Perceptions about dementia clinical trials among underrepresented populations: A nationally representative survey of U.S. dementia caregivers

Background: The research community has historically failed to enroll diverse groups of participants in dementia clinical trials. A unique aspect of dementia care research is the requirement of a study partner, who can attest to the care recipient’s clinical and functional capacity. The aim of this study is to assess racial and ethnic differences and the importance of various trial considerations among dementia caregivers, in their decision to participate in clinical research as study partners. Method: We embedded a vignette about a hypothetical dementia clinical trial in a nationally representative survey of U.S. dementia caregivers, oversampling non-Hispanic Black and Hispanic caregivers. Dementia caregivers were asked about their willingness to participate in the trial with their care recipient and rated the importance of nine considerations in hypothetical decisions to participate. Caregiver demographic characteristics were analyzed as predictors of trial participation in a base demographic model. In a second reasons model caregiver demographic characteristics and the rated importance of the nine considerations were separately analyzed as predictors; both models used survey-weighted logistic regression. Result: The sample consisted of 610 dementia caregivers, including 156 non-Hispanic Black and 122 Hispanic caregiver participants. In the base demographic model, hypothetical trial participation was negatively associated with older caregiver age (OR (odds ratio) = 0.72, p = < 0.001). In the reasons model, the rated importance of a social responsibility to help others by participating in research was significantly associated with participation (OR = 1.56, p = 0.049), while the importance of the possibility of the care recipient experiencing serious side effects was negatively associated with participation (OR = 0.51, p = 0.003). In both models there was no significant difference in hypothetical participation between non-Hispanic Black and non-Hispanic White caregivers, or between Hispanic and non-Hispanic White caregivers. Conclusion: Hispanic and non-Hispanic Black dementia caregivers were not less likely than non-Hispanic White dementia caregivers to participate in a hypothetical dementia clinical trial. Our study suggests that failures to recruit diverse populations in dementia clinical research are not attributable to less willingness among members of underrepresented groups but may instead reflect structural barriers and historic exclusion from trial participation.


Introduction
Lecanemab, a newly approved anti-amyloid monoclonal antibody that modestly slows the progression of Alzheimer's disease, has been heralded as a "step forward" towards a future era of more effective disease-modifying therapies for dementia. 1Controversies over the approval and coverage of new antiamyloid treatments have also focused attention on historic failures of the research community to enroll diverse groups of participants in dementia clinical trials, 2,3 raising concern that populations most affected by dementia may be denied the bene ts of society's investment in dementia clinical research.As examples, Hispanic Americans and non-Hispanic Black Americans are nearly twice as likely to experience dementia compared to non-Hispanic White Americans 4,5 ; yet are underrepresented in dementia clinical trials.As structural and medical factors underlying increased risk for dementia in these groups (including undertreated chronic medical conditions, environmental injustice, experiences of racism including within the health care system, and other social determinants of health) could also in uence the safety and e cacy of new treatments, dementia clinical trials that do not represent the U.S. population at risk for dementia may lack generalizability.
A special feature of dementia clinical trials that in uences enrollment is the requirement of a study partner, who accompanies the patient to visits and attests to the patient's clinical and functional status. 6,7 Fmily and friend caregivers' willingness to serve as study partners, and their opinions about the advisability of patients' participation, are major factors in whether patients can feasibly participate.
Therefore, in efforts to improve diversity in dementia clinical trials, researchers must consider the perspectives of family/friend dementia caregivers, who are needed as study partners and who often also assist in communicating and interpreting the patient's own values in care and research. 8ior research has studied the impact of the type of study partner on dementia clinical trial enrollment, nding that spousal caregivers are disproportionally enrolled compared to non-spousal caregivers. 9,10 her work has documented dementia study partners' perspectives on the burdens of research participation and considerations in uencing willingness to enroll in clinical trials.A limitation of many of these studies is that they sample dementia caregivers who are already enrolled as study partners in Alzheimer's disease research centers, and probably do not re ect the concerns of dementia caregivers who decline participation or, in many more cases, have never been approached for participation.Efforts to expand clinical research participation will depend crucially on the perspectives of caregivers who are not presently engaged in research.
In this preregistered study we embedded a vignette about a hypothetical dementia clinical trial in a nationally representative U.S. survey of dementia caregivers.To examine the concerns and perspectives of underrepresented dementia caregivers, we assessed for racial, ethnic, and other demographic differences in decisions about trial participation and estimated the in uence of various clinical trialrelated considerations (such as social responsibilities to participate in research, the risk of side effects, or the inconveniences of participation) on decisions to participate.

