Attitudes and Viewpoints Toward Prevention Trials in Alzheimer’s Disease
Abstract
Abstract: Alzheimer’s disease (AD) prevention studies use biomarkers to determine risk in asymptomatic study participants. This involves multifaceted implications. Determinants regarding participation in these trials are therefore of particular relevance. We used semistructured individual interviews to interview uninvolved persons (n = 10), relatives of Alzheimer’s patients (n = 10), and patients with mild cognitive impairment (n = 5) and analyzed the interviews using qualitative content analysis according to Mayring. We discovered various factors to be positive motivations for participation; the most significant inhibiting factor was concern about negative psychological effects. These motivations and concerns should be specifically addressed in the study design of AD prevention trials. The fears and concerns expressed highlight the importance of a good methodological and ethical framework to increase participant acceptance.
Alzheimer’s disease (AD) is the most frequent dementia subtype and will certainly increase in the context of demographic change, which represents both a great personal and sociomedical challenge (Wetzstein, 2005). The treatment of AD still focuses on symptomatic therapies, the modification of modifiable risk factors, and the treatment of comorbidities (Mattle & Fischer, 2021). Clinical trials are essential in developing progression-modifying treatment options. For example, delaying the disease by 5 years with targeted prophylaxis would halve the prevalence (Schmidtke & Otto, 2012).
Recently, the approval of the monoclonal antibody for amyloid β aducanumab in the United States provides renewed hope, although the data situation is controversial (Kuller & Lopez, 2021). In Europe, there are currently no approved causal therapy options (Grossberg et al., 2019), although various causal therapy options are being researched.
The etiopathological changes, such as the deposition of AD fibrils and Aβ plaques, precede the clinical presentation of dementia by up to 15 years. It thus seems advantageous to conduct clinical drug trials to test causal or disease-modifying therapies as prevention studies (Schweda et al., 2018) targeting healthy study participants with an increased risk of developing AD. Researchers usually perform risk stratification by biomarker findings, including memory tests, MRIs, CSF diagnostics, and genetic testing for the APOE ε4 risk allele. The diagnostic precision of this risk evaluation is constantly being improved, for example, by the development of more specific MRI sequences and nuclear medicine techniques such as PET and SPECT with specific ligands (Valotassiou et al., 2018). How and whether the personal risk of disease is subsequently communicated to the study participants depends on the respective study design and should consider both their desire for information and their right not to know (Schweda et al., 2018).
Several studies have already examined participants’ interest in determining their personal AD risk but did not provide a consistent picture in this regard. For example, one study showed that about 60% of the adults surveyed (n = 1,641) were interested in knowing their personal AD risk (Roberts et al., 2014). In this context, knowledge of one’s personal dementia risk presents both positive and negative effects for the individual. However, little is known to date about why an individual would decide for or against participation in AD prevention studies.
The present qualitative study explored the determinants for participation in prevention trials. It considered the specific ethical challenges of disclosing risks in healthy participants without being able to offer a disease-modifying therapy, as well as the increasing importance of AD prevention studies.
Material and Methods
Study Design
The present qualitative study explores the experience of people who have had no or various contact with AD. We used the COREQ checklist (Electronic Supplementary Material, ESM 1) for the comprehensive reporting of qualitative studies (Tong et al., 2007). Conduct of this study was funded by Novartis.
Participants
We conducted qualitative interviews with people from three different target groups: (1) uninvolved persons: neither these persons nor first-degree relatives had been diagnosed with dementia; (2) relatives: first-degree relatives in the families with a diagnosis of AD; (3) persons with a diagnosis of mild cognitive impairment (MCI) using core clinical and biomarker-based research diagnosis criteria (Albert et al., 2011).
We applied the following inclusion criteria: membership of one of these groups, age > 18 years, and sufficient knowledge of the German language. Exclusion criteria were manifest brain diseases except for persons with MCI.
The target sample consisted of 10 subjects per cohort (n = 30), considering contrast or saturation (Patton, 1990).
Recruitment
Recruitment took place between November 2019 and October 2020. However, because of the COVID-19 pandemic, recruitment had to be stopped parallel to the nationwide lockdown. The recruitment of the group of uninvolved persons and the group of relatives was carried out via a contact list from the Department of Neurology, University Hospital Schleswig-Holstein, Kiel (UKSH), which contained former probands and relatives of probands who had showed interest in the studies. In addition, we posted information in local churches and sports halls. Furthermore, through a former study participant, we made contact with a regional nursing home, where relatives had expressed interest in participating. Potential participants of the MCI group were also recruited through a contact list from the Department of Neurology (UKSH). Participation was voluntary, and all interviews were personally conducted by a male member of the study group (PP), who was trained by KH and KG in performing these interviews.
