Making Alzheimer’s and dementia research fit for populations

Two decades ago, the established view was that ageing and Alzheimer’s disease arise from distinct pathophysiological processes. Tremendous scientific efforts were underway to separate and characterise their biological bases. At the time, reflective contributions were made by the corresponding author that raised concerns about this approach, arguing from an epidemiological perspective that what cognitive decline actually constituted in the unselected ageing population should be carefully examined.^1-3 The view was expressed that investigations into the biological underpinnings of ageing and dementia were being biased by assumptions about causality, through reification of particular diagnostic entities without the necessary empirical evidence from relevant populations.

We propose that the accepted framework has generally inhibited the discipline from making advances that might benefit the many people with usual dementia. The little progress that has been made in dementia prevention calls for reflection on successes and failures of the substantial investment over the past decades by governments, the commercial sector, and charities.⁴ The poor understanding of ageing and prostate cancer, and the application of an inadequate screening test that has led, many believe, to over treatment, harm, and expense, has been called the “great prostate mistake”.⁵ Is it too late to avoid the “great Alzheimer’s mistake”?

A need for standardised definitions of dementia led to the development of diagnostic criteria based on clinical measures of symptoms and observations. However, even in fairly homogeneous cultural settings, these criteria had the potential to be interpreted differently by individual clinicians and researchers. The diagnosis of dementia has remained an entity with indistinct boundaries. Although few disagreed about what constituted moderate and severe dementia, studies including milder cognitive deficits led to much less consistent estimates of dementia prevalence.⁶ To some extent, the variability in reported prevalence has been mitigated by use of more uniform approaches to operationalised definitions, but huge variation remains.^7,8 Establishment of definitions for this intermediate cognitive state is currently of great interest but attempts have led to some degree of unnecessary duplication of effort. Contemporary definitions look remarkably similar to those proposed more than 20 years ago for minimal or questionable dementia.⁹

Because of the absence of clear-cut identifiers to predict dementia (or its subtypes) for any given individual, attention has turned to the value of the addition of biomarkers (eg, amyloid β on imaging, or peptide ratios in cerebrospinal fluid) to neuropsychological domains or even the consideration of such markers as diagnostic entities in their own right.¹⁰

Major difficulties exist for the validation of proposed biomarkers in relation to dementia as an outcome in relevant populations and in appropriate timeframes. The sheer volume of evidence from huge population-based studies and randomised trials that contributed so much to our understanding of blood pressure and cholesterol— and their association with future cardio vascular disease— does not exist for dementia of any type, particularly in the age groups at greatest risk. This evidence took many decades to establish, and investigators of enormous longitudinal studies and meta-analyses are still looking at emerging risk factors.¹¹ We do not have anything on a similar scale for the specific risk factors of interest or biopathological profiles in dementia. Understanding of the meaning of these biomarkers and their natural history at particular ages, in particular cohorts, and over time is crucial before they can be applied widely,¹² with the recognition that this approach has the potential to identify most of the middle-aged population as having a disorder.¹³ Furthermore, the effect of age on total dementia risk has so far over shadowed any other associations under investigation,^14,15 a fact often downplayed in discussions of the potential effect of modifiable risk.

Even though large studies are called for, funds to establish truly representative populations are difficult to raise. Imaging is expensive, as is blood taking and appropriate storage. Response rates are decreasing, and attrition and dropout are substantial in older populations, with little ability to address potential bias. However, if vast amounts of money are to be spent on long-term, regular investigation, detection, and treatment (along with any adverse effects) of preclinical syndromes from middle age, this is the type of evidence that would be needed by any body with responsibility for recommendations and financing on health-care spending (such as the National Institute for Health and Clinical Excellence in the UK). There is, as yet, no systematic or coordinated effort to support researchers exploiting the opportunities from existing cohort studies.

Much of the research and rhetoric ignores the difficulty inherent in conflating the dementia syndrome with the notion of Alzheimer’s disease.⁴ In the ageing brain, pathologies associated with frank dementia are often seen in people who die without dementia. As already noted, most prostate cancer is in situ, and will not affect the lifespan or quality of life in the older male population. The understanding of why some men’s prostate cancers become aggressive is incomplete, so screening interventions that merely detect the mass of prostate tissue (prostate-specific antigen testing) lead to more harm through unnecessary biopsies and consequent interventions than reduced cancer-specific mortality. Similarly, why specific neuropathologies in some older people are associated with expression of dementia whereas in others these same pathologies are not, remains unexplained.¹⁶ Without better understanding of these factors, pursuit of the definition of pre-dementia according to biological measures will lead us down the same route as prostate cancer screening. What older people want to know is whether they will get dementia and how to plan for it—not whether they will fit some biopathological profile.

