What Influences the Willingness of Blacks and African Americans to Enroll in Preclinical Alzheimer’s Disease Biomarker Research? A Qualitative Vignette Analysis

INTRODUCTION

Alzheimer’s disease (AD) is a progressive neurodegenerative condition leading to cognitive impairment and is typically diagnosed with the onset of cognitive symptoms and functional decline [1, 2]. Yet, growing evidence demonstrates that pathophysiological changes underlying AD can be detected by biomarkers in a “preclinical” phase before symptoms appear [3]. Biomarkers for AD are becoming increasingly important as diagnostic and prognostic tools. Establishing validated and prognostically useful biomarker tests is critical to identify treatment populations and improve diagnosis of symptomatic cognitive impairment due to AD [4]. Preclinical AD biomarkers can be used to identify appropriate clinical trial cohorts or to detect AD in the stages of the disease when intervention may be more effective [5]. The US Food and Drug Administration (FDA) has recently approved the first disease-modifying treatment for AD on the basis of its reduction of amyloid plaques [6]. In the future individuals with late onset AD, which accounts for over 90% of AD cases [7], will likely need biomarker evidence of AD to obtain treatment [8].

Most biomarker research to date has been conducted in White, non-Hispanic samples [9,10, 9,10], as has most biomedical research overall. Despite over 30% of the US population being members of racial and ethnically underrepresented groups, these individuals only make up around 17% of participants in clinical trials [11]. Data from clinical and genetic research in international cohorts shows a similar lack of diversity [12, 13]. The significant need for more inclusive research across diseases has been recognized, such as in large-scale research on the intersection of genetics and lifestyle [14]. Specifically in AD research, a recent systematic review demonstrated that a median of 89% of participants of those studies reporting race and ethnicity were White [15]. There is a great need for more inclusive research. Incidence and prevalence of AD and other dementias is higher among Black/African American and other underrepresented groups, with some estimates suggesting twice as much AD risk among Blacks/African Americans when compared to Whites [16]. Blacks/African Americans face a number of disparities in dementia care, as they tend to be diagnosed in later stages of the disease and use fewer services, resulting in higher care and financial burdens for families [17, 18].

The limited inclusiveness of biomarker study samples raises concerns about the validity and reliability of biomarker data in underrepresented groups [19]. Data shows that biomarker changes in AD can vary between Black/African American and White populations, and similar biomarker profiles can be associated with divergent cognitive function [20, 21]. The current lack of reliable biomarker data for underrepresented groups limits the diagnostic, prognostic, and therapeutic validity of biomarkers for clinical use in these populations, and has the potential to further exacerbate health disparities [9].

The data that exists about attitudes towards AD biomarker research shows that interest is generally high among those who consider themselves to be at risk for AD or are already involved in AD research [22, 23]. However, the decision to enroll in a biomarker research study is complex [24]. Little is known about how individuals weigh factors like personal AD risk or procedure invasiveness when deciding to participate in research. In an analysis of interest in a preclinical AD trial, participants were just as willing to join a study where they learned their biomarker results as one in which they did not, indicating reasons other than learning amyloid results may drive actual participation [25]. Other reasons influencing participants may include the invasiveness of procedures involved [26], or an altruistic desire to contribute to research [27].

Prior studies on recruitment and retention in AD research have indicated the importance of aspects such as trust in researchers, study burdens, socioeconomic context, personal attitudes, and levels of education [11, 28]. However, these studies have focused on participation in clinical trials rather than biomarker studies [29, 30]. Research has typically compared Black/African American and White populations, and focused less on a comprehensive account of Black/African American perspectives. This approach may characterize the perspective of specific groups with respect to similarity or difference to the perspectives of Whites, and potentially reduces the ability to explore the breadth of perspectives within that specific group. One survey study evaluating willingness to participate in a biomarker-based clinical trial showed that Blacks/African Americans were generally less likely to enroll, and rated study risks and procedures as being more important to their decision than Whites. Blacks/African Americans were also somewhat less interested in receiving their personal study results than White participants [29]. A survey in a community-based registry suggested that underrepresented groups, including Blacks/African Americans, were less willing to enroll in AD studies than Whites [30]. In a qualitative study among community-dwelling Blacks/African Americans, mistrust of research was the major barrier to participation in biomarker research [31]. Though mistrust limits the involvement of Blacks/African Americans in research, enrollment in dementia research can be increased with comprehensive and community focused recruitment strategies [32]. Altruism is also an important factor motivating ongoing research participation [28], but it is unknown how altruism impacts participation in biomarker studies, or what strategies might improve enrollment specifically for this research.

