Health Outcome Prioritization in Alzheimer’s Disease: Understanding the Ethical Landscape

Public health and distributive justice

A key ethical aspect of contemporary AD management is the shift toward public health prevention [10] away from clinical medicine [20], to contain the costs of supporting an expanding and aging population in which AD prevalence will increase [21–23]. However, the benefits of a preventive approach should not be overstated [20, 24]; rather, the benefits of promoting general health advice may extend to dementia [10]. This shift is important for determining an ethical prioritization of outcomes in two respects.

First, public information about how to reduce the risk of dementia through lifestyle modifications from early life onwards affects the relationship between the state and its citizens [25]. Pressure to make certain choices may be viewed as an infringement of liberty [26, 27], particularly where the state establishes policies that expect individuals to modify their behavior; or prioritize treatment based on following preventative recommendations. Moreover, recommending lifestyle modifications that provide no guarantee to prevent AD may be viewed as unacceptably paternalistic and corrode trust.

Second, the application of Quality Adjusted Life Years (QALYs) to individual priorities may not adequately capture the subjectively bound nature of ‘quality of life’ or ‘well-being’, despite the centrality of both to ensuring a successful outcome for people with AD, given that personal evaluations of concepts such as these differ [28, 29]. Furthermore, ‘benefit’ and ‘value’ may be interpreted differently. From a health economic perspective it is essential to attach a particular price to a particular level of benefit [30], however, the priorities of individuals with AD are likely to differ from other stakeholders, such as patients, their carers, health care professionals, providers, and payers of medical treatments [31].

Scarcity of resources

Outcome prioritization requires distributing limited resources to achieve desired outcomes. How these distribution decisions are made differs geographically. For example, in the UK, NICE prioritizes cost-effectiveness, whereas cost-effectiveness does not inform decision-making in Germany, and in the Netherlands it informs decision-making but only above a certain price threshold (very cheap drugs do not attract scrutiny) [32].

Irrespective of particular metrics used, the finitude of resources means that some people will be denied access to interventions that would benefit them [33–35]. This is ethically significant since the needs of some will be de-prioritized in favor of the needs of others, and the resulting gap may conflict with the clinical duty of care (this also holds for prioritization between people with the same condition and people with different conditions). As Hermeren et al. [36] summarize baldly, to prioritize is inevitably to say ‘no’ to somebody.

This is especially acute in the AD context, in which many people are unable to derive significant value, given that no curative treatments are yet available and evidence for the effectiveness of preventative interventions is weak. In light of this, some have concluded that the greatest need is for high-quality long term care, and similarly high-quality support for family carers, such that the lives of people with AD and their families are made as satisfying as possible in the absence of any treatment that would decisively reverse the disease [5, 37]. Indeed, research carried out by Kelly et al. (2015, p. 990) [38] with people with dementia, their carers, clinicians, and other health professional finds preferences of this kind in the top ten overall prioritized outcomes across all groups.

Encouragingly, for the findings of our own analysis, there is also significant parity with the Kelly et al. [Ibid.] study insofar as ethical dilemmas over finite resources report shared concerns, for example: negotiating the balance of benefits between pharmacological and lifestyle or social interventions; evaluating the value of early diagnosis in light of its psychological impact in the absence of a cure; how to optimize outcomes for people with advanced dementia at the end of life; and how to also support carers of people with AD as well as people with AD themselves.

Heterogeneity and changing circumstances

Prioritization decisions are ultimately concerned with both outcomes and endpoints, which are related but distinct parameters. Outcomes denote measured effects of treatment, whereas endpoints are pre-identified targets of a study built into its design [39]. From an international perspective, the outcomes and endpoints considered important may differ, depending on characteristics of particular markets [39]. Moreover, the definition, diagnostic cut-off and mechanism of measuring the numerous potential outcomes and endpoints continue to be debated; and the difficulty of determining preferences for these—for example living longer, declining more slowly, or dying sooner before more serious incapacity—is compounded by the plethora of available assessment tools. A further challenge in AD, and in the context of other conditions, is that assessment tools measuring a wide range of domains including memory, spatial orientation, semantic processing, speech, emotion, mood, apathy, aggression, and mobility [40–42] are not ideally sensitive or specific and so do not yield perfect validity either in earlier and preclinical stages of the disease [40] or in more severe stages [41, 42].

