What matters to people with memory problems, healthy volunteers and health and social care professionals in the context of developing treatment to prevent Alzheimer's dementia? A qualitative study

Abstract Background Alzheimer's disease (AD) is recognized as one of the greatest global public health challenges. There is increasing consensus that optimal disease modification using pharmaceuticals may best be achieved earlier in the disease continuum before symptoms occur. However, more needs to be understood about what outcomes are meaningful to potential participants in clinical trials within this preventative paradigm and how people make trade‐offs between risks and benefits. The Electronic Person‐Specific Outcome Measure (ePSOM) programme is developing an app to capture person‐specific outcomes and preferences in clinical trials. Objective As one phase in the ePSOM programme, this study explored what matters when developing new treatments to prevent AD and how trade‐offs are made between risks and benefits, from three perspectives. Design Focus groups were conducted with people living with memory problems (n = 21) and healthy volunteers (n = 10), and telephone interviews with health and social care professionals (n = 10). Differences and overlap between the three groups were explored. Results Outcomes that matter lie in five key domains in relation to what matters in everyday life: Everyday Functioning; Relationships and Social Connections; Enjoying Life; Sense of Identity; and Alleviating Symptoms. Insights were gained into the significance of reducing the risk of developing dementia with drugs and the processes of weighing up risks versus benefits. Discussion and conclusions The key domains identified are being used to inform the next stage of the ePSOM programme which is to develop a survey to be distributed nationally in the UK to explore these issues further.


| BACKG ROU N D
Within health and social care, a central tenet of national policy is to ensure services work to support people to achieve their personal outcomes, defined as the things important to people in their lives and that help them to achieve well-being. 1 A similar focus on personal outcomes has been developing in parallel within clinical medicine: Patient-Reported Outcome Measures (PROMS) assess the quality of care delivered to patients from the patients' perspectives 2 and are increasingly used in clinical practice and in clinical trials.
Dementia, a syndrome whose most common form is Alzheimer's disease (AD), is recognized as one of the greatest global public health challenges. 3 In the absence of a cure, people with dementia require a complex mix of pharmaceutical and non-pharmaceutical approaches to lessen their symptoms and help them live in the way that matters to them. Evaluating the effectiveness of such interventions necessarily requires the use of outcome measures which capture the range of disease effects, not limited to assessing cognition and the functional impact of cognitive impairment using pre-defined criteria of "normal" functioning, but also including outcomes considered most important to the person themselves. Work is underway to establish a core outcome set for evaluating non-pharmacological interventions for people living at home with dementia. 4 In the context of the development of pharmaceutical interventions, it is widely argued that better testing of clinical meaningfulness and the lived experience of individual patients is essential in AD clinical trials. [5][6][7] The rising incidence of dementia and associated challenges in health and social care provision is linked to population ageing.
However, developments in imaging and molecular medicine are beginning to redefine our understanding of the natural development of dementia, leading to a focus on an earlier phase of the disease continuum. In certain forms of dementia, neuropathological changes associated with the gradual development of dementia may precede symptomatic disease by decades (pre-clinical stage of the disease). As the pathology progresses, this eventually leads to cognitive change where there is no functional decline to warrant a dementia syndrome label (prodromal Alzheimer's dementia), before finally reaching a state of overt dementia with progressive clinical severity (Alzheimer's dementia). 8,9 There is a belief that one reason that clinical trials conducted involving individuals with dementia may have failed to cure or delay disease progression is because the pathological process is too far advanced for therapeutic intervention to have an effect. 10 An emerging view is that optimal disease modification using pharmaceuticals will best be achieved at earlier stages of the disease before dementia develops. 11 This involves modification of the pathological process after the onset of disease but before the onset of symptoms: secondary prevention. 10 Individuals who are at the pre-clinical and prodromal stages of the disease may provide a window of intervention opportunity before overt and irreversible cognitive change occurs. This has led to a paradigm shift where AD trials will enrol people with mild and no cognitive impairment, focusing on the pre-dementia stages of the disease. 12 However, there are methodological and analytical challenges, 8 two of which are the focus of this paper.
The first challenge in drug development in AD is that there is no consensus on the optimal approach for outcome assessment in dementia research, 6  The electronic Person-Specific Outcome Measure (ePSOM) development programme aims to explore outcomes and preferences that matter to "patients" in assessing drug efficacy in Alzheimer's disease.
There are four sequential stages in the ePSOM development programme (a) literature review, (b) focus group study, (c) national survey and (d) development of an app for capturing person-specific outcomes.
An overview of the development programme incorporating the literature review is reported elsewhere. 13 This paper reports stage two of the ePSOM programme and specifically addresses two of the key challenges in developing new treatments in AD (outlined above): outcomes that matter to people and factors influencing risk decisions. The findings of this empirical study are informing the development of a UK-wide survey to explore the issues further-ultimately leading to the development of an app, which would incorporate patient preferences and capture PROMs that could be used in AD clinical trials.

