Understanding the pathogenesis of cerebral small vessel disease (CSVD) and vascular contributions to dementia (VCID) is increasingly important to help protect the cognitive and mental health of an aging population. Recent technological advances now permit us to measure thousands of proteins and metabolites simultaneously in body fluids including cerebrospinal fluid (CSF), and single cell and spatial transcriptomics reveal tissue pathology at unprecedented resolution. Leveraging these new technologies to investigate CSVD and VCID will help to unravel the complex and heterogeneous mechanisms underlying these diseases. Here we take advantage of three resources led by our institution to best pursue these investigations. The first resource is a large collection of CSF samples from the Washington University Knight Alzheimer’s Disease Research Center (Knight-ADRC) and Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohorts. The second resource is a collection of human brain tissue specimens from these same cohorts. The third is extensive neuroimaging and analytical pipelines that can identify dissociable patterns of white matter hyperintensities (WMH), which are a key neuroimaging feature of CSVD. By combining these resources together, our first aim is to identify specific CSF proteins and metabolites related to each of 5 different WMH spatial patterns (i.e., topographies). This approach is likely to identify both shared and separate molecular correlates for each of the WMH topographies, which differentiate vascular risk factors and Alzheimer’s disease related pathologies. We will also determine how identified CSF correlates of CSVD relate to the development of cognitive impairment. Our second aim is to sample 5 regions of the brain, based on each of the different WMH topographies, from Knight-ADRC and ADNI human brain specimens. These will then undergo single cell and spatial transcriptomics, as well as further analysis using a vessel enrichment technique. We will relate these transcriptional data to premortem imaging and postmortem histopathology features from each specimen. The third and last aim is to perform a parallel transcriptomic analysis in rodent models of hypertension and cerebral amyloid angiopathy, both without and with treatment. Comparing rodent data to the human results will shed light on the validity of these rodent models for understanding CSVD in humans and may potentially reveal specific molecular mechanisms that underlie these diseases. We intend to use the results from all three aims to identify potential biomarkers and druggable targets. We are strongly committed to sharing all of the data produced by these efforts openly, and collectively hope that they will lead to a clearer mechanistic understanding of CSVD and VCID.