Prevention of dementia by targeting risk factors

Lack of understanding of the drivers of neurodegeneration and confusion of the causes and consequences of the disease due to the long latent phase of dementia have been major contributors to the large number of unsuccessful drug and lifestyle trials for dementia. The Lancet 2017 Commission on dementia prevention recommended targeting 9 risk factors to prevent dementia, but the expert group acknowledge that limitations in evidence, such as reverse causation bias, may affect these conclusions. We propose an ambitious programme of work which will evaluate risk factors that can be used to prevent dementia via health policy interventions, and will examine a wide range of plasma metabolites that can be used as early dementia biomarkers and candidates for disease-modifying dementia treatments. The objectives of our multi-cohort research programme are to: (1) examine associations of the Lancet 2017 Commission risk factors with cognitive decline, clinically-verified Alzheimer's disease and dementia using the largest individual-participant dataset in this field and a novel analytic strategy to account for bias due to reverse causation; (2) expand analyses to examine how trajectories of chronic diseases over the adult lifecourse shape risk of dementia; and (3) evaluate 233 metabolite biomarkers, singly and in combination, as early predictors of cognitive function, Alzheimer's disease and dementia, with a focus on biomarkers assessed at least 10 years before dementia diagnosis. The sources of data used in the analysis include the IPD-Work consortium of 43 cohort studies, the Dementia Platform UK cohort data resource, UK Biobank, the US-European metabolomics-dementia consortium of 11 studies, and the University College London-London School of Hygiene and Tropical Medicine-Edinburgh-Bristol (UCLEB) Consortium, in total of >1.5 million adults from the UK and elsewhere. This programme is timely because robust evidence must be generated before progress toward effective therapeutic interventions can be made.

The objectives of our multi-cohort research programme are to: (1) examine associations of the Lancet 2017 Commission risk factors with cognitive decline, clinically-verified Alzheimer's disease and dementia using the largest individual-participant dataset in this field and a novel analytic strategy to account for bias due to reverse causation; (2) expand analyses to examine how trajectories of chronic diseases over the adult lifecourse shape risk of dementia; and (3) evaluate 233 metabolite biomarkers, singly and in combination, as early predictors of cognitive function, Alzheimer's disease and dementia, with a focus on biomarkers assessed at least 10 years before dementia diagnosis. This programme is based on existing data related to very large numbers of people with long follow-up (N up to 1.5 million), allowing to examine the temporality underpinning the established associations between risk factors, biomarkers and dementia. The sources of data include the IPD-Work consortium, DPUK, UK Biobank, the US-European metabolomics-dementia consortium, and the UCLEB consortium. Our analytic approach emphasises the importance of "time windows" when considering the role of risk factors and biomarkers for dementia. Thus, we stratify analyses by length of time between risk factor assessment and onset of dementia, assuming that the closer the risk factor/biomarker assessment is to the onset of clinical dementia, the greater the possibility the risk factors are a consequence of preclinical dementia rather than a cause. Resources are requested for research data curation and harmonisation across cohort studies, data analysis, administration and travel.

We will seek to maximise our project's impact by involving lay and professional partners in steering and shaping the research, disseminating the findings to academic and non-academic beneficiaries, and working with beneficiaries to support changes to policy and practice.

Dementia patients, carers and the public: The benefits to the public of the proposed multi-cohort analysis relate to the generation of robust evidence on modifiable risk factors for dementia and biomarkers for cognitive impairment, Alzheimer's disease and dementia than has been available previously. The datasets represent diverse populations, including occupational and general-population samples, different age groups, white- and non-white ethnicities, a wide range of socioeconomic statuses, those with high and low education, and individuals with and without genetic susceptibility to dementia. This diversity will allow us to provide evidence on the generalisability of new findings.

Policy and public health guidelines: With detailed analyses separating risk factor and biomarker assessments at a healthy state and at preclinical and clinical stages of dementia and, in addition, taking into account trajectories of diseases, the project will increase understanding of the drivers of ageing outcomes with major public health relevance, such as cognitive impairment, Alzheimer's disease, dementia and multimorbidity. This in turn will inform the development of preventative interventions and health policies across the adult life course that will expand healthy life span, and reduce the burden of ill health, disease and disability at older ages.

Beneficiaries of our programme of work will be the National Institute for Health and Care Excellence (NICE) and other organisations with guidance, advice and information services for health, public health and social care professionals; national policymakers such as those in the Department of Health, Public Health England, NHS Commissioning, Clinical Commissioning Groups, Health and Wellbeing Boards, and the Association of Directors of Public Health; Charities, such as the Alzheimer's Society; as well as those in local government, who require evidence on where to invest vital resources (e.g., the relative benefit to investment in behaviour change at different life stages); third-sector campaigning agencies (representing the older population, patient groups); and medical practitioners.

Academic capacity and funders: Large-scale epidemiological studies, such as this, have been used as primary evidence of international and national guidelines for prevention of major chronic diseases. Findings from longitudinal population studies may also highlight directions for further interventional and experimental research by identifying risk factors and biomarkers that may be important even at a population level. Such work will provide valuable information about relevant targets for prevention as well as about which stages in the adult life course remediation of the risks is possible. A further advantage is that with large data sets it is also possible to show (and publish) absence of associations convincingly and in this way help reduce investments on research and interventions that are unlikely to be successful. All this information, in combination with subsequent evidence from trials and mechanistic studies, may ultimately enable highly cost-effective dementia prevention measures to be developed.

Industry: The paradigm that has dominated dementia research to date revolves around the amyloid cascade hypothesis. After hundreds of failed trials of potential disease-modifying drugs, major pharmaceutical companies are withdrawing from research on neurodegenerative diseases. Our research aimed at identifying early (non-amyloid) biomarkers for Alzheimer's disease and dementia might provide new targets for research on disease-modifying drugs.