Our laboratory has worked for almost 30 years to understand how brain blood vessels may be involved in Alzheimer’s disease (AD). Our work is timely and important, as a large body of evidence indicates that cardiovascular risk factors, i.e., conditions that affect blood vessel (vascular) function, increase one’s risk for developing AD. We were the first to show that brain blood vessels in AD are a source of toxic proteins; a process we term “vascular activation.” If blood vessel-derived toxic factors contribute to a cascade of events that lead to dementia in the AD brain, then blocking “vascular activation” should be beneficial to cognitive (memory) function. This idea is novel, testable and is supported by our preclinical study, which showed that inhibiting vascular activation did improve cognitive performance in AD transgenic mice. In the current project we will determine how cardiovascular risk factors (such as diabetes and cholesterol) in mice carrying a gene associated with late-onset AD lead to vascular activation by identifying the cellular pathways and biochemical proteins that drive this pathologic process. Results from this study will reveal novel therapeutic targets for AD and other neurodegenerative diseases. Identification of new therapeutic targets is a critical barrier to progress in the AD field. Results from this project would, for the first time, identify a cascade linking cardiovascular risk factors to brain blood vessel activation, and highlight novel targets for improving vascular function with wide-ranging implications for brain health.