This study aims to understand factors influencing cognitively intact Blacks’/African Americans’ willingness to participate in preclinical AD biomarker research. We present data from the Alzheimer’s Biomarker Survey, a telephone survey designed to gather quantitative and qualitative data on willingness to enroll in hypothetical biomarker studies. Here, we report qualitative information with the goal of understanding the relative significance of different themes in influencing willingness to enroll. Our sample consists of individuals who are already involved in AD research and have high levels of education, and is thus not broadly representative [33]. Research must ultimately become more inclusive, enrolling Blacks/African Americans not involved in research and with diverse educational backgrounds. Given the dearth of available data about Black/African American participation in biomarker research, this study contributes to understanding the factors involved in decision-making, which can ideally be leveraged to increase participation of those Blacks/African Americans already involved in research, and spur further research moving towards more inclusive research outside of those populations typically represented in AD cohorts. Representative research will ultimately be necessary to reduce disparities in AD-biomarker research as well as clinical interventions. Given that treatment with amyloid targeting drugs will require biomarker evidence of AD pathology, furthering biomarkers that can accurately diagnose AD in diverse populations can also move the field further towards equitable care for AD.

METHODS

RESULTS

Participants described several themes that influenced their willingness to participate in biomarker research. The first section presents themes motivating participation, and the second, themes discouraging participation. An overview of themes and how frequently they were mentioned by participants is shown in Table 3. The third section examines the relationship between the themes and willingness to participate in biomarker research.

DISCUSSION

This work adds to an understanding of factors that influence willingness to participate in AD biomarker research among Black/African Americans. Moreover, it increases the representativeness of the literature examining willingness to of potential participants to enroll in biomarker studies. Overall, individuals in the current cohort considered several motivating or discouraging factors when weighing whether to enroll in research. A fuller assessment of these themes is necessary to characterize the facilitators and barriers to biomarker research, and may suggest opportunities to increase enrollment [39]. Most biomarker and AD research has enrolled non-diverse samples, which limits the generalizability of findings, potentially undermining the provision of accurate diagnosis and appropriate treatment for Blacks/African Americans and other underrepresented groups. Thus, strategies to improve the inclusiveness of research are critical.

Motivations to participate in biomedical research can be complex. They may involve pragmatic aspects such as time investment or transportation [40], or personal attitudes such as trust or altruism around research [28, 42]. The concerns motivating participation may also change over time, depending on participants’ personal circumstances and relationships [43], and may continue because of a desire to continue a previous commitment to research [44]. Our study highlighted several of these themes that were particularly salient to enrolling in biomarker research, though it was not designed to clarify other aspects of the decision-making process, such as how much each individual theme influences willingness to enroll or how these might change over time. As expected, themes motivating participation in research were cited most frequently among those who were most willing to enroll in biomarker research. Themes discouraging research were cited most commonly among those least willing to participate. Individuals undecided about participating cited a mix of themes that influenced their decision. While this study identified themes relevant to enrollment, it was not designed to clarify other aspects of the decision-making process, such as how much each individual theme influences willingness to enroll. Arguably some concerns, such as the specific psycho-social consequences of biomarker testing, utility, and stigma are specific to this research, and informational material that concretely address these concerns may affect willingness to enroll. For instance, studies might provide information about the impact of disclosure on future planning during recruitment. Focusing on understanding personal risk for AD might involve more emphasis on explaining the value of biomarker information for prognosis.

The usefulness of testing has been primarily discussed from a theoretical perspective, rather than with evidence about participant viewpoints [45]. However, several individuals in our study questioned what the usefulness of a positive test result would be, a theme we term “utility”. Around one-third of those who were ‘not at all’ or ‘a little’ willing to participate did not believe biomarkers had any utility, for instance because AD was not treatable. Some previous work has shown that withholding biomarker results does not change willingness to enroll, which may imply that the personal relevance of results does not influence decision-making [25]. The utility of biomarker results may become more salient in the future: with the recent approval of an amyloid-targeting agent, and additional similar agents in the pipeline [46], biomarker testing may lead to actionable information for participants.

Participants also felt that biomarkers would have limited utility because the results would be ambiguous. This is similar to findings from a qualitative study of long-term outcomes after disclosure. After being told they had elevated amyloid, individuals wanted more precise information than ‘elevated’ or ‘not elevated’ [47]. Efforts to refine prognosis are ongoing, and evidence from risk communication in other fields has also shown that information may need to be tailored to specific groups, and be presented using multiple strategies [48]. The current knowledge gap may provide an opportunity to explore if prognostic information influences enrollment, and what types of prognostic information are useful, such as timelines or other visualizations [49]. The significance reported by participants of the psychosocial impact of disclosure and utility of testing suggests that future research should examine trial designs with more prognostic elements and how willingness to participate in biomarker research is impacted by information about the consequences and individual benefits of testing.