In addition to this heterogeneity in assessment tools, changing background circumstances also affect prioritization decisions. Prioritization is also made complex by the heterogeneity of AD itself, in that the disease affects different individuals in different ways, in different cultural contexts, and at different stages of the disease; indeed, priorities are likely to differ in line with the progression of the disease, since the impact of MCI, for example, is less severe than very advanced AD later in life [12, 41]. As such the AD community itself cannot be assumed to be homogeneous with respect to how members of it are affected by the disease [42, 43], which underlines the risk of assuming that the priorities of one AD population subgroup is necessarily representative of other subgroups or the AD population at large. Moreover, not only are resources for people with AD limited (as above), but their availability is not necessarily constant. For example, external or short-term political factors and election cycles can affect both health policy and budgets, which shape prioritization decisions [44]. Equally, prioritization is shaped by new advances in medical science that expand what is therapeutically possible. Furthermore, global trends towards population growth and increasing life expectancy may mean a future in which more people are competing for fewer resources [45]. Outcome prioritization should therefore be viewed as an ongoing process, requiring reflection and revision, according to changing circumstances, as needs and options change [46–48].

Knowledge of treatment

Determining what counts as fair prioritization of outcomes depends partly on what needs to be known to make the relevant decision [1, 49]. Data from randomized trials is considered the ‘gold standard’ for establishing efficacy; however, there are a number of challenges that make it expensive and time consuming to test the efficacy (or effectiveness) of a drug, and make it difficult to determine optimal clinical practice for long term treatment management in AD.

First, there is the challenge of attrition compromising the validity and/or generalizability of results from trials [50]. There is evidence that older, sicker individuals in particular are more likely to drop out of studies [51, 52], die before the trial is concluded or to discontinue the study treatment due to adverse effects.

Second, people in symptomatic stages of AD are typically older and more likely to have comorbidities, making them complex [53–55]. RCTs of new drug products may investigate drug-drug interactions to some degree, but this is not always exhaustive. Data from RCTs about drug-drug combinations may be underpowered or simply unavailable. Since interventions may have trade-offs between desirable effects and undesirable side-effects, weighing these is less straightforward where comorbidities requiring different types of treatment are present [56]. Polypharmacy is common, without clinicians fully knowing the risk of harm due to lack of evidence. Indeed, separate studies are designed to address these issues [57], and knowledge of the mechanism of action of certain drugs contributes usefully to decision-making. Notwithstanding the challenges outlined, therefore, clinicians are not uninformed when prescribing certain drugs. Rather, the biggest challenge arises when patients have multiple comorbidities which all require treatment [58] since it may become necessary to prioritize the treatment of some rather than other in order to realize an all-things-considered, rather than ideally, desirable outcome. As such, ensuring an optimal balance of outcomes in the context of chronic disease in old age is particularly challenging [59]. This uncertainty poses a further challenge for realizing priority outcomes which depend on the effectiveness of a particular drug.

Values and circumstances

The importance of patients being able to make their own decisions is reflected in the contemporary centrality of ‘patient-centered care’ [60, 61]. Properly respecting the values and circumstances of patients does not mean swapping a paternalistic approach for an equally polar norm in which patients have absolute autonomy over all courses of action [62, 63]. Nevertheless there is an inevitable imbalance between the clinical expertise of doctors and patients who are experts in their own experience and the subject of the disease and its treatment [64–66]. As such, patient-centered care and prioritization of outcomes in AD should be conceived as a collaboration known as ‘shared decision-making’ [67, 68].

Knowledge-related power imbalances underline the ethical importance of remembering that it is the patient who must have the final say. Indeed, this is especially important in the case of AD, where treatment options are limited. For example, if faced with the prospect of cognitive decline a patient may, for example, decide not to accept a pacemaker to prevent heart failure. It is not obvious in such circumstances that the decision against prolonging life as long as possible is either irrational or to be avoided. As van Summeren et al. [3] report, a dilemma often faced by patients, carers, and clinicians is how to balance factors such as the benefit of palliation of symptoms and maintenance of life or independence against the discomfort caused by the side effects of a potentially complicated drug regime. Examples such as this thus remind us of the primacy of the AD patient’s right to choose, even within a shared decision-making model.

Conflicting priorities

Complications arise when determining and combining preferences. For example, the difference between qualitative and quantitative findings present a challenge when pooling and attempting to weigh different forms of evidence [69, 70]. To mitigate this, preference elicitation techniques [71–73] exist to help individuals to arrive at a decision or ranking of the various outcomes and permutations.

