Abstract Vascular dementia (VaD) is the second most common cause of dementia, often triggers progressive cognitive impairment similar to that of Alzheimer’s disease (AD). The current treatment strategies focusing on local lesions for AD and dementia have not led to satisfactory outcomes. Therefore, comprehensively understanding of the pathogenesis of VaD and AD is urgently required to address the unmet scientific and clinical needs. Vascular pathologies across all vasculature have also been linked to VaD and AD. Most notably, atherosclerosis, stroke and hypertension accelerate the progression of cognitive impairments and dementia of all causes. Multiple large genome-wide studies identify the atherosclerosis risk gene apolipoprotein E (APOE) as a strong genetic risk factor for AD. However, despite shared genetic risk factors, atherosclerosis and AD are often separated in clinical management and mechanistic studies. Pan-vascular diseases represented by coronary artery disease, ischemic stroke, aneurysm and peripheral artery disease are all associated with VaD, thus, investigating pan-vascular changes that impact cognitive functions may open up new avenues to understand VaD and AD. The current application represents our long-term goals to uncover novel mechanisms linking vascular dysfunctions in the cardio and cerebrovascular systems to VaD and AD. Our effort has led to the discovery of a new role of the Runt-related transcription factor 2 (Runx2) in regulating both aortic and cerebral vascular pathologies and cognitive functions. We and others previously reported that Runx2 is an integral regulator for vascular calcification. Our preliminary studies identified novel function of Runx2 in regulating atherosclerosis, arterial stiffness, cerebral blood flow and cognitive function in mice; and uncovered upregulation of Runx2 in aging, atherosclerosis and AD mice as well as in human AD/VaD tissues. Single cell RNA sequencing analysis further discovered a novel regulation of Runx2 on SMC phenotypic switch, beyond its known activity in promoting SMC calcification. With an array of molecular, biochemical, proteomics and bioinformatics approaches, preliminary studies uncovered Runx2 interaction with an essential contractile SMC regulator, serum response factor (SRF), supporting a novel Runx2/SRF regulatory network in SMC phenotypic switch and calcification. Elucidating the novel function of Runx2 and Runx2-dependent signaling in regulating VaD will provide new insights to fill the knowledge gaps, which may lead to novel strategies for clinical management or treatment of VaD and AD.