Design and subjects
As described in our preregistration (https://osf.io/uk3g7),this study was designed as a nationally representative cross-sectional survey of U.S. dementia caregivers.To enhance our ability to assess potential racial and ethnic differences in perspectives on dementia clinical trials, we deliberately oversampled Hispanic caregivers and non-Hispanic Black caregivers.
Participants for this study were recruited from the NORC AmeriSpeak panel.Operating at the University of Chicago, NORC AmeriSpeak is a large probability-based panel that is representative of the U.S. household population and has been widely utilized for public opinion polling and academic research.The NORC AmeriSpeak panel is built and maintained by applying area probability and address-based sampling based on the U.S. Census.A two-stage recruitment process is utilized to minimize nonresponse; households are recruited by mail and phone, and households that do not respond initially receive a follow-up including enhanced incentives and in-person eld interviews.The panel provides sample coverage of at least 97% of the U.S. household population.Written informed consent was obtained from participants during enrollment in the AmeriSpeak Panel, and the NORC Institutional Review Board approved all panel recruitment and survey procedures.
To identify dementia caregivers in the NORC AmeriSpeak panel, we presented panel members with a dementia-speci c screening question based on a stem used in ve AARP/NAC Caregiving in the U.S. surveys from 1997-2020: 11 "At any time in the last 12 months, have you provided unpaid care to a relative or friend 50 years or older who has Alzheimer's disease, dementia, or other mental confusion, to help them take care of themselves?This may include helping with personal needs, household chores, money management, arranging services, or regular visits to see how they are doing.This person need not live with you." The study survey was elded from July 22-August 8, 2022, by both the internet (including the mobile web) and telephone and was available in both English and Spanish.

Caregiver measures
Standard demographic data on caregiver participants were provided by NORC from previous surveys and included caregiver gender, age, education, race/ethnicity, household income, rural/urban residence, and employment status.Caregiver gender was obtained by a self-report question with response options "female", "male", "transgender", and "do not identify as male, female, or transgender."In this manuscript we follow a contemporary distinction between sex and gender, instead using the categories "women" and "men" for gender.
Race and ethnicity was provided as a combined variable including 6 categories: White, non-Hispanic; Black, non-Hispanic; Other, non-Hispanic; Hispanic; 2+, non-Hispanic; and Asian, non-Hispanic.
Participants who self-identi ed as non-Hispanic and as Native Hawaiian or Paci c Islander were included within the Asian non-Hispanic category.Participants who self-identi ed as non-Hispanic and as American Indian, Alaska Native, or another race not listed were included in the Other, non-Hispanic category.
Caregiver educational attainment was recorded in ve categorical responses: less than high school, high school graduate, some college (vocational, tech school, associates), bachelor's degree, and postgraduate study or professional degree.Employment status was reported in categorical responses: working as a paid employee, self-employed, temporary layoff, looking for work, retired, disabled, and other.Household income was reported in 16 categorical responses (such as $35,000 to $39,999).
NORC determines rurality by utilizing census tract and zip codes and calculating Rural-Urban Community Area (RUCA) codes.Participants with RUCA codes 4-10 were classi ed as rural, participants with RUCA codes 1-3 and who did not reside in the largest city in the area were classi ed as suburban, and participants with RUCA codes 1-3 and who resided in the largest city in the area were classi ed as urban.