Ordering outcomes according to their desirability may not be straightforward, given the different ways in which a disease and its symptoms may affect daily living and wellbeing. For example, in patients with multiple conditions or comorbidities, countervailing factors will need to be taken into account [10] to arrive at what is, overall, the best balance between benefits and risks of one approach to treatment rather than another [74, 75]. Ordering outcomes is also complex because the ‘best’ balance of risks and benefits may be plural, that is, there may be more than one ‘right’ decision in any given scenario. This is especially pertinent in the AD context, given that no cure is available at present. Were there curative treatments it may be easier to calibrate the relative desirability of different options since, presumably, reversing the disease would be always be prioritized over other outcomes. In the absence of curative treatment, deciding on the ‘right’ course of action must be made by the careful weighing of other, suboptimal, options.

Ethical challenges in outcome prioritization also emerge when priorities conflict, for example between short- and long-term treatment goals, considering that the development of drugs and tests is slow and resource intensive [76], even when research funding prioritizes a particular condition [77]. Moreover, there may be challenges in involving all relevant stakeholders in the prioritization process [78]. For example, factors such as linguistic barriers and insensitivity to different cultural values mean that minority ethnic groups are under-represented in research [8, 79–81].

There may also be intractable conflicts of priorities in relation to decisions concerning the end of life. Qualitative research by Goodman et al. [5] reminds us that for many people with dementia, death may be preferable to a severely impaired life with dementia. Since family members and carers cannot (legally) hasten death to bring an end to unwanted suffering, it is not obvious how such wishes can be meaningfully accommodated.

As Hunter [82] writes, questions about whose responsibility it is to engage in the process of prioritizing outcomes are also ethically contentious. This creates a further set of practical ethical complexities around the balance of duties and responsibilities between patients, carers, society at large, clinicians, policy makers, health economists, and other bodies with a stake in optimizing care. For instance, prioritization can be complex when making choices regarding prevention or disease progression, such as whether to provide treatment to those who are most in need, or those who would benefit the most. There is no straightforward way to resolve dilemmas such as this, which reminds us we cannot assume that priorities will be uniform and agreed between patients, their carers, clinicians, and the wider general public [47, 48, 83]. Indeed, such dilemmas may be fundamentally unresolvable, given that, ultimately, one group’s interests will be relatively de-prioritized.

We can go further still than this to reinforce the point if we keep in mind that allocation dilemmas in a specific context such as AD are not unique in their complexity, since in the vast majority of instances, notwithstanding certain paradigmatically immoral acts such as torture or rape, ethical judgements are always contestable. Since there is no objectively agreed standard of measurement or value as is more readily available in the sciences, it is the nature of moral deliberation that grounds for rational disagreement can never be completely extinguished. Returning to the extant context of health outcome prioritization in AD, therefore, this general characteristic of ethical discourse underwrites the claim that what counts as a successful decision and legitimate prioritization of outcomes will consist in the fastidiousness of the process by which the decision was reached in terms of considering the views of as wide a range of stakeholders as possible [84], rather than the decision itself.

Communication, autonomy, and caregiver issues

AD impedes communication [84], cognition [85], autonomous decision-making [86], social participation [87], and independence [88] and has a psychological and emotional impact affecting relationships and perceptions of self and personhood [89, 90] as the disease progresses from mild cognitive impairment (MCI) onwards [4, 48]. This becomes increasingly significant as the disease advances and compromises more aspects of life, as family carers may often need to spend an increasing amount of time supporting their relative with AD and making decisions on their behalf on the basis of what they take to be the relative’s wishes [4, 91].

Questions of self-determination are immediately relevant in this context. Seeking out the preferences of people with AD and other dementias is crucial as far as it is possible to do so [92], and it is important not to assume that people with dementia are necessarily unable to speak for or represent themselves, albeit that sensitivity and flexibility must be shown to the varying lengths of time that someone with AD may need to make choices or communicate their wishes [93]. For example, at the end of life it is of the utmost importance that the dying person’s wishes are understood as explicitly as possible in advance [94–96], moreover, it should not be assumed that people will be unable to express their preferences in some form, even at later stages of the disease or at the end of life [11, 97]. This is vital when considering who has a say in determining which outcomes matter: firstly to ensure that those who can contribute do so; and secondly to ensure that first-hand experiences of different disease stages are represented. This is an issue of both fairness—in that there should be no systematic exclusion based on assumptions about capacity at particular stages; and validity—in that the actual priorities of patients are heard above the hypothetical priorities of those imagining being in such circumstances.

