This project will define the molecular spectrum of white matter vascular lesions that drive vascular cognitive impairment and dementia (VCID). Cerebral small vessel disease (CSVD) is a spectrum that begins in the vessel but progresses to include brain-wide changes in inflammation, dysregulated cell-cell communication, and cortical disconnection, ultimately leading to VCID. The goal of this research proposal is to develop a VCID Center With Out Walls (CWOW) that will advance a mechanistic understanding of the molecular pathways driving VCID while testing the efficacy of multiple VCID therapeutics. Converging evidence indicates that white matter vascular lesions resulting from CSVD modulate the location, severity, and progression of neuroinflammation, tauopathy, and neurodegeneration in AD-ADRD conditions. However, a key knowledge gap is the precise identification of molecular pathways both within cerebral small vessels and in brain networks at-large that mediate the cognitive impairment and dementia associated with white matter vascular lesions. Recent work and preliminary data from our group points to distinct molecular pathways driving inflammatory signaling and disrupted cellular communication in white matter endothelial cells, that produce disordered signaling in the microenvironment of cells around white matter vessels (the neurovascular niche), which leads to white matter axonal damage and then cortical disconnection acting through molecular pathways linking CSVD and AD. This vessel inflammation-to-cognitive impairment progression will be characterized using sophisticated viral, genetic, BRAIN initiative imaging technology, and human-to-rodent data alignment. Further, we will test three candidate therapeutics, developed by the PI’s, that interdict this vessel inflammation to brain disconnection progression. We will test this hypothesis using an unparalleled combination of prodromal, isolated, recurrent, and mixed ADRD rodent models of CSVD. We will use mechanistic studies aimed at identifying and validating molecular systems regulating white matter inflammation (SA1) as well as cortical dysfunction (SA2), and by developing a unique human single-cell sequencing dataset and applying translational VCID imaging biomarkers to rodent models of VCID to exploit regional differences in brain resilience (SA3). End point metrics will include: i) inflammatory vessel signaling cascades shared across prodromal CSVD models (aging, obesity, hypertension, and AD backgrounds); ii) inter-regional and inter-hemispheric measures of cortical disconnection that vary across lesion type and neurodegenerative comorbidity, iii) cellular, molecular, and imaging correlates of regional brain resilience to white matter vascular lesions, and iv) therapeutic efficacy of three novel VCID therapeutics targeting these pathways. This project and its research team leverages recognized leaders in VCID with relevant technical expertise to advance a VCID CWOW framework that will ac...