Care recipient measures
Characteristics of the people with dementia who were cared for by panel participants were not included in NORC's preexisting data.We asked participants directly about their care recipients' demographic and clinical characteristics such as age, gender, rurality, race/ethnicity, dementia stage, and dementia diagnosis.
Options for dementia diagnosis included Alzheimer's disease, vascular dementia, Lewy body dementia, frontotemporal dementia, Parkinson's disease, primary progressive aphasia, Huntington's disease, dementia only (no further label), mild cognitive impairment, has not received a medical diagnosis, and has received a diagnosis unknown to the respondent.More than one option could be selected as many patients have received multiple diagnoses.
Dementia stage was categorized as very mild, mild, moderate, or advanced.These were determined using the Quick Dementia Rating System (QDRS)-derived Clinical Dementia Rating (CDR). 12Participants answered portions of the QDRS regarding their care recipient's memory and recall, orientation, decision making and problem-solving abilities, activities outside the home, function at home and hobby activities, and toileting and personal hygiene, to which the CDR scoring rules were then applied. 13

Relational measures
Relational characteristics were obtained by asking participants about their relationship to their care recipient, where the care recipient lived, whether they were the primary caregiver for the care recipient, and how frequently they visited the care recipient.To avoid collinearity with care recipient gender, caregiver relationship options were gender neutral.The options included the following: parent; spouse/partner; grandparent; sibling; another relative; and a friend, neighbor, or someone else who is not in the family.Caregivers described their care recipient's residence as: in the caregiver's home, a home with someone else, an independent living or retirement community, an assisted living facility where some care may be provided, a nursing care or long-term care facility, or somewhere else.Caregiver visit frequency options included more than once a week, once a week, a few times a month, once a month, few times a year, and less often.Primary caregiver status was designated to caregivers who either provided all the unpaid care, provided most of the unpaid care with help from one or more people, or split most of the care evenly with one or more people.

Clinical trial vignette measurements
We assessed willingness to participate in a dementia clinical trial with a vignette describing a hypothetical clinical trial of a disease-modifying agent for dementia, with overall trial features and risks modeled after recent trials of anti-amyloid monoclonal antibodies (see Supplementary Section 1, Additional File 1).After reading the vignette, caregiver participants were asked if they would participate (or would have participated, for caregivers who had provided care in the preceding 12 months but were not currently providing care at the time of the survey) in this study with their care recipient with dementia.Responses were collected on a 4-point Likert scale (e.g., de nitely yes, probably yes, probably no, de nitely no).Respondents then rated the importance of nine considerations that could be reasons for either participating or not participating in the trial: the possibility of direct clinical bene t, social responsibilities to participate in research, the possibility of bene ting one's community, access to better caregiver support by being connected to experts, the risk of side effects, distrust of the drug company, the chance of receiving a placebo, concerns about the privacy of health information in a study, and trialrelated inconveniences of travel and time commitments.Responses were collected on a 4-point Likert scale (e.g., not at all important, not very important, somewhat important, very important).The speci c wording used is included in Table 1.
Table 1 Nine considerations that caregivers rated the importance of in their reasons for either participating or not participating in the hypothetical dementia clinical trial.Responses were collected on a 4-point Likert scale (e.g., not at all important, not very important, somewhat important, very important).
Reasons for either participating or not participating in the clinical trial Clinical bene t for the care recipient "There is a chance that your care recipient will get the drug and it could help them" Placebo "There is a 50% chance your care recipient will get the placebo" Side effects "There is a chance your care recipient will have a serious side effect from the drug and will get hurt" Privacy "You are not sure that your information and your care recipient's information will be kept private and con dential"

