Acronym: BRIDGET Start date: May, 2016 Duration: 66 months End date: March 31, 2021 Project coordinator: Prof. Stephanie Debette, University of Bordeaux Consortium: 7 partners and 7 external collaborators- major universities and research institutes - from 9 countries Total funding: € 2 518 874 Australian contribution: € 727 646
With expanding longevity, the number of dementia cases is expected to triple over the next 40 years, resulting in a major burden at the individual and socio-economic level . Pathological processes leading to Alzheimer disease (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. Establishing efficient prevention strategies for dementia and AD is a major health priority for the coming years.
Our main objective is to enrich our understanding of the biological mechanisms underlying early structural brain alterations that portend an increased dementia risk, and thus contribute to the discovery of novel therapeutic targets. More specifically, we aim to:
Identify rare (and common) genetic variants associated with structural markers of brain aging in older community persons
Explore lifetime determinants of brain aging, with longitudinal profiling of genomic, epigenomic, and environmental markers
Assess the impact of genetic determinants for structural brain aging on cognitive performance and dementia and perform extensive functional exploration of these genetic variants
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. We aim to translate this findings into the basis for the development of novel preventive strategies for dementia and AD.
TF1: Sequencing, joint calling TF2: Image processing - harmonization WP1: Rare variants and MRI-markers of brain aging (older cohorts); Common & rare variants and novel MRI-markers; Spatial and temporal mapping WP2: Association with early structural brain changes in the young; Epigenetic (methylome) associations with structural brain changes; Interaction with vascular comorbidities & psychosocial factors WP3:Association with cognitive performance / decline & dementia; Functional exploration of susceptibility loci
Data & Power
We will utilize extensive phenotypic and genomic data gathered from the largest European population-based samples with high resolution brain imaging combined with extensive cognitive testing, incident dementia surveillance, and extensive and repeated assessment of clinical comorbidities and socio-economic factors. All the cohort-studies comprise about 36.700 participants and cover a broad age range from very young to late-middle-aged to older participants. For extension of our findings we will explore results obtained in the discovery in a large (N~1,000) Japanese genomic study on brain imaging. In addition, a lifetime approach using brain imaging studies in young participants will capture the impact of genetic / epigenetic determinants on early structural brain alterations.
Enriching our understanding of the biological mechanisms underlying early structural brain alterations that portend an increased dementia risk, we can contribute to the discovery of novel therapeutic targets. Findings from this project may also:
contribute to identifying populations at higher risk of accelerated brain aging, more likely to benefit from early interventions aiming at preventing dementia;
help define quantitative intermediate endpoints for future clinical trials;
provide useful information on the optimal timing for preventative interventions.
Taken together, this project has an important potential of facilitating the development of novel preventive strategies for dementia and AD.