BRain Imaging, cognition, Dementia and next generation GEnomics: a Transdisciplinary approach to search for risk and protective factors of neurodegenerative disease

Establishing efficient prevention strategies for dementia and Alzheimer's disease (AD) is a major health priority for the coming years as the Australian population ages. Importantly, the pathological processes leading to AD begin many years before clinical diagnosis. However, our understanding of the causes of AD is still rudimentary. Brain imaging measures may capture early structural brain changes, reflecting the underlying pathological processes leading to dementia, many years before diagnosis. We propose to elucidate the genetic and epigenetic determinants of brain structural markers to increase our understanding of the molecular pathological processes leading to AD. Currently, few studies have focussed on examining rare genetic variants, novel brain imaging phenotypes and the methylome. The proposed BRIDGET consortium of 14 richly phenotyped studies, including two Australian cohorts, will examine these questions across the lifespan. We will extend our analyses of identified variants to undertake gene-environment interaction analyses and to examine whether identified variants influence cognitive performance and decline and dementia. Our Australian cohorts will make significant contributions to the BRIDGET consortium and the genetic work undertaken will strengthen the cutting-edge genetic and epigenetic data available for our cohorts enabling us to take the lead on other international ageing and dementia projects. By undertaking this work and using these approaches we will likely provide crucial data on the mechanistic factors that drive resilience and risk for dementia, leading to novel therapeutic targets. It will also assist in the identification of those at risk and who are most likely to benefit from early interventions.