Center Uniform Data Set; subjective complaints in both participants and their study partners were associated with greater risk for MCI than were subjective complaints by either the participant or the study partner alone [34]. These results suggest that study partner reporting may be essential to maximize data integrity in preclinical AD trials.

Study partners have key roles in assuring the validity of other aspects of preclinical AD trials. One role is minimizing missing data by preventing drop out. Preclinical AD trials are lengthy and participation can be burdensome, requiring many complex visits. Previous AD prevention trials have incurred greater than expected dropout [35], putting statistical power at risk. In both AD dementia [36] and MCI trials [37], participants lacking a spouse are at increased risk for dropout. As with trials in individuals with cognitive impairment, preclinical AD trial participants who lack a support network such as a study partner may be at increased risk for dropout.

Based on US Food and Drug Administration (FDA) guidance, AD dementia trials assess efficacy using dual primary outcomes—typically a measure of cognitive performance and a measure of global or functional performance. The latter is required to demonstrate the clinical benefit of the cognitive performance. The first AD dementia trials used instruments based only on clinician assessment of the patient to assess clinical meaningfulness [38]. Expert consensus [38] and research demonstrating the benefit of informant reporting [39], however, led to a state of the art in which AD dementia trial co-primary outcomes incorporate or exclusively rely upon study partner reporting.

In preclinical AD, FDA guidance indicates that reducing decline on a single primary outcome measure may be sufficient to achieve approval [40], with post-approval studies to confirm that treatments result in clinically meaningful functional benefit. Though novel approaches to demonstrating clinical benefit should be pursued, such as assessing resource utilization through medical record or claims data [41], long-term extension studies using traditional global or functional outcome measures seem the most probable approach. These outcome measures require a study partner. Study partner-based tools will also be vital to examining the public health implications of preclinical AD treatment, including the time to dementia onset, the number of dementia cases, and the economic burden of disease [42].

Preclinical AD trials will change how society and medicine conceive of what is AD [4]. These trials must instruct not only the use of new therapies, such as drug dosage and safety, but also how to provide care in this new model of AD. In the absence of a drug that halts the onset of cognitive decline across all patients, some patients will suffer cognitive impairment. AD will remain a disease that requires planning, support, and care. No standards exist for this clinical practice in persons who have preclinical AD. Trials should be an essential source of data to develop and refine this practice.

Trial results should instruct the clinical practice of widescale biomarker and genetic testing and disclosure. Truth and honesty in diagnostic disclosure, no different from that recommended in AD dementia [43], includes communicating the prognosis of cognitive decline and functional impairment. Discussing this information will necessarily engender other conversations to make plans to further reduce the risk of cognitive decline, such as exercise and cardiovascular health. Patients will likely begin to consider financial matters such as the timing of retirement and where they will live. Issues of future healthcare decisions will be considered [44]. Such planning will be critical not only to maximize health, but also to minimize the risks associated with early signs of cognitive impairment such as medication errors, driving accidents [45], and financial error and abuse [46].

A sensible means to do all of this is to involve another person in the life of a patient with preclinical AD. This person should be the study partner. Patients should want to have someone, such as a partner, adult child, or close friend, to help them to plan for this future. Patients may need to have someone to watch over them because, in time, as preclinical becomes clinical AD, patients will need the help of someone else to manage their problems. Physicians providing clinical care for persons with preclinical AD will strongly recommend the involvement of such a person in both diagnostic and treatment phases of management. Filling this role, or helping to identify a network that can support these needs, should be part of the role of a study partner.

Many potentially eligible preclinical AD trial participants lack a person who can fill the study partner role. While this may effectively limit the pool of participants, the requirement may also produce sample bias. Understanding the implications of this bias and ensuring that those who lack the support network needed to enroll in trials can still benefit from the knowledge gained through them will be necessary to maximize the public health impact of preclinical AD research.

The relationship between criteria to serve as study partner and the integrity of informant data has not been established in preclinical AD, or in AD dementia for that matter. In AD dementia, spousal study partners differ from non-spousal study partners in the accuracy of cognitive assessments [47] and in their concordance with patient ratings of quality of life [48]. No study of informant assessment of cognitive function in preclinical AD has explored the qualifications of the study partner and whether some individuals may yield more sensitive identification of participant cognitive decline than others. Requiring study partners will preclude some potentially eligible participants from enrolling. Ensuring that those who are enrolled will provide high-integrity data will be essential to safeguarding trial value and justifying the cost of the requirement.

A critical aspect of preclinical AD trial conduct is to protect participants from unwanted disclosure of genetic or biomarker information through electronic medical records [4]. However, the risk for stigma in the home and in social situations remains in these trials and one open question is how often and with whom do preclinical AD trial participants share their testing results?

In a study of preclinical AD trial enrollment decisions, in which participants were randomly assigned to consider a hypothetical trial that did or did not require biomarker disclosure, we found that the study partner requirement was a more important barrier to enrollment when disclosure was required [12]. The requirement was rated as more important than drug risks in the disclosure arm of this study. These preliminary data suggest that preclinical AD trial participants may be reluctant to share with others that they have biomarker evidence of AD. Some participants may face an unenviable choice: have others potentially learn information about their health they do not want shared, or forego enrolling in a study in which they wish to participate.

Further study will be necessary to instruct optimal means to overcome the study partner requirement as a barrier to enrollment without sacrificing participant privacy and confidentiality. Greater understanding of the frequency and extent of this occurrence are needed. Modifying or improving the disclosure process, which does not currently emphasize the role of the study partner, may improve the willingness of participants to share biomarker information. Ensuring that participants are comfortable and ready to share AD risk information may be critical, as may be education and counseling of others in their support network.

Respecting participant autonomy is an ethical requirement in clinical research. Requiring preclinical AD trial participants to involve another person in the study does not disrespect autonomy. If this requirement does not align with a person’s values of identity, privacy, and authority, he or she can freely choose not to enroll. Among those who do enroll, the requirement may foster their autonomy. These participants are at risk for cognitive and functional impairments. A study partner may become the participant’s trusted advocate to whom the participant can tell how they would like to be cared for and other plans for the future. The advocate can also monitor the participant for signs of impairment. These activities are recognized as a means to maintain autonomy despite the loss of capacity.

A vast scientific literature on the caregiver has informed interventions to improve the lives of patients with AD dementia [49]. Some preclinical AD participants will become clinical AD patients and need a caregiver. Little is known about the implications of who is available to preclinical AD patients for support, to aid with planning, and for assistance with instrumental ADLs with high cognitive demand. The field will ultimately need to know who these people are, if and when they change, and what if any characteristics predict their performance in these roles. Moreover, these individuals will likely need interventions to assist them in these roles, not unlike the interventions to assist dementia caregivers.