Throughout the human body there are specialized, dynamic and complex cellular barrier interfaces that play a central role in tissue homeostasis. The cerebrovasculature (CV) is the largest interface of blood-to-brain contact, and every neuron is supplied by its own capillary. Dynamic processes at the CV prevent the uptake of unwanted molecules from the blood, remove waste products from and supply essential nutrients and signaling molecules to the brain. CV dysfunction is re-emerging as a key component of cognitive dysfunction in a number of disease states. Our goal is to identify and therapeutically target mechanistic pathways that underlie CV dysfunction in aging and neurodegenerative disorders including Alzheimer’s disease.