Prevention of dementia by targeting risk factors

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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.