In this proposal, we aim to explore several aspects of the genetic and environmental (non-genetic) risk factors of cerebrovascular disease. The first two parts of the proposal focus on genetic (Task 1) and environmental (Task 2) risk factors of covert MRI-defined cerebrovascular disease (MRI-CVD) and the interaction between both. We will be using a competitive genome-wide approach for Task 1 and various standardized risk factor measurements including sophisticated structural and functional vascular endophenotypes in Task 2. The third part of the proposal aims at exploring the link between covert MRI-CVD and cognitive decline and to assess whether genetic susceptibility factors to MRI-CVD are also associated with an increased risk of cognitive decline (Task 3). This will be performed within the ongoing 3C Study and the EVA Study, 2 large prospective cohort studies on French community-based participants. In Task 1 our goal is to identify genetic risk factors of MRI-defined cerebrovascular disease (MRI-CVD) in community-dwelling older persons. We plan to perform three genome-wide association studies on the following phenotypes: (i) white matter hyperintensity (WMH) volume; (ii) GWAS of WMH progression; (iii) extensive MRI-CVD (defined by the presence of at least one covert MRI-defined brain infarct [CBI] and / or WMH volume in the top quartile of the distribution). For all these analyses the discovery cohort will be the 3C-Dijon MRI Study (N=1,746 for cross-sectional analyses and N=1,298 for longitudinal analyses, mean age = 72.4 years). For the GWAS on WMH volume and on extensive MRI-CVD the replication cohort will be the EVA-MRI Study (N=758, mean age = 68.9 years). For the GWAS on WMH progression no longitudinal MRI data is available in the EVA study, we are planning an in silico replication and meta-analysis within the CHARGE consortium, including several large population-based studies with brain MRI and genome-wide data (Cohorts for Heart and Aging Research in Genomic Epidemiology - www.chargeconsortium.com). The neurological working group within this consortium is currently working on a GWAS meta-analysis project of WMH progression (letter attached). In Task 2 we aim to explore environmental (non-genetic) risk factors for WMH volume progression, as well as the interaction of these with genetic risk factors. In the first two subprojects we plan to explore the relationship of vascular stroke risk factors and associated biomarkers with WMH progression and to assess whether subclinical markers of atherosclerosis in cervical and peripheral arteries are associated with an increased risk of WMH progression. In the third subproject we intend to explore interactions between genetic susceptibility factors and hypertension (one of the most powerful risk factors of WMH known so far) on the association with WMH volume. The analyses will be performed in the 3C-Dijon MRI Study, with a replication analysis in the EVA-MRI Study for the third subproject. In Task 3 we plan to explore the association of MRI-CVD with clinical events and test whether genetic risk factors of MRI-CVD are also associated with an increased risk of these clinical events. In a first part we will explore the differential association of CBI and WMH volume with the risk of dementia and evaluate the association of WMH volume and WMH progression with cognitive decline. This will be performed in the 3C-Dijon MRI Study, after exclusion of participants with dementia and a history of stroke at baseline. In a second part we will test the association with cognitive decline of genetic variants found to be associated with MRI-CVD. This will be performed in the 3C Study participants with good quality DNA and at least 2 neuropsychological assessments available, with a replication analysis of significant association in the EVA study.