Blood-Based Biomarkers of Vascular (Dys)function in Alzheimer's Disease

Background As individuals age, blood vessels can become damaged. This is a problem that impacts blood flow in the brain and other parts of the body. Research suggests that vascular (blood vessel) damage may also impact an individual's risk for many brain diseases. Studies show loss of brain blood vessel (or cerebro- vascular) function may be an early brain change in Alzheimer's. These changes may lead to nerve cell damage and death observed in disease. Tthe biological mechanisms by which cerebrovascular dysfunction may be associated with early brain changes observed in Alzheimer's remain unclear.A specialized structure called the blood-brain barrier (BBB) is a highly selective barrier that helps maintain a healthy brain environment by tightly regulating what goes in and out of the brain from the circulating blood. The BBB is composed of different cells that help clear toxic debris from the brain. These cells include pericytes, a specialized type of cell located in the walls of blood vessels. Pericytes work closely with many other kinds of cells to keep the brain functioning and can become disrupted in Alzheimer's. However, the biological mechanisms underlying how pericytes work to keep the BBB healthy are not well understood.Research PlanIn previous work, Dr. Nilüfer Ertekin-Taner and colleagues discovered 83 genes related to brain vasculature that had different activity in individuals with Alzheimer's and those with no cognitive impairment. For this study, the researchers will first analyze these genes for their connection with cerebrovascular disease, cognitive decline in Alzheimer's, and mild cognitive impairment (MCI, a state of subtle memory loss that may precede Alzheimer's). They will analyze samples of blood from individuals with Alzheimer's and MCI and individuals with no cognitive impairment, as well as brain tissue from individuals who had Alzheimer's or MCI and individuals without cognitive impairment. Dr. Ertekin-Taner hopes to identify several molecules that are associated with BBB health and are also present in the blood as potential blood-based biological markers (biomarkers) of vascular dysfunction in Alzheimer's. Next, the research team will study the 12 most promising molecules in different types of genetically engineered Alzheimer's-like mice. The researchers will also study a subset of these molecules in human brain cells grown in laboratory dishes to learn more about their activity.ImpactThe results of this project may shed light on dysfunction of the blood-brain barrier in Alzheimer's. If successful, the findings may identify biomarkers in the blood that reflect vascular dysfunction and influence the development of new diagnostics or therapeutics for Alzheimer's.