All interviews and documentation adhered to the same predefined quality criteria (e.g., documentation of time/any issues or interruptions encountered during the interviews). We requested sociodemographic data from participants before starting the interviews.
Course of Study
The interviews were conducted between January 2020 and October 2020 (except during the nationwide lockdown) in compliance with the required pandemic-related hygiene and distance rules. Most interviews took place in the same office of the Department of Neurology (UKSH); three interviews with relatives were conducted in a nursing home.
Data Collection
An interprofessional team consisting of a sociologist, a health services researcher, neurologists, and a clinical ethicist developed a semistructured interview guide. After we did a literature review and held discussions within the study team, the interview guide came to focus on the following:
- •Encouraging motives for participation in a prevention study,
- •Inhibiting motives for participation in a prevention study.
We tested the interview guide with a student and a lecturer for comprehensibility and the sequence of the individual questions (ESM 2).
Data Analysis
We recorded all interviews via digital audio recording and transcribed them verbatim according to predetermined transcription rules. We did not submit the transcripts to the participants for comments or corrections. During transcription the texts were anonymised before undergoing qualitative content analysis, according to Mayring’s method (Mayring, 2010). We used ATLAS.ti 8.4 (Scientific Software Development GmbH 2020) software to assist in qualitative content analysis.
The working group used a deductive-inductive approach to create the thematic categories. First, it deductively developed a preliminary category system based on the interview guide guidelines and adapted the preliminary category system during the analysis according to the content of the transcripts, inductively adding newly identified categories. The interviewer (PP) independently coded the transcripts into main and subcategories. Second, two members of the working group (KH, KG) independently reviewed these categories following a discussion that continued until an agreement was reached (PP, KH, KG). All quotes from research participants were translated from German into English for publication.
Ethical Approval
The Ethics Committee of Kiel University, Germany (D503/18) approved the project, which was conducted in accordance with the Declaration of Helsinki. We obtained informed consent through a signed consent form that included permission to publish the anonymized quotes.
Results
A total of 25 persons participated in the interviews, 10 of whom belonged to the group of uninvolved persons (U), 10 to the group of relatives (R), and 5 to the group of persons diagnosed with MCI. Table 1 provides an overview of the sociodemographics of the interviewees. The average duration of the interviews was 39 minutes (minimum 23 minutes/maximum 83 minutes).
Presentation of Content
The following discussion presents the motivations for participating in AD prevention studies. We identified the motivating and inhibiting factors, which were distributed among different subcategories. Table 2 gives an overview. We use anchor examples to illustrate key aspects from the interviews.
Main Category: Motivating Factors
A variety of motivating factors influencing participation in AD prevention studies emerged in the interviews (see Table 2). A distinction was present between individual/personal factors and those perhaps conducive to an overall gain in knowledge. The motives for study participation were primarily determined by a basic altruistic attitude in the three interviewed groups. One respondent from the group of relatives expressed: “I’m thinking less about myself, and rather about research […] to be able to help the general public, to be able to help others, […] not to gain any advantage for myself” (R06).
Participation in prevention studies to help science was also associated with the hope of positively influencing one’s own outcomes if they contracted the disease: “If Alzheimer’s is diagnosed, yes, you hope that while you’re still clear in your head, that the pills would help” (MCI04).
Another relevant reason for being willing to participate in this type of study included being proactive and concerned about health status. At the same time, the respondents from the group of relatives and uninvolved persons expressed that this could provide an opportunity to obtain new information regarding an AD-protective lifestyle: “If I were in this situation, I would be encouraged to say, ‘Yes, that’s where I’m heading, maybe there’s still something that can be done.’ Maybe I can still change something myself” (U02).
Likewise, interviewees from the group of people diagnosed with MCI hoped that participation would provide them with further information on how to monitor their own course of disease, and how their behavior could positively influence the course. At the same time, participation in such prevention studies was associated with finding medications that would slow the progression of the disease and thereby improve participation in life: “[…] that there will be a slowdown or that it will occur later. Which would be positive for me, if I stayed healthy, then I could still live a good few years” (U02).
According to the interviewees, another encouraging factor on the individual level was the chance to consciously shape their lives by planning for the future and organizing their personal affairs, which served to maintain their quality of life: “Because I would make my time […] as productive as possible and fulfill my wishes, for example, by traveling” (U01).
Some interviewees made clear that, if they were at increased risk of dementia, they would actively promote their own health in the hope of slowing down the progression of the disease: “I would probably try to do more things to inhibit the disease” (R05).
Participants with a diagnosis of MCI mentioned that participation might positively influence their lifestyle as well as the progression of the disease: “It sharpens the mind. That’s also a great thing in this context. It raises awareness. Gosh, anything can be done. Maybe you can still do something for yourself. You always have hope” (MCI03).