Despite the media hype, the promise of many risk factors and therapies has yielded little in terms of tangible outcomes for dementia. The best present intervention for Alzheimer’s disease is still based on symptomatic improvement. Why so little progress? Perhaps there has been too much focus on findings that might be the product of a selection bias for people with dementia who have been admitted into various clinical services. There is the real danger of residual confounding or inadequate attention to the fact that apparent protective factors might only be markers for some other less measurable, more fundamental, mechanism for risk or protection. This mistake has been made for other disorders: most apparently, hormone replacement therapy seemed to have a protective effect against heart disease in observational studies, but in trials was shown to cause harm.¹⁷ The same has also happened for Alzheimer’s disease— eg, in trials of anti-inflammatory drugs, and vitamin-based and endocrine-based interventions.

Selection bias is a major limitation for the generalisability of research findings. Much observational epidemiology has been done on volunteer samples. Selective participation and attrition are mostly unaddressed,¹⁸ and these have the potential to systematically affect the direction of findings. Recruitment into treatment trials from memory clinics tends not to be representative of those with most dementia and comorbidity,¹⁹ and so interpretation should be informed by detailed scrutiny of how generalisable findings from such a setting would be to the entirety of people with dementia. By only studying groups in specialised clinical settings in which a sufficient proportion will develop frank dementia over a relatively short time,²⁰ there is substantial risk that the same measures applied in the population (ie, unselected settings) will have lower positive predictive values, leading to more false positives. This effect has been shown for mild cognitive impairment in many studies, with the Medical Research Council Cognitive Function and Ageing Study providing the most systematic assessment of the performance of different definitions.²¹

Population prevalence of the actual ages of people with dementia shows the largest proportion is aged 80 years and older, and this proportion will further increase substantially over coming decades (appendix p 1). People with dementia at every stage and age will have greatly different needs, including pathways through dependence to death. Clinical and epidemiological research should reflect these variations if it is to have appropriate generalisability.

Most dementia research is not done in those aged 85 years and older. Appendix p 2 shows schematically why—as in the Buddhist parable of blind men gaining vastly different impressions of an elephant from examining only one part each—different sectors in the research community have such varied perceptions of dementia, and why research findings seem to produce conflicting results. Each clinical setting and specialist group dealing with people with dementia has different filters from the whole population, but each group tends to generalise its experience to the entirety. Thus we have the call for screening from old-age psychiatrists in memory clinics, but those in primary and secondary care who deal with the bulk of the older population know that this approach would overwhelm our systems. The provenance of the research should be more clearly framed in the context of its meaning for the whole dementia population, with limitations for generalisation clearly articulated.

An important but under-researched component of dementia epidemiology is the recognition of terminal decline. The prevalence of dementia and cognitive decline is common at varying intervals before death.²² Attention has been focused so strongly on prevention, detection, and cure that terminal decline, through which so many of us will pass, has been relatively neglected.

In the appendix we attempt to explain why, if we take dementia as one entity, to make sense of the apparently divergent and diverse findings about dementia from different research disciplines is not possible. However, if a longitudinal and population perspective is taken, we can see the many different effects on who is seen by whom and ends up where, and who is being represented by the research from these varied settings. Of crucial importance is that approaches and findings are anchored to the reality of dementia in the true population, if we are not to continue to drain public and commercial resources on the basis of overextended claims.

One approach would be to review the existing and emerging evidence to assess its place and likely relevance for the whole population with dementia syndrome, and over what timescale. This approach would emphasise the exact nature of any investment needed to take findings forward and provide some estimate of the likely effects. We advocate an approach to dementia that is driven by true-population awareness, not merely restating the size of the problem, and for researchers to argue the true place of their research with respect to real populations. Additionally, we suggest that research mapping in a systematic way for primary, secondary, and tertiary prevention of dementia and then simulating population effects will help to inform the scope and direction of future research.