This proposal is in response to RFA-NS-21-005, which is a continuation of RFA-NS-16-020. The overall goal of the project is to study the impact of vascular disease on Alzheimer’s disease (AD). Small vessel disease is the major vascular disease associated with dementia. Cerebral small vessel diseases such as arteriolosclerosis and cerebral amyloid angiopathy are independently associated with worse cognitive performance and greater likelihood of vascular cognitive impairment and dementia (VCID). MarkVCID1 consortium shared subject clinical neuropsychological test data, MRI results and biological samples to validate the biomarkers. The NIH identified 11 biomarkers from MarkVCID1 that could be used in future clinical trials. The UNM site made major contributions to both the MRI and fluid biomarkers: UNM and UCD led the work on the Free Water (FW) biomarker, and contributed data to all of the other MRI biomarkers. UNM was one of the few centers that collected cerebrospinal fluid (CSF) and matched blood on all subjects, contributing to all of the fluid biomarkers selected to move into MarkVCID2. Our group contributed CSF and blood samples to multiple sites for validation of the angiogenic and inflammatory biomarker kits, including CSF placental growth factor (PlGF), and blood exosomes and endothelial inflammation kits. We used MesoScale Discovery assays for fluid analysis, and have recently purchased a Quanterix HD-X single molecule assay (SIMOA) instrument that we will use it to measure neurofilament light (NfL) and PlGF. The UNM Specific aims are: 1) to continue to lead to development of the FW biomarker kit in collaboration with UCD to make this trial ready and to add imaging data to the other MRI biomarkers kits; 2) to continue to collect CSF and blood samples to contribute to the validation of all the CSF and blood biomarker kits; and 3) to recruit 200 new underrepresented patients over two years to add to legacy subjects. UMN anticipates to have longitudinal data for 3 years on many participants. UNM has a large number of patients with VCID, AD, and mixed dementias, as well as subjective cognitive complaints that have been studied as part of two RO1 grants (2006-2016) and the MarkVCID1 (2016- present) with data on clinical cognitive test results, MRI, CSF, and blood. Many of these patients have longitudinal data from multiple follow-ups. UNM is committed to achieving the goals and milestones laid out by NIH for MarkVCID2, and to contribute to the completion of the evaluation of the biomarkers that will be used with study-ready cohorts for clinical trials in vascular cognitive impairment.