Harms were a significant theme that discouraged willingness to enroll. This is consistent with other studies finding potential harms to be an important consideration for Black/African American groups [29, 31]. Concerns about physical harms as a result of participating in biomarker research have been infrequently reported in the literature. In the limited existing data about harms, typically from White cohorts, individuals report concerns about potentially negative psychological consequences or stigma as reasons discouraging research participation [50]. However, this may be a specific concern among Blacks/African Americans [31], who are less willing to participate in research involving lumbar punctures than compared to Whites [26, 51]. While more research is needed on whether specifically lumbar punctures represent a barrier to research among Blacks/African Americans, the rapid progress towards blood-based biomarker testing may lower barriers to research participation [52].

Though our study was not designed to provide robust quantitative correlations, the number of times each theme was mentioned does suggest trends. It is notable that concerns about harms were relatively stable across groups who were ‘a little’, ‘somewhat’, or ‘very’ willing to participate. A possible explanation is that among individuals already participating in research, familiarity with study procedures or additional potential harms may not substantially change their willingness to participate in further research. Instead, they may decide to participate based on other factors (e.g., altruism or concerns about psychosocial outcomes). As our study did not generate the type of data necessary to explain this finding, this should be considered a hypothesis to explore in further studies.

Participants also cited concerns about negative psychological consequences and stigma as causing anxiety about health, as has been reported previously for prospective participants in biomarker studies [53]. Other work has shown that after disclosure, individuals with an “elevated” result may have a wider range of positive or negative outlooks on the future, in comparison to the more uniformly positive outlook expressed by those with a “not elevated” result [54]. Prior research using standardized mood assessments has shown that there is no increase in mood symptoms up to one year after disclosure, indicating that disclosure is generally safe [10, 55]. However, given the spectrum of psychosocial consequences cited in our study, such as feelings about “the end of one’s useful life”, it is possible that the consequences of biomarker disclosure may manifest in a number of ways, not all of which may be fully captured by standardized scales evaluating mood. Safety data also come from White, non-Hispanic individuals without significant mood disorders and in people willing to learn their biomarker results, which may not be not representative of clinical populations [56]. Future studies may try to characterize such consequences for health anxiety, and do so in populations reflecting a broader range of mental health experiences.

Previous research has shown that Blacks/African Americans are often reluctant to enroll in biomedical research because of negative experiences with research or feelings of mistrust. Proposed solutions have focused on increasing trust and community engagement [39]. We did not find that themes of mistrust or reputation of the researchers and institution were prominent. In our cohort, feelings of altruism were a significant motivating factor, which is perhaps not surprising given that participants were already involved in research. For a handful of participants (n = 5), this altruism was linked to specific desire to help the Black/African American community through research. This finding is similar to other work that has shown altruism to be an important motivator for joining AD biomarker research [27, 57]. Altruism is a major factor motivating participation in AD research among Blacks/African Americans [28]. This may have important implications for increasing the involvement of Blacks/African Americans who are already participating in non-biomarker research. Further research could explore whether enrollment is impacted by researchers sharing the importance of biomarker research, or how it relates to other research the participants are engaged in. Biomarker research is closely directed at diagnosis and treatment, which may appeal to those who are participating in AD research to find treatment (as some of our participants suggested in the above quotes). Mistrust may not have been a prominent theme due to a difference in samples: because participants in our study were already engaged in research, they may have already developed higher levels of trust versus community participants without previous research involvement. This finding may also indicate that trust develops, or mistrust decreases, with increased time and engagement in research. Future research could explore how attitudes vary not only among underrepresented groups, but also among recruitment source (e.g., already involved in research versus community-based).

This study has several limitations. First, enrollment of samples into AD research has been influenced by recruitment strategies [33, 58], and these research samples may not reflect the composition of future clinical populations [56]. Our sample was drawn from participants who are already extensively involved with AD research and may hold views that differ from more general populations. Our sample also had high levels of education, and higher educational attainment is associated with more interest in research participation among Blacks/African-Americans and other groups [40, 60]. The prior involvement in research and levels of education may also limit the ability to generalize to other Black/African American populations not already involved in research, since a main barrier—trust—may not have been as salient for our sample. Individuals in our sample may have had a higher interest in learning their biomarker results, as many were already enrolled in longitudinal studies because of their family history of AD. Increased risk due to family history of AD has been associated with a higher interest in participating in AD disclosure research [22]. Finally, our population was primarily composed of women (74%), and was too small to discern differences between genders. These limitations suggest the importance making research populations more inclusive in not only in terms of racial and ethnically minoritized status, but also regarding gender, levels of education, and prior involvement in research.

Second, methodological limitations include the necessity of using a vignette. The vignette instructed individuals to ignore factors such as the time the study would take or travel involved. This may have resulted in the importance of burdens being under-reported in our sample, since some participants mentioned burdens despite these instructions. Participants also responded to a hypothetical question, which might not reliably predict their actual enrollment in research in the future, or their reasons for doing so. Finally, data was generated from a free response item, but we were not able to include follow-up questions. This is best suited to identify important themes that are related to enrollment, and can suggest relationships between themes and a decision to enroll, but does not provide more comprehensive information about participants’ reasoning.