Abstract Alzheimer’s disease (AD) and cardiovascular disease (CVD) share critical common risk factors, including type 2 diabetes (T2D), chronic inflammation, and hypercholesterolemia. The coexistence of CVD and AD can lower the threshold for cognitive impairment, indicating a synergistic interaction among those diseases. Meta- analyses have demonstrated that atherosclerosis, a leading underlying cause of CVDs, is positively associated with AD. Human genetic studies uncovered that variants in the CCDC92 gene are significantly associated with coronary heart disease and T2D. Our recent studies demonstrated that CCDC92 ablation reduces insulin resistance and hypercholesterolemia in mice. In the parent grant, we demonstrated that CCDC92 has a prominent role in atherosclerosis via inducing vascular smooth muscle cell (VSMC) phenotypic switch and the release of VSMC-derived proinflammatory cytokines. In addition, CCDC92 is a potent regulator of transcription factor EB (TFEB), which suppresses inflammation and controls autophagy and lysosomal biogenesis. Notably, strong evidence shows that TFEB overexpression in neurons and astrocytes inhibits AD pathogenesis. Our preliminary data indicate that CCDC92 expression is regulated in AD patients' cerebral vessels. However, vascular CCDC92-dependent behavioral studies, neuropathology, and neuroinflammation have yet to be determined. This Administrative Supplement will examine the central hypothesis that VSMC CCDC92 contributes to AD formation and progression via modulating neuroinflammation. Male and female VSMC- specific Ccdc92 knockout (KO) mice and knock-in (KI) mice carrying the Ccdc92 S70C coding variant on a low- density lipoprotein receptor-deficient (Ldlr KO) background, as well as TFEB activators, will be utilized for these studies, which are within the scope of the parent grant. We will examine this hypothesis utilizing two specific aims. Aim 1 will determine the role of VSMC-specific Ccdc92 in neuroinflammation and atherosclerosis-induced AD. Aim 2 will determine the effect of the CCDC92 S70C coding variant on neuroinflammation and the development and progression of AD. Cerebrovascular function, atherosclerosis, β- amyloid deposition, neurofibrillary tangles, and neuroinflammation will be measured in those mice. Single-cell RNA seq analysis will be conducted to understand the gene regulatory networks and cell-cell communications in AD brains. We will use Morris Water Maze test to evaluate cognitive function and magnetic resonance imaging to assess cerebral blood flow. Elucidating the role of CCDC92 in cerebral vessels and neuroinflammation may yield targets with high therapeutic potential for AD.