| Involving people who experience decline and those at risk of developing dementia
As a first step, it is good practice to involve patients in PROM development. 19 The FDA recommends that patients, as well as health professionals and family carers, should be involved in instrument item generation using focus groups or interviews. 20 This is to ensure the focus is on issues of greatest importance and relevance to patients and to ensure completeness and understanding of the items to be included. The focus towards the earlier stages of AD means that those who might participate in trials to develop new treatment, and thus also in the development of PROMs, are not yet "patients." It is necessary, therefore, to include healthy volunteers.
However, the views and experiences of people who are living with either prodromal or the early stages of Alzheimer's dementia are also important for identifying subtle changes which new treatments might prevent and can be incorporated into PROMs. It is necessary to understand more about the attitudes, beliefs and values of the target population in the preventative model in the preclinical stage who are currently healthy; people in the prodromal stage who are currently functioning; people with a diagnosis who have already made such decisions in relation to currently available treatments and how they make trade-offs between benefit and potential harm. The experiences of health professionals who have treatment discussions with patients experiencing memory problems are also relevant.

| Study design
The study comprised focus groups with healthy volunteers and people with memory problems, and telephone interviews with health and social care professionals who provide care for people with dementia. It is now recognized that the subjective experience of those with mild and moderate dementia can be accessed, particularly when the focus is on feelings rather than facts. 21,22 The advantages of using focus groups with people with memory problems are that there is less pressure to contribute compared to individual interviews, people can feel supported and empowered when they are with people who share similar experiences, and sharing experiences may trigger recall. 21 There were two focus groups with healthy volunteers and three focus groups with people with memory problems. The number of focus groups was based on the resources available and deemed sufficient given that in later groups, no new themes were arising, thus achieving data saturation. 23 Telephone interviews were conducted with health and social care professionals. Telephone interviews are a valid and recognized method for collecting qualitative data with the advantage of being low cost in terms of time and money and therefore pragmatically achievable. 23 The study was approved by the NHS Research Ethics Committee (Reference Number 17/SS/0135).

| Recruitment and sample
People aged over 50 years who self-identified with subjective cognitive impairment, self-identified or had been diagnosed with mild cognitive impairment (MCI) or been diagnosed with mild Alzheimer's dementia, or a healthy volunteer was recruited through three routes:

The Centre for Dementia Prevention at the University of
Edinburgh is a study partner and holds a database of people who have consented to be approached by researchers about suitable studies. All those who met the inclusion criteria were initially contacted by a researcher (JW or SS), sent an information sheet if requested and then followed up by a phone call and the opportunity to ask questions. Nine people with memory problems were recruited through this route.

