Taking the long view: Identification of plasma protein biomarkers for dementia risk (360G-Wellcome-221854_Z_20_Z)

The overarching goal of this collaborative project is to make a step change in knowledge of dementia biomarkers by focusing on plasma proteome. We hypothesize that plasma is biologically informative due to the presence of protein signals: imprints of subclinical dementia progression that can be identified via repeated proteomic profiling decades before clinical symptoms, providing novel candidate targets for preventative treatments. We will use the largest plasma proteome platform currently available, with three aims, to (1) prospectively examine 4,993 plasma proteins in relation to subsequent accelerated cognitive decline and clinical dementia across multiple cohort studies; (2) determine whether the protein hits identified in aim 1 have a causal association with dementia, whether modifiable and druggable, using analysis stratified by time between protein measurement and dementia onset and Mendelian Randomization framework in relation to novel genome-wide, and druggable-genome arrays; and (3) examine whether proteins predicting dementia risk are imprints of risk factors for dementia. The expected new outcomes include protein targets for drug development; improved identification of potentially modifiable lifestyle risks; dementia trials surrogate outcomes; improved diagnostic markers, plus data resource for future in-depth research on the multisystem aetiology of dementias and proteomics of a range of major diseases beyond dementia