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

Acronym	BRIDGET (Reference Number: 60)
Duration	01/10/2015 - 30/06/2019
Project Topic	Establishing efficient prevention strategies for dementia and Alzheimer disease (AD) is a major health priority for the coming years. An important hurdle is that pathological processes leading to AD begin many years before clinical diagnosis, hence efficient prevention should be initiated very early. This requires identifying individuals in the general population who are at high risk of developing dementia and exploring the molecular pathways underlying the structural brain alterations that precede the occurrence of dementia, an essential step for identifying novel relevant drug targets. We propose to explore the genetic and epigenetic determinants of quantitative MRI-markers of brain aging that are powerful predictors of dementia/AD risk, and to examine the clinical significance of the markers in a population-based setting. Leveraging the extensive information collected within the largest European population-based cohort studies with neuroimaging data, we will first search for genetic variants associated with established and novel MRI-markers of brain aging, focusing particularly on rare variants, using both agnostic and candidate locus approaches (loci identified through GWAS of AD or MRI-markers of brain aging). In contrast with GWAS signals, rare variants may lead to the discovery of causal variants, and have hardly been explored in association with structural MRI-markers. Second, we will take an original lifetime perspective, through examination of samples in various age categories spanning from young to older age, many of which with repeated MRI and blood sampling. Indeed, there is increasing evidence that early-life factors play an important role in the occurrence of late-onset neurodegenerative diseases. We propose an innovative exploration of lifetime changes in methylation associated with structural brain alterations using a novel bisulfite sequencing technology, to help identify functional and disease relevant variants. We will also study the modifying effects of vascular risk factors and socio-economic status on genetic/epigenetic determinants of brain aging. Third, we will explore the clinical and functional significance of the genetic and epigenetic markers. We will examine their association with cognitive performance & decline and risk of dementia/AD, capitalizing on elaborate cognitive testing and prospective dementia surveillance. For functional exploration, we will utilize cutting-edge bioinformatic methods, large epigenome maps in multiple tissues including brain, and in vivo experimental verification of predicted molecular mechanisms using established in vivo assays in Drosophila.
Network	JPco-fuND
Call	Neurodegenerative diseases: risk and protective factors, longitudinal cohort approaches and advanced experimental models

Project partner

Number	Name	Role	Country
1	University of Bordeaux	Coordinator	France
2	Medical University Graz	Partner	Austria
3	McGill Genome Center	Partner	Canada
4	Medical University of Greifswald	Partner	Germany
5	Erasmus MC University Medical Center	Partner	Netherlands
6	University of Edinburgh	Partner	United Kingdom
7	King’s College, London	Partner	United Kingdom
8	University of New South Wales	Partner	Australia