3.
The study was advertised through Alzheimer Scotland's social media networks, and those interested were asked to contact researchers directly. Three people with memory problems were recruited through this route.
A convenience sample of health and social care professionals known to the research team was invited to participate. This sampling method is appropriate for the exploratory aims of the study. 23  Table 1. Two researchers facilitated the groups (JW, SS). Discussions were audio recorded with consent and fully transcribed. Detailed notes were taken from telephone interviews. All names were removed and each participant given a unique code.

| Data analysis
Two researchers (JW&SS) undertook an initial reading of the transcripts from the three perspectives. An initial list of codes were inductively derived. Areas of agreement and disagreement between the two researchers were discussed until agreement was reached.
A further reading of the transcripts was undertaken by JW (an experienced qualitative researcher), and the inductively derived codes were grouped into two overarching themes with five and two subthemes, respectively. Repeated reading of the transcripts was undertaken by JW to ensure the thematic framework developed was comprehensive and covered the three perspectives.
Data were managed using NIVIVO software. Key themes and data coded to these themes were presented to the full study team for discussion and consideration of the next steps in developing a survey.

| Key findings
The sample comprised 41 participants (Tables 2 and 3) involving two focus groups with healthy volunteers, three focus groups with people with memory problems and ten telephone interviews with health and social care professionals who care for people with dementia.
When focus group dates were being arranged between participants and researchers, some of those who identified as having subjective cognitive impairment, but without a formal diagnosis of dementia, opted to join a healthy volunteer group and others opted to join a group for people with memory problems. This meant healthy volunteer groups did include some people with subjective memory problems and the memory problems group contained people with a range of impairments, some of whom did not have a formal diagnosis.  Tables 4-10.

Interview guide for people with subjective memory problems, MCI and mild Alzheimer's disease
Invite people to tell their own story of how they make sense of their condition • What tells you that you are having a good day?
• What tells you that you are having a bad day?
• Is there anything that tells you that you might be getting less well?

| What matters in everyday life
There were five key interdependent subthemes which emerged as important in everyday life which are relevant to considerations of what matters in developing new treatments.

Everyday Functioning
People with memory problems primarily want to be able to keep confidently doing taken-for-granted everyday things at home (Table 4 quote 1), such as doing laundry (Table 4 Quote 2). Not being able to care for family through, for example cooking, led to strong emotions

Interview guide for people with subjective memory problems, MCI and mild Alzheimer's disease
We would like to understand you own experience of dementia of anger and frustration (Table 4 Quote 3) and the fear of being a burden on family (Table 4 Quote 4).
While maintaining independence was part of the desire to retain Everyday Functioning, for people with memory problems, it went further in that even when help is needed, people still want to be recognized fundamentally as a person in charge of themselves and make their own decisions ( Table 4 Quote 5).
Maintaining Everyday Functioning was echoed by healthy volunteers (Table 4 Quote 6), also picking up on computer skills as being an essential everyday function (Table 4 Quote 7). Equally, the theme of maintaining Everyday Functioning was underlined by health and social care professionals as what matters most to people with memory problems (Table 4 Quotes 8 and 9).

Sense of Identity
Linked with the desire to maintain Everyday Functioning and coupled with the need to be recognized fundamentally as a person (Table 4 Quote 5) was the theme of Sense of Identity. A person with a memory problem spoke about how the effect of losing confidence in doing taken-forgranted everyday things, coupled with other people losing trust in their ability to do them, undermined their Sense of Identity. This made them feel like they were becoming invisible as a person (Table 5 Quote 1).
Equally, health and social care professionals recognized maintaining a Sense of Identity in ways unique to each person as important (Table 5 Quotes 2 and 3).
From the perspective of healthy volunteers, the loss of self-identity was not raised in the context of what matters in everyday life but is discussed further below in the context of the significance of the risk of dementia.

Relationships and Social Connections
Health and social care professionals identified how people can become isolated from their social networks when they have dementia (Table 6 Quote 1) and how people seek treatment to address this issue (Table 6 Quote 2). People with memory problems revealed the mechanisms by which this marginalization within social networks happens and the embarrassment associated with it ( Live alone 4 6 Consider themselves to be having memory problems 21 (all) 4 Dementia diagnosis 12 0 Diabetes diagnosis 2 1 Heart conditions 3 1

Arthritis diagnosis 2 3
Cancer diagnosis 2 1 Depression/anxiety 9 3 Annual household income of focus group participants £0-£24 000 10 6 £24 001-£60 000 9 3 More than £60 000 0 1 Do not know In contrast, healthy volunteers did not fully appreciate the implications of forgetting names for the person themselves, but saw it as less important than other effects of dementia, as it has less impact on those around the person with dementia ( Table 6 Quote 5).