By participating in a prevention study, some interviewees hoped to gain knowledge of the relevant medicine: “I would like to help make progress in this research and eventually find a drug or something to stop this disease” (U10).
Especially in the statements of the uninvolved group, it became evident that, by enabling advance planning, prevention studies could allow autonomous decision-making about different treatment options: “I am interested in the truth. Especially in the early stages, you can still decide what to do or not to do, because if drugs are used later on, even though you yourself can’t really decide anymore what’s good for your body, I think it’s much better if you know that beforehand and can adjust to it (U09).
Regarding gaining knowledge, the interviewees repeatedly expressed that crucial progress can be made in medical research through participating in a prevention study: “I favor participating in these studies as much as possible so that the research can maybe help people with AD” (R04).
Another facilitating factor is the hope of new medicines being developed, especially in light of a family history of the disease: “Yes, when I see the course of the disease in my grandmother and my mother, and being the next generation, I would hope that progress has already been made which could help me” (U01).
Across all three interviewed groups, a high level of confidence was evident regarding the feasibility of medical interventions: “As a service to science, that’s good. I’d like to be involved in that. I’d like to see that evolve. It takes people who are willing to participate, and I want to be part of that” (R07).
Main Category: Inhibiting Factors
The inhibiting factors comprise five subcategories: negative psychological effects, the burden on relatives, concerns about medical diagnostics, the pharmaceutical industry, and organizational aspects.
Participants across all three groups mentioned the fear of potential psychological side effects for study participants as an important factor, particularly anxiety and depression, as illustrated by the following statement: “I think it is a psychological burden when you know that Alzheimer’s is already knocking at the door” (U04).
In individual interviews, it emerged that study participation could lead to suicidal thoughts if an increased risk for dementia was disclosed: “Knowing that I will get Alzheimer’s in the foreseeable future is a very bad realization. […] I imagine I would then want to leave life earlier, because I don’t want to get into a state where I can’t be in control anymore” (MCI05).
The groups of relatives and uninvolved persons expressed concerns about any required medical examinations. The main concerns were about pain and the side effects of the mandatory lumbar punction. Nevertheless, most interviewees indicated that these concerns would not be a fundamental exclusion criterion: “I hesitated momentarily when I read that cerebrospinal fluid has to be taken. But if it has to be done, it has to be done” (R05).
In very few cases, interviewees indicated they would rather refrain from participating in a study if lumbar punction was necessary: “So, because of this lumbar punction, which has to do with the spine, I would decline” (R06).
In isolated cases, interviewees also mentioned that participation in a study would first have to be discussed with their relatives, as they could be affected by the results. They expressed concern that participation in a study and the diagnosis of increased risk or manifest AD would burden their relatives: “Such knowledge can be worrying. It could be burdensome to my wife if it’s established that I’m going to get Alzheimer’s. I would want to spare her that burden” (MCI01).
A few respondents expressed isolated concerns about the involvement of pharmaceutical companies in drug trials: “You have to trust the pharmaceutical industry, and I have certain reservations about that” (A10).
About half of the uninvolved group expressed moderate concerns about the organizational feasibility of the study. These were directed primarily at the 5-year timeframe in the study description and the extensive time commitment. However, it was also evident from statements that some participants, especially those diagnosed with MCI, had no serious concerns about the organizational feasibility. Overall, these concerns were moderate, and the consensus of the groups was that it would be possible to organize participation in the study if there was enough interest.
Discussion
This interview study explored reasons for or against participation in AD prevention trials and examined attitudes toward communicating personal AD risk.
Among the groups we surveyed, we identified as key motivations for participating in prevention trials altruistic factors aimed at supporting Alzheimer’s research and thus improving treatment options in the future. Consistent with our findings, altruism and solidarity were also important factors in our analysis of the motivation to donate data for research purposes (Richter et al., 2018).
Most respondents found it of great interest to know the personal AD risk, another main reason for participating in a prevention study. Despite the current lack of therapeutic options, respondents expected better chances of early therapy and positive personal results in the future. The respondents thought these personal results could be gained by early risk disclosure, including, for example, the possibility of settling personal affairs timeously, adjusting one’s own plans for the future, and making changes to adopt an Alzheimer-protective lifestyle. These specific motivations, which also demonstrate the personal interest of the participants in the preventive approach of these studies, underline the importance of conducting prevention studies in Alzheimer’s research. The Generation Study, an initiative of the Alzheimer’s Association®, is already promoting targeted research approaches to prevention, early diagnosis, and causal therapy of AD (Reiman, 2022).
