INTRODUCTION: White matter hyperintensities (WMHs), a major cerebral small vessel disease (cSVD) marker, may arise from different pathologies depending on their location. We explored clinical and genetic correlates of agnostically derived spatial WMH patterns in two longitudinal population-based cohorts (Three-City Study [3C]-Dijon, LIFE-Adult). METHODS: We derived seven WMH spatial patterns using Bullseye segmentation in 2878 individuals aged 65+ and explored their associations with vascular and genetic risk factors, cognitive performance, dementia and stroke incidence. RESULTS: WMHs in the frontoparietal and anterior periventricular region were associated with blood pressure traits, WMH genetic risk score (GRS), baseline and decline in general cognitive performance, incident all-cause dementia, and ischemic stroke. Juxtacortical-deep occipital WMHs were not associated with vascular risk factors and WMH GRS, but with incident all-cause dementia and intracerebral hemorrhage. DISCUSSION: Accounting for WMH spatial distribution is key to deciphering mechanisms underlying cSVD subtypes, an essential step towards personalized therapeutic approaches. HIGHLIGHTS: We studied spatial patterns of WMHs in 2878 participants. Blood pressure was associated with frontoparietal and anterior PV WMHs. Anterior PV WMHs predicted dementia and stroke risk. Juxtacortical-deep occipital WMH burden was not associated with blood pressure or WMH genetic risk. Juxtacortical-deep occipital WMH burden predicted dementia and intracerebral hemorrhage.Read less <