The completion of advance directives by individuals before their dementia becomes too advanced to communicate their preferences towards the end of life are one option for negotiating likely future communication issues [98]. However, these are not without potential ethical problems; for example that they are often left incomplete such that the individual’s wishes are uncertain or unknown to carers and others [95]; and the validity of advance directives can be disputed or undermined given that it is possible an individual’s preferences change after they are no longer able to communicate this to others [92]. As such, when attempting to make prioritization decisions in the later stages of AD, it is important to keep in mind that advance directives, while undoubtedly a vital tool for eliciting preferences, are nevertheless fallible.

Given the progressive, degenerative nature of AD, it can become increasingly difficult to know the priorities and preferences of the person affected. Often caregivers, whether professional or unpaid, family members, or partners, are able to understand the affected person’s wishes as their ability to clearly communicate their preferences diminishes [84, 99–101]. However, this presents a challenge for ensuring that carers properly represent the affected person’s interests and, crucially, that they respect and protect the dignity of the person with dementia [102]. This is a considerable ethical challenge, as knowing what we ought to do for people with AD if their preferences are only indirectly discernible or require interpretation raises the risk of erroneous decisions. Again, the limitations of advance directives should also be taken into account in relation to this point.

People with AD are vulnerable if they cannot communicate effectively and may be more reliant on their carers to represent their interests. While most carers will do this, it cannot be assumed that all risks of misrepresentation or mistreatment are eliminated [103]. For example, carers’ evaluations of the quality of life of people with AD are typically negative [104], but we cannot verify this precisely because of the impaired communication that the disease brings about. Similarly, there is evidence to suggest that carers wish patients to remain in the milder stages for as long as possible and decline rapidly toward the end to minimize the impact that it will have on them, but we cannot assume that this is what the person being cared for would also wish [105]. One reason may be that the burden and risk of isolation experienced by carers increases as the patient’s disease progresses, and their judgement of the patient’s quality of life can be negatively influenced by the deterioration in their own quality of life [106, 107]. Nevertheless, it is important here to consider carers as stakeholders with a legitimate voice of their own regarding outcome prioritization, separate from the extent to which they can reliably interpret the wishes of those for whom they are caring [108, 109].

Disclosure of risk

The risk of progressing from MCI to AD may be an important outcome for people in early stages of cognitive decline; however, the uncertainty of such predictions and the limited ability to act on it, make knowledge of one’s risk ethically complex. For instance, although preclinical testing for AD is advancing in accuracy and scope [110], understanding the wishes of all those to whom such testing may be relevant is important for harm reduction [111] and ensuring individuals have the greatest scope for decision-making that they wish to have, whatever their decisions and preferences following risk disclosure might be. People identified at high risk of developing AD, such as some MCI patients, will already feature in such considerations, since, as Rose [112] points out, the best indicator of major disease in future is often the existing presence of minor disease. Indeed, the current diagnostic guidelines state that AD dementia is preceded by MCI, and MCI is preceded by an asymptomatic preclinical AD phase [113]. However, as algorithms become better at predicting risk in asymptomatic individuals, namely, those who have biomarkers of the disease but no symptoms, those to whom this will become relevant will increase in line with the increasing accuracy of predicting AD at the asymptomatic stage.

In each group deemed at risk, the ethical ramifications of testing center on how individuals, and those close to them, should respond to risk information as well as what responsibilities fall on those disclosing the risk status. For example, this will extend to family members, as knowledge that a relative will or is likely to develop AD will affect their lives, not least because some of those family members or partners may have to become carers [43, 114]. Moreover, in the case of genetic risk factors for AD which can be identified at any age, such as APOE, genetically related relatives may be faced with a decision about whether they too wish to undergo testing for presence of such markers [115].

These scenarios are ethically challenging as long as AD remains incurable. For example, while cognitively normal, asymptomatic, individuals may be able to reduce their risk of developing MCI or AD by making lifestyle changes in mid-life, there is an absence of high-quality, reliable evidence for the effectiveness of these changes, and as such they do not guarantee it [116, 117]. As such, it cannot be assumed that individuals will necessarily prioritize receiving risk information in the absence of a guarantee that successful prevention is possible. Nevertheless, there may be benefits to early risk assessment and diagnosis, since it enables patients to more capably make legal and care arrangements and change their lifestyle so that they can maximize the time they have with significant others [118, 119] or to make plans to end their lives before dementia makes that impossible.

