Introduction

Alzheimer’s Disease (AD) is currently the sixth-leading cause of death in the United States, and is the only disease in the top ten for which there are no disease-modifying medications. The Collaboration for Alzheimer’s Prevention and other organizations have highlighted that doing clinical trials in individuals with mild cognitive impairment (MCI), or participants with no cognitive impairment but at increased risk for AD (e.g., genetic factors, potential AD biomarkers, etc.) is essential for the development of interventions that are effective in the eventual treatment of AD [1]. There are approximately 300 clinical trials underway, or soon to be underway, in the United States that are designed to determine the ability of different interventions to prevent or delay the development of AD [2]. Some of these strategies involve pharmacological interventions, while others involve non-pharmacological approaches including environmental or behavioral based interventions [3], [4]. Currently, it is unknown what motivates or deters an individual from participating in different types of clinical trials related to AD. Understanding the factors that influence, or predict, the willingness of an individual to participate in the different types of interventions is important for developing the most effective recruitment strategies for a specific type of clinical trial [1], [5].

Pharmacological interventions are one type of intervention with some success in dementia-related clinical trials; SomeScurrent pharmacological interventions slow cognitive decline in individuals at risk of developing AD [6–8]. Unfortunately, research on these interventions is limited by a number of obstacles, including the limited availability of individuals willing to participate in dementia-related clinical trials [9]. A large number of issues including medical comorbidities and lack of a widespread registry of potential clinical trial participants hampers recruitment into dementia-related trials [10]. Other factors such as the use of concomitant medications, and the lack of an adequate informant or study partner to complete study measures also lead to exclusion from dementia-related clinical trials [11]. This dearth of eligible participants may contribute to prolonged periods of recruitment for Phase II and Phase III multisite dementia-related drug trials; one study found the median time for recruitment across 29 dementia-related studies was 17 months [12].

Among individuals who are qualified to participate, many still fail to enroll for a variety of reasons including a lack of interest and logistical issues associated with participation (e.g., time, travel). In a large, multi-center prevention study using a supplement (Ginkgo Biloba), investigators aimed to recruit individuals with normal cognition or mild cognitive impairment (MCI) and found that a lack of interest was the primary reason individuals declined to participate [13]. Research using focus groups has shown that logistical issues such as difficulty arranging transportation and distance to research facilities are frequently cited as a barrier to participation in dementia research in general [14], [15].

Individuals may also be disinclined to enroll in clinical drug trials because they are averse to the potential risks associated with drug treatment; when presented with hypothetical scenarios, nearly half individuals gave a response indicating fear associated with taking a drug for research purposes [16]. Compared to other types of research studies, individuals often indicate less interest in enrolling in clinical drug trials. For example, when presented with hypothetical research scenarios, caregivers of AD patients were more likely to express interest in having the patient enroll in a study that involved neuroimaging and neuropsychological tests as compared to a study that included the use of an experimental drug [17]. In another study using hypothetical scenarios, AD patients reported a greater willingness to take part in a hypothetical blood draw study than a drug study [18].

Aversion to drug studies may reflect a broader aversion to risk-taking that is typical in older individuals [19]. While those with MCI may underestimate risks and be more willing to enroll in trials [20], AD patients may be more risk adverse than cognitively healthy individuals [18].

Participants and caregivers who participate in AD research, including clinical drug trials, most commonly cite the potential for direct benefits and a desire to help others as reasons for participation [21–23]. Among those already enrolled in an AD research registry, more favorable attitudes toward research was associated with a larger number of positive responses to being approached about research studies [24]. More favorable attitudes towards research also predicted a greater positive response to enrollment in a hypothetical clinical drug trial [25].

Given the promise that pharmaceuticals hold with regard to improving cognitive outcomes in dementia populations, there is a substantial interest in determining how to increase enrollment in dementia-related clinical trials. The aims of this study were: 1) to compare participant interest in pharmacological interventions to their interest in other types of research studies varying in benefits, requirements, and intervention type, 2) to compare beliefs about likely success of pharmacological interventions to other types of interventions, and 3) to identify individual difference factors associated with a lack of interest in participating in clinical drug trials. To extend existing research, we focused on variables which have been less explored as predictors of interest, including health, subjective memory concerns, and beliefs about the likely success of future drug treatments.

Methods

Results

Pharmacological Intervention vs. Other Study Characteristics

Table 1 shows the percentages of participants indicating increased interest, no change in interest, or decreased interest given the presence of various study characteristics. Potential benefits for self and others were generally strongly associated with increased interest in participation. A large number of participants (52%) indicated decreased interest if the study was a pharmacological trial. The only study characteristics associated with greater decreased interest in participation were having to receive a lumbar puncture (68%) or having to come in for study visits three times a week (73%) or daily (86%).