Enjoying Life
Connected to all of the above was the theme of Enjoying Life, recognized across all groups as an important aspect of everyday life and therefore an important measure of the effectiveness of treatment. Health and social care professionals also recognized the importance of Enjoying Life, but also how what is enjoyable varies from person to person (Table 7 Quote 4).

Alleviating Symptoms
Among the already known symptoms of dementia (see Table 1 for prompts used), people experiencing memory problems prioritized "memory" as the most difficult symptom and an important target for treatment. In terms of outcomes of treatment, people with dementia wanted to see memory restored ( Worries about behavioural changes, such as becoming violent, also were an important symptom for treatments to target for people with memory problems (Table 8 Quote 2).
Healthy volunteers also prioritized memory as the key symptom affecting quality of life (Table 8 Quote 3). There was an acknowledgement that there may be other symptoms that are important but that the one most commonly associated with dementia is memory (Table 8 Quote 4).
Health and social care professionals did not prioritize improved memory as an indicator of effectiveness of treatment as highly as others. While they recognized memory as important, in their experience, they had seen people benefit from treatments and support through regaining confidence in Everyday Functioning, even if their scores on memory tests did not improve (

| What matters in making decisions about treatments
This section explores the theme of what matters in making decisions about treatments and explores two subthemes identified as important in weighing the chance of detrimental outcome of treatments against benefit.

The significance of reducing the risk of dementia with drugs
This subtheme came from data collected from healthy volunteers only. It was not explored with those who were in the memory problem group and prevention of dementia using drugs was not something the health and social care staff had experienced with their own patients.
For some healthy volunteers, dementia and particularly loss of memory was seen as a problem worth trying to prevent, even if the chances of developing these were less than 30 per cent (Table 9 Quote 1).
Previous family experiences of caring for someone with dementia, and experiencing this as burdensome, also influenced perceptions of dementia and the significance of preventing it (Table 9 Quote 2). This links with the section above in relation to Everyday Functioning and not becoming a burden being what matters to people. Some of the fear of developing dementia in the future was also linked to previous experiences of relatives who were cared for in care homes (Table 9 Quote 3).
However, in terms of prevention, people also grappled with the complexity of disentangling change in memory associated with normal ageing from changes due to dementia (Table 9 Quote 4).

Balancing risk against benefits
There were two categories of risk considered in relation to the decision-making about preventative treatments: the risk of developing dementia and the risk of side-effects of drugs. In the current context of no cure for dementia, knowing your risk of developing dementia was seen as unhelpful by some healthy volunteers ( (2) And if the person has a hobby that's music and they can't hear, but if they can hear and they've got sore knees, that's not so important, but if their hobby is playing golf and they've got sore knees, that is important, so…Quote 2 022 TA B L E 8 Alleviating Symptoms from the perspective of people with memory problems, healthy volunteers and health and social care professionals (Each quote labelled with quote number plus unique identifier code of each participant)