Analysis
All analyses were conducted in R (version 4.4.0:2024-04-24) using the RStudio environment and the tidyverse, survey, srvyr, gtsummary, cowplot, and mediation packages.Survey-weighted analyses were conducted using weights provided by NORC AmeriSpeak.As described in our preregistered analysis (https://osf.io/uk3g7), to assess for racial, ethnic, and other demographic differences in hypothetical decisions about clinical trial participation, we generated four nested survey-weighted logistic regression demographic models, with clinical trial participation (dichotomized to yes/no) as the outcome.To compare racial/ethnic differences, non-Hispanic White was used as the reference category because of our aim to assess potential differences between groups that are adequately represented and groups that are underrepresented.For similar reasons, urban and suburban respondents were grouped together for comparison with rural respondents.Prior to modeling and the dichotomization of the clinical trial participation outcome variable, Likert-scaled responses were examined across demographic groups to check for differences in the intensity of response (de nitely/probably) that would not be captured by our logistic regression procedures.
Across the four nested demographic models, the base demographic model (Model 1) included basic caregiver demographic characteristics as predictors: age (mean-centered and scaled by decade), gender, race/ethnicity (limited to Hispanic, non-Hispanic Black, and non-Hispanic White to avoid estimation errors due to small cell counts), and rurality.Model 2 included all predictors from the base model and added care recipient clinical characteristics: age, gender, race/ethnicity, rurality, dementia stage, dementia diagnosis (limited to Alzheimer's disease, dementia only, MCI, no diagnosis, and diagnosis unknown to respondent to avoid estimation errors due to small cell counts, all entered independently as dichotomous variables), and whether dementia was the primary condition for which the care recipient required care.Model 3 included all predictors from Model 2 and added further caregiver characteristics: education, household income, and current employment status (simpli ed to working, retired, disabled and other unemployed).Model 4 included all predictors from Model 3 and added relational characteristics: care recipient relationship to caregiver (simpli ed to parent, spouse, other relative and non-relative to avoid estimation errors due to small cell counts), care recipient residence (simpli ed to in the same home as the caregiver, in a separate home, or in a facility), whether the caregiver was the sole/primary caregiver, and how frequently the caregiver visited the care recipient.Predictors in all four nested demographic models were tested for multicollinearity with a threshold GVIF of 5. Model selection was determined by successively assessing improvements in model t between each model (starting with the base demographic model) and the next more complex model using an ANOVA test with a signi cance threshold of p = 0.05.
To estimate the importance of various clinical trial-related considerations among dementia caregivers we generated another survey weighted logistic regression model, which we refer to as the reasons model.Caregivers' ratings of the importance of considerations that could be reasons for participating (the possibility of direct clinical bene t, social responsibilities to participate in research, speci c bene ts to one's own community, and caregiver support from researchers) or not participating (lack of trust, the possibility of being randomized to placebo, breach of con dentiality, the possibility of side effects, inconvenience) were inputted in the reasons model as predictors of clinical trial participation alongside base caregiver demographic characteristics (Model 1).For demographic predictors from Model 1 that were signi cantly associated with trial participation, we tested whether this effect was mediated by any of the trial consideration predictors (reasons model) in a causal mediation model.

Exploratory tests of moderation
In addition to our preregistered analyses, in exploratory analyses we evaluated whether the in uence of any clinical trial-related considerations on trial participation was moderated by race and ethnicity.As an initial test of moderation we modeled the interactions between such predictors and race/ethnicity; if signi cant at a threshold of p = 0.05 we assessed for potential differential effects of these predictors in subgroups restricted to Hispanic caregivers, non-Hispanic Black caregivers, and non-Hispanic White caregivers.) In an exploratory model testing interactions between age and race/ethnicity, the interaction between age and the contrast between Hispanic and non-Hispanic White caregivers was nonsigni cant (OR = 1.15, p = 0.51), as was the interaction between age and the contrast between non-Hispanic Black and non-Hispanic White caregivers (OR = 0.90, p = 0.55).

Adjusted demographic model
In the adjusted demographic model, older dementia caregivers were less likely to participate in the clinical trial (OR = 0.73, p = < 0.001), consistent with the base demographic model (Table 3).Caregivers with care recipients who have not received a diagnosis were less likely to participate (OR = 0.28, p = 0.012).

