Abstract COVID-19 increases the risk of vascular contributions to cognitive impairment and dementia (VCID). VCID is one of the most prevalent forms of dementia, so the potential public health impact of the COVID-19 pandemic on future VCID is substantial. However, the mechanisms by which COVID-19 modifies VCID are unknown. Identifying mechanisms that regulate how prior COVID-19 influences the brain endothelial cell response to vascular stress is important. Here, we provide preliminary evidence that COVID-19 decreases resistance to VCID by weakening the blood-brain barrier (BBB). This is accompanied by cerebrovascular inflammation. This grant will test the novel mechanism that SARS-CoV-2 infection accelerates VCID by suppressing cerebrovascular Wnt/β-catenin signaling. In Aim 1, we determine how prior SARS-CoV-2 infection influences BBB permeability and cognition upon subsequent vascular insult, by genetic and epigenetic modification. In Aim 2 we use endothelial-targeted genetic interventions to assess the contribution of Wnt/β- cat targets to resistance to post-infectious VCID. In Aim 3, we ask whether established post-infectious VCID can be reversed by increasing cerebrovascular Wnt/β-catenin. These studies could lead to novel approaches to identify individuals at high risk for VCID and novel potential therapeutic strategies to mitigate the impact of prior infection on the development of dementia.