These findings are supported by the results of a study (Lim et al., 2016) in which participants were informed by a PET scan whether they were at an increased risk of developing AD: On the one hand, carriers of an increased risk often adapted their lifestyle by living more healthily, for example, starting cognitive training or changing their diet; on the other hand, they reported planning their future at an earlier stage. Comparable findings concerning protective lifestyle changes and autonomous future planning exist for the early diagnosis of Parkinson’s disease (Schaeffer et al., 2020). Improved adherence and willingness to make protective lifestyle changes support the significance of research in this area and the provision of targeted services. This is especially important as, in socioeconomic terms, lifestyle changes can also offer a cost-effective and sustainable preventive approach with an excellent benefit/risk profile compared to drug-treatment approaches.
However, many of the interviewees from all three groups expressed concern about experiencing increased psychological stress from participation and risk disclosure. The interviewees thus identified a core problem of such prevention studies with currently existing inconsistent data. For example, in a prospective study of adult participants (Bartzsch et al., 2015; N = 106), the authors used MRI-based hippocampal volumetry to stratify Alzheimer’s risk. They then dichotomized the outcome into increased and decreased risk. Before and after risk stratification, they employed structured interviews to evaluate the anxiety, depression, and well-being of the participants. As expected, the findings without evidence of increased risk led to improved well-being and reduced anxiety and depression. Yet, even in persons with increased risk, they found no evidence of significant deterioration in mental health or long-term increases in anxiety and depression. For most participants, the result of the examination rather led to positive conclusions for the future, with a high acceptance of the examination method (94%). Results after communication of the genetic risk status (APOE ε4) to subjects with MCI also point in this direction (Christensen et al., 2020). In contrast, the Socrates Study (Largent et al., 2020) clearly showed adverse effects in participants with amyloid deposition (N = 50) in terms of a considerable test-related burden because of the severity of the potential disease and possible stigmatization by society, friends, and family. This point is of particular relevance as there is evidence that anxiety and depression unfavorably impact disease dynamics: A baseline study of 333 healthy elders (Pietrzak et al., 2015) was followed up by reexaminations at 18, 36, and 54 months. The examinations included a PET scan for Aβ, tests for depression and anxiety, and comprehensive tests of various cognitive abilities. The participants who tested positive for Aβ and responded with severe anxiety and depression to the disclosure showed a significantly accelerated decline in cognitive abilities, compared to the participants who responded with less anxiety and depression. Results from the Alzheimer’s Prevention Registry online survey, which asked interested individuals (N = 4,036) about their attitudes toward the disclosure of personal AD risk, also reflect this dichotomy. While approximately 90% of the participants suspected they would respond to a personal risk disclosure with positive lifestyle changes, 10% of participants indicated they would even consider suicide if they were at increased risk (Caselli et al., 2014). This aspect, which also came up in our interviews, requires intense consideration, at least in the form of close monitoring as well as scientific-empirical monitoring to determine whether increased suicidality results for the group of “risk patients.” In addition, it should be further investigated how to detect and mitigate negative psychological effects early on in the context of risk disclosure. Providing psychological support to the participants seems obligatory as well as communication training to performing physicians (Ursin et al., 2021).
Another inhibiting reason for many of our respondents from the relatives and uninvolved persons groups was the need for invasive diagnostics in the form of a lumbar puncture. The study design of prevention trials should specifically address this issue. It was previously shown that, for example, uncertainties about lumbar punctures could be reduced by means of standardized video education (Babapour Mofrad et al., 2021). Proposals for supported decision-making with persons with dementia were also published recently (Wied et al., 2021) and could serve as a helpful tool for obtaining informed consent even in cases of already established cognitive impairment, thereby enabling autonomy. However, the concerns about lumbar punctures highlight the importance of replacing this examination with serum parameters in the future (Nabers et al., 2018).
There is a need for further research beyond the study population of older people examined here: What are the risks and benefits of communicating personal AD risk to younger individuals? And at what age, if any, does risk evaluation gain relevance?
Limitations
The results of this qualitative study stem from self-reports, that is, the subjective statements of the participants, so we can make no statement about the accuracy of the data. Selection bias is possible as the study attracted interested participants who were open-minded about the topics discussed. Note also that the qualitative study design does not allow a generalization of the results. Nevertheless, we did achieve the desired number of participants and thus the desired saturation. Furthermore, any interpretation of the results must consider that a large proportion of the participants had previously participated in different studies, and that some of the participants already had experience with AD and were thereby sensitized to the disease. These aspects may have contributed to a bias favoring an altruistic attitude in our groups.
Electronic Supplementary Material
The electronic supplementary material is available with the online version of the article at https://doi.org/10.1024/1662-9647/a000311
The authors express their gratitude to the participants in this study.
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