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Table 1. Research Designs and Interest in Study Participation.

https://doi.org/10.1371/journal.pone.0159664.t001

Discussion

Given the number of pharmacological interventions planned or underway for delaying or preventing the onset or progression of AD, and the challenges in recruitment for those studies, understanding factors that increase or decrease enrollment in research is an important goal for clinical trial researchers. Some barriers to enrollment cannot be solved by increasing interest when potential participants are identified (e.g., exclusions from enrollment due to medical comorbidities or stage of disease). However, other barriers are related to an individual’s interest in a study and decision to enroll or decline participation. For example, fewer positive attitudes towards research and an aversion to drug-related side effects have been associated with disinterest in clinical trial participation [11], [13], [21–23]. In this study, we explored how interest in pharmaceutical trials compared with interest in clinical research studies with different characteristics, including studies using other types of interventions. We also explored whether individual differences in health, subjective memory concerns, and beliefs about the likely success of pharmacological interventions were related to interest in participation. Participants were those already enrolled in a longitudinal study of aging, an important source of potential recruitment into intervention studies given the emphasis of many clinical trials to recruit healthy individuals or individuals with mild cognitive impairment into interventions designed to delay potential future pathological changes.

The current study showed that individuals were more likely to enroll in research studies when they believed that their participation would help improve the health of others and themselves, as well as learn about their health. These findings are congruent with those of prior studies examining the decision-making of both AD patients and caregivers, two of which found that the main reasons patients joined a dementia registry, were to help others (44% of patients) and themselves (29%) [21], [23]. Similar to previous work, individuals in the current study were less likely to enroll if participation would require significant amounts of time and traveling (i.e., traveling to the study site several times per week) [14], [34].

The type of intervention involved played a significant role in individuals’ interest in participation. Although 95% of participants reported that they would be more likely to participate if a study led to a treatment for a disease, the type of intervention still mattered. Interest in a pharmacological trial (48%) was lower than interest in all other types of interventions: dietary, exercise, meditation, acupuncture, yoga and computer-based interventions. Of note, some of these other interventions were rated as less likely to lead to a treatment for diseases like AD compared to pharmacological interventions. A total of 71% of participants viewed pharmacological interventions as being likely or highly likely to lead to a treatment compared to interventions such as meditation, acupuncture, yoga, and computer-based interventions.

Beliefs that drug treatments would lead to cures for diseases, current memory concerns, the number of current medications taken, and cardiovascular risk did not predict the participants’ interest in clinical trial participation. These results extend prior work that found that subjective memory and cardiovascular disease did not predict willingness to participate in AD research more generally [35]. Future work is aimed at identifying individual difference factors related to interest in various types of clinical trials.

Although sample size is a limitation, the number of participants in this study is comparable to previous studies using a similar survey-based approach to assessing older adults’ interest in research [16], [24]. We conducted a logistic regression with four predictor variables and 34 events for 65 participations. In order to conduct a logistic regression, ten events per predictor variable is a common rule of thumb for sample size [36]; however, others have argued that this may be too strict, with simulations showing that as few as five events per predictor may be acceptable [37]. It should be noted that majority of variables were measured using a single item which may have limited reliability. This format was chosen to allow for the inclusion of a number of study features which could be asked about independently; future studies may wish to use more realistic scenarios in which participants are provided with more details about specific studies to gauge their interest in participation.

It should be noted that only 36% of the final sample were individuals with MCI, limiting our generalizability to that population. We did not directly compare individuals with and without MCI in this manuscript as that categorization overlaps significantly (although not entirely) with the subjective memory complaints variable we used as a predictor. At least one previous study did find a difference between those with MCI and cognitive healthy older adults in their interest in participation in a drug trial presented in a hypothetical vignette [38]. As both of these groups are target populations for clinical trials, future studies should continue to explore possible differences between these groups in factors affecting their interest in trial participation.

Another limitation of this study was that participants were not responding to questions about actual available clinical trials. Throughout completion of the questionnaires, participants were aware that they were expressing interest in participating in studies that were not currently being held at the IDRP, and thus their responses had no bearing on their actual enrollment in any studies. This may have led to an overestimation of the actual number of participations who would have participated in an actual trial. Previous work in another domain (HIV prevention) indicates that participants are more likely to report a willingness to enroll in medication intervention trials when the study is presumed to be hypothetical [39].

The use of hypothetical studies in survey research is common in the clinical trial literature for MCI/AD; few studies have experimentally manipulated variables to observe effects on trial enrollment [40]. Those that have done so have limited their focus to factors such as the type of study advertisement (direct mailings vs. newspaper advertisements vs. community outreach [41] or the party to which advertisement efforts were targeted (primary care provider vs. larger community [42]. To our knowledge, the effect of manipulations in how study information is presented to participants on recruitment has not been studied in actual pharmacological treatment trials.

Given research showing that fear of potential side effects is one barrier to participation in pharmacological treatment trials [16], to the extent such perceptions are inaccurate or fail to consider potential benefits, future research could investigate the effect of manipulations in how information on risk and benefit is presented to potential participants in clinical trials. In the larger literature on medical decision-making, a number of communication strategies have been successfully used to improve understanding of risks and benefits [43]. Given individuals’ willingness to be contacted about enrolling in future AD studies has shown susceptibility to change over the time course of participation in a longitudinal study [44], researchers should continue to explore ways to increase enrollment in pharmacological intervention trials in individuals already enrolled in a research registry.

Acknowledgments

The authors thank the participants of the LABrainS study for their participation, which made this work possible.