Reasons model
In the reasons model (Table 4), older dementia caregivers were again less likely to participate in the clinical trial (OR = 0.69, p = < 0.001); no signi cant differences were observed for caregiver gender, race/ethnicity, and rurality.Caregivers who rated social responsibility to participate in research as an important consideration were more likely to participate (OR = 1.56, p = 0.049).Caregivers who rated the possibility of the care recipient having serious side effects as important were less likely to participate (OR = 0.51, p = 0.003).The rated importance of the possibility of clinical bene t (OR = 1.70, p = 0.063) and bene t to one's own community (OR = 1.66, p = 0.070) approached statistical signi cance as predictors of participation.The in uence of caregiver age on clinical trial participation was not mediated by any of the consideration predictors from the reasons model.
In an exploratory test of effect moderation, there was no signi cant interaction between the contrast between Hispanic and non-Hispanic caregivers and any of the nine considerations tested.However, interactions between the contrast between non-Hispanic Black and non-Hispanic White caregivers and the rated importance of caregiver support (OR = 0.35, p = 0.033) and the possibility of side effects (OR = 2.83, p = 0.023) were signi cant, and between this contrast and bene t to one's speci c community (OR = 3.59, p = 0.051) were nearly signi cant (Supplementary Section 2, Additional File 1).In exploratory tests of the reasons model restricted to members of each racial or ethnic subgroup, trial participation among non-Hispanic Black caregivers was predicted by the rated importance of bene t to one's own community (OR = 5.79, p = 0.002) and the possibility of receiving placebo (OR = 0.53, p = 0.031); among non-Hispanic White caregivers was predicted by the rated importance of the risk of side effects (OR = 0.34, p = 0.002); and was not signi cantly predicted by the rated importance of any listed consideration among Hispanic caregivers (Supplementary Section 3, Additional File 1).

Discussion
In this preregistered, nationally representative survey, Hispanic and non-Hispanic Black dementia caregivers were not less likely than non-Hispanic White dementia caregivers to participate in a hypothetical dementia clinical trial.In a base and an adjusted demographic model, older caregivers were less likely to participate than younger caregivers.The contrast between Hispanic caregivers and non-Hispanic White caregivers in demographic models was nearly signi cant, but this principally re ected the associations of Hispanic ethnicity and of trial participation with age; while Hispanic caregivers were similarly likely to participate as non-Hispanic White caregivers overall (29% vs. 34%), they were almost signi cantly less likely to participate than non-Hispanic White caregivers of similar age.Caregivers who rated social responsibility to participate in research as an important consideration were more likely to participate, while caregivers who rated the possibility of serious side effects as an important consideration were less likely to participate.In exploratory analyses, Black caregivers' hypothetical participation was sensitive to potential bene ts to one's own community (positively) and the risk of receiving placebo (negative); whereas White caregivers' hypothetical participation was sensitive to the risk of negative side effects from the active intervention.
Our main ndings on race and ethnicity indicate that a lack of diversity in dementia clinical trials is not attributable to a reduced willingness to participate among underrepresented groups.While Hispanic caregivers may be less likely to participate than would be predicted given their younger age, this does not translate into meaningful overall differences in willingness to participate.Particularly regarding Black Americans, our ndings from a large nationally representative survey contrast with prior studies (typically in smaller, nonrepresentative samples) identifying distrust of investigators and research procedures to be a signi cant barrier in enrolling Black Americans in dementia clinical trials. 14,15,16 Wle trustworthiness and developing rapport are crucial in research with all communities, our ndings suggest that the shameful historic legacy of the Tuskegee syphilis study and other research abuses 17 is not a su cient explanation for the low enrollment of underrepresented populations in dementia clinical trials.
One potential structural explanation for low Black and Hispanic enrollment in clinical trials is that Black and Hispanic Americans with dementia are diagnosed later in the course of disease, if they receive a diagnosis at all, compared to White Americans. 18,19 ost current clinical trials of disease-modifying treatments for dementia, such as recent in trials of aducanumab and lecanemab, 20,21 restrict participation to patients in very early stages of disease.Another structural contributor to underrepresentation in clinical trials is the presence of strict exclusion criteria for comorbidities, which are more common in Black and Hispanic older adults. 22In clinical trials for aducanumab, people with stroke, cardiovascular disease, and chronic kidney disease were excluded. 23Given worse management for chronic health conditions and related disadvantages in social determinants of health, Black and Hispanic older adults experience signi cant health disparities, which in turn exclude them from dementia clinical trials, in turn yielding poorer evidence to guide their care, perpetuating further health disparities.Furthermore, the underrepresentation of Black and Hispanic dementia clinical researchers may mean that, even if Black and Hispanic Americans are willing overall to participate in dementia clinical research, the speci c recruitment strategies applied in a particular study are less likely to be culturally congruent or to address community-speci c barriers to participation (such as lost wages for younger adult caregivers needed as study partners).Finally, participatory methods for community engagement and partnership with community-based organizations are less utilized and less understood among dementia researchers than in many other elds; 24 dementia researchers could improve our work by incorporating lessons from these elds.Particularly among Black caregivers, such strategies may be especially powerful for those who are motivated by the prospect of bene ts to their own communities.
Two unanticipated ndings from our study warrant further discussion.First, across all demographic groups, only a minority of caregivers (37% overall) would choose to participate in the hypothetical trial.
This could represent features of our speci c vignette and how the risks and bene ts of participation were framed, but disease-modifying therapies currently under investigation are highly burdensome with frequent infusions and complex monitoring requirements, and these features themselves limit participation.Second, in our study, older caregivers are less likely to participate than younger caregivers, contrasting with an earlier study conducted with participants in a single Alzheimer's Disease Center's research registry in which older study partners and spouse study partners (highly correlated characteristics) were more likely to participate in a hypothetical dementia clinical trial. 25While the perspectives of members of research registries are important for immediate success in enrollment for upcoming trials, efforts to expand participation in research will depend more on the perspectives of people not currently included in research efforts.At present, dementia clinical research relies heavily on spouse caregivers, in part because adult child caregivers and other caregivers may face logistical hurdles due to full-time employment or young children for whom they also provide care; 26 given this historic reliance, it is also likely that many studies' features are structured on the assumption that the study partner is a spouse who lives with the patient.Our ndings suggest that addressing logistical and other barriers to participation by younger caregivers could enhance study enrollment overall.It is also noteworthy that in our nationally representative sample only a very small minority of dementia caregivers (6%) are spouse caregivers, which is comparable to previous nationally representative samples. 27r study has several limitations.While we used representative sampling techniques with deliberate oversampling for Hispanic and non-Hispanic Black caregivers, we did not have the ability to oversample other groups that are underrepresented in dementia research, such as Asian Americans, 28, 29 and groups that are underrepresented and at increased risk for dementia, such as Indigenous Americans. 30,31,32 M focused work must be done to address speci c barriers to research participation in these communities.Additionally, while we used an existing population-based survey platform to facilitate the demographic representativeness of our sample, and while the NORC AmeriSpeak panel uses a multistage recruitment process to limit nonresponse bias, people who agree to join a panel and then respond to surveys on that panel may differ from those who do not.As our study speci cally addresses willingness to participate in research, some motivations for nonparticipation may not be re ected using these techniques (or potentially, any techniques that depend on informed consent).Our use of a relatively large, population-based sample enhanced our ability to detect and generalize across group differences, but lacked the exibility of qualitative or mixed-methods approaches to explore individual participants' reasons for participation or nonparticipation.

