PROJECT SUMMARY Vascular cognitive impairment (VCI) is any level of cognitive alteration that is attributable to cerebrovascular pathologies. After Alzheimer disease, VCI is the second leading cause of dementia and accounts for ~15-30% of all dementia cases. Cerebral small vessel disease (cSVD) accounts for up to 20% of all strokes and is the most common pathology underlying VCI. Importantly, the pathogenesis of cSVD is incompletely understood which represents a major barrier in developing therapies for the disease. Using genetic models of human cSVD we have identified two potentially novel molecular mechanisms in different cell types that only manifest in aged mice and that may contribute to progressive cSVD. Our data suggest that cSVD may represent a mechanistically diverse collection of diseases that share similar endpoints and that investigation of multiple disease models will be required to understand the full pathophysiological profile. Our interdisciplinary team of experts will incorporate unique genetic resources, vascular pressure myography, patch-clamp electrophysiology, calcium imaging, specialized magnetic resonance imaging modalities and learning and memory behavior assays to 1) Develop and characterize multiple novel genetic models of cSVD using genes that contribute to both familial and sporadic disease in humans 2) test a potential disease-modifying intervention and functionally stratify potentially distinct classes of mutations and 3) compare the relative contributions of different neurovascular unit cell types and address the extent to which defects are cell autonomous or non-autonomous. Our long-term objective is to understand the heterogeneity underlying cSVD and determine if there are convergent or overlapping pathways that might represent therapeutic targets for mechanism-based interventions.