To the extent that a foundational duty of healthcare professionals is avoiding and preventing harm, it is necessary to keep in mind a broad conception of harm that encompasses not only physical and cognitive impairment caused by the progression of AD, but psychological and emotional damage that may come to people by knowing their risk. It is straightforward to state that individuals are entitled to be informed of all the findings of their scan, however distressing these might be, if they wish to and understand the implications of what they might be told. However, it should not be assumed that, for example, cognitively normal but amyloid positive individuals [13] should automatically be informed of the results of their scan without prior discussion as to the individual’s preferences for disclosure [120], as it may cause significant distress even if the information is sought. Indeed, amyloid positive individuals may live to old age [121] or die before developing notable symptoms, either because of another condition or an accident, even though there is a consensus among clinicians that these individuals would have developed dementia had death not intervened first. In these cases, it is important to elicit what an individual’s preferences are with respect to AD, relative to other health risks that they face, also taking into account how legal rights to the disclosure of information to individuals are framed in different jurisdictions.

Aside from the harms of the disease, therefore, disclosure may pose a risk of psychological and emotional harm to affected individuals [122], their carers and families, and the interpersonal relationships between them [123]. Finally, for individuals with private health coverage rather than the majority in the European context who depend on state health provision, known information relating to the risk of disease may affect individuals’ insurance premiums and coverage and cover if they are obliged to disclose this to insurers [23, 64, 108, 109, 124], and a the risk of harm that may come from the exploitation of this information by insurers should be taken into account when balancing the priority of potential outcomes. The risks outlined are some of those adduced in arguments against dementia screening [125, 126] and help to demonstrate that although an assumption that diagnosis and knowledge of one’s condition would and should always be one’s priority may look prima facie reasonable, when subjected to scrutiny the situation reveals itself too complex for the assumption to be applicable or necessarily beneficial.

Limitations

This is a non-systematic narrative review. One potential limitation may come from the type of conducted search, where only the titles were searched for presence of keywords. This limitation was mitigated by subsequent snowball sampling of further relevant manuscripts, which significantly increased the number of papers eligible for review. Another potential limitation may come from the single-reviewer process applied to this study at the abstract selection and initial full-text review stages. This limitation was to some extent mitigated by the iterative analysis process, where all contributors reviewed, discussed, and contextualized the results, reaching back to the original sources as needed; and by the reviewing of a subset of titles by a co-author and comparison of decisions for inclusion and exclusion. A further limitation is that since we have only used English language studies in this paper, we are unsure of the reliability of our findings for non-English speaking AD communities. However, this was unavoidable given the resources available to the authors.

A final limitation is that since the later stages of editing post-peer review were carried out during the initial lockdown phase of the 2020 COVID-19 pandemic, the authors are unable to review literature about the ethical implications of outcome prioritization in AD in the context of the current pandemic and potential future ones. Given that the paper is based on a review of the relevant literature, while AD-relevant studies produced in light of the pandemic will undoubtedly emerge, the paper has not been produced sufficiently long after the initial global infection for such material to be published made available for analysis.

Nevertheless, we can make a tentative remark that it would be worthwhile to investigate in future work. It is likely that situations such as the COVID-19 pandemic may change what are considered acceptable trade-offs in outcome prioritization within the eight themes that we identify in this study. A possible concrete example of this might be accepting the additional safety risks associated with remote monitoring of people with AD living on their own, in order to shield them from the more immediate infectious disease risk that would come with usual levels of face-to-face contact.

Conclusion

Our analysis demonstrates the essential role that ethical deliberation plays in ensuring the just prioritization of outcomes. Given that discussions about how we ‘should’ allocate resources is an irreducibly normative question, expertise in ethical and philosophical reasoning are indispensable for a task such as this, irrespective of the fact that the task is an applied one and these kinds of expertise are putatively theoretical. Of course, the evidence to which we refer is similarly indispensable, since without empirical information about how and why different stakeholders prioritize outcomes in the way that they do, no rational negotiation of these towards a just outcome can be carried out. Nevertheless, what ought to be done cannot simply be read off these descriptive data. For this reason, allied with the compelling need to find new strategies for managing AD in view of the growing societal pressure that it is exerting, we conclude by reiterating the central role that ethical reflection contributes in decision-making processes regarding the prioritization of patient outcomes.