People with memory problems Healthy Volunteers Health and Social Care Professionals
(1) I think memory is the big issue for a lot of people, I'm not saying everybody. But suddenly starting to remember names again, and you know, remembering words again. Just everything, basically, because all the things you've lost, you want to see them come back out again… that's more important for me than anything else. (Quote 1 013) (3) I think memory must be one of the most important things that we have. If we can't remember what we did last week, then it must reduce our quality of life (Quote 3 005) (5) The benefits are around "soft skills" … feel less anxious, feel more confident. It is the relatives who report this. These benefits help families. They are not hard and fast benefits such as "he remembers such and such better" (Quote 5 HSP010) Some healthy volunteers did not initially hesitate to consider taking drugs to prevent dementia when asked early in the discussion about taking them. However, they sounded a more cautious note later in the discussion once they had considered the various tradeoff between benefits and harmful side-effects of drugs in more depth (Table 10 Quote 2).
For most people already experiencing memory problems, some of whom were already taking currently available treatments which aim to slow progress, the decision to take them was not difficult as they took them "because the doctor said so." They were prepared to accept the uncertainty of both benefits and chances of harmful sideeffects (Table 10 Quote 3).
The side-effects that people would be prepared to tolerate varied across all participants and the discussion in both healthy volunteer groups and people with memory problem groups revolved around the severity of various symptoms, whether or not symptoms could be alleviated and how much disruption they would cause to daily life (Table 10 Quote (Table 10 Quote 6).
Healthy volunteers were overall more able to engage in thinking about how to trade-off the probability of benefitting from a drug treatment against the probability of experiencing a side-effect (Table 10 Quote 7).
However, the complexity for everyone of making decisions, whereby the chance of benefitting from a drug treatment has to be traded off against the chance of side-effects of varying degrees of severity, was recognized (Table 10 Quote 8).
Health and social care professionals were cautious when considering the benefits of currently available drug treatment to slow or prevent dementia and their approach was to manage people's expectation and be honest about the degree of benefit they could expect (Table 10 Quote 9).
In terms of the trade-off between benefits and harms of drug treatment, health professionals recognized that there has to be a "real-life benefit" to taking medication, otherwise it is not worth it ( (3) As far as the care goes, I know in nursing homes, thinking of the few that my cousin was in, they get to a stage where the patients are taken into a chair, perhaps in a room with other folk, perhaps just sitting up in their own little room, and they're left and that's it, and the television might be on, and they might talk to somebody else, they might not, and we've all seen pictures of these rooms with lots of armchairs and people sitting in them and that's all they do. So the stimulation and keeping the brain stimulated doesn't happen, which is very distressing.  Our results show that previous experiences of having known or cared for someone with dementia shaped views of the significance of living with the possibility of developing dementia in the future. This is in keeping with previous studies. 27 Connected with this was the view that we are defined by our minds: dementia was seen as taking away the mind and, by implication, the person. Being defined by "my mind" reflects contemporary culture which holds rationality, cognition and memory as core aspects of the self. 28 When dementia leads to the loss of these aspects of selfhood, the person is diminished in the eyes of society and, as shown here, in their own eyes. Insights from some of the people with memory problems show how they felt like "I'm not there" when family members denied them the opportunity to continue with everyday tasks such as doing the ironing. Milne et al (p. 982) 27 describe this as being "corporeally present but cognitively absent" and it underlines how overlooking embodied aspects of selfhood 29 leads to exclusion and suffering of people with dementia as they become seen as non-persons. This may shape views of risk decisions about developing dementia in powerful ways. Hearing the direct experience of those already experiencing this is important as it highlights that some of the solutions to the loss of identity can be found in changing attitudes towards people with dementia and creating enabling rather than disabling environments.
As with previous studies, people were able to engage to a degree with thinking about trade-offs between harms and benefits in clinical trials. 14 However, engaging with the probability of harm against the probability of benefit was more challenging for those with memory problems. The challenges of making probabilistic judgements are an important consideration going forward in the ePSOM development programme.
Our results suggest that the assessment of risk and how much potential harm, in the form of side-effects, a person is prepared to accept may also be shaped by fears about inadequate care provi- there is still much that can be achieved using these non-pharmacological approaches to address some of the aspects of everyday life that matter to people living with dementia and those who may develop it in the future.

ACK N OWLED G EM ENTS
The authors wish to thank all those who took part in focus groups and interviews for this research.

CO N FLI C T O F I NTE R E S T S
There are no competing interests.

AUTH O R S' CO NTR I B UTI O N
All authors contributed to the conception and design of the study.
JW and SS involved in acquisition of data. JW, SS and CC performed analysis and interpretation of data. JW drafted the article. All authors involved in revising and final approval of the article.

E TH I C A L A PPROVA L
The study was approved by the NHS Research Ethics Committee (Reference Number 17/SS/0135).