Conclusion
In summary, our results indicate that low enrollment of underrepresented populations in dementia clinical trials is not attributable to less willingness among caregivers from underrepresented groups; such under enrollment instead likely re ects structural barriers and historic exclusion from trial participation.The lack of diversity in dementia clinical trials may not only undermine generalizability but also exacerbate health disparities.These ndings emphasize the importance of improving recruitment strategies and conducting more focused work to addressing structural barriers that hinder non-Hispanic Black and Hispanic populations from participating.
BL and WC: study design, data collection, data analysis, and writing the manuscript.DMH: data analysis and critical assessment of manuscript.AJJ: study design, data collection, and critical assessment of manuscript.RWL, CCW, and JM: critical assessment of manuscript.All authors read and approved the nal manuscript. Figures

Table 2
Demographic characteristics of dementia caregivers in the study sample model excluding age and a model including age indicates a suppression effect.(That is, Hispanic caregivers were not less likely to participate than non-Hispanic White caregivers overall, but when considering caregiver age, Hispanic caregivers were almost signi cantly less likely to participate than non-Hispanic White caregivers of similar age.

Table 3
Estimates from the base model and adjusted demographic model.Characteristics on the left were entered as predictors in a logistic regression model and the outcome measured was hypothetical clinical trial participation.

Table 4
Estimates from the reasons model.Characteristics on the left were entered as predictors in a logistic regression model and the outcome measured was hypothetical clinical trial participation.