2024 Alzheimer's Association Clinician Scientist Fellowship (AACSF)
Neuroimaging Genetics of the Glymphatic System in Alzheimer`s Disease
How may a waste-removal system in the brain become dysfunctional and promote Alzheimer’s?
Kyan Younes, M.D.
Stanford University
Palo Alto, CA - United States
Background
Alzheimer’s is a progressive disorder, and scientists are looking for ways of understanding brain changes in the earliest phases of the disease. Such work may lead to better ways of detecting Alzheimer’s at a stage when treatments can be most effective. One area of early Alzheimer’s research involves analyzing disease-related changes in the brain’s waste-removal systems. These systems clear unwanted substances from the brain, including dementia-related proteins such as beta-amyloid and tau. In early Alzheimer’s, waste removal in the brain can become dysfunctional, which may promote the formation of amyloid plaques and tau tangles – two hallmark Alzheimer’s brain changes. Researchers, however, do not yet know exactly how waste-removal dysfunction occurs in the brain and promotes dementia risk.
One waste-removal process in the brain is called the glymphatic system. This system involves the movement into and out of the brain of cerebrospinal fluid (or CSF, the biological fluid surrounding the brain and spinal cord). Scientists can assess the health of the glymphatic system by using magnetic resonance imaging (MRI) brain scans to measure perivascular spaces (PVS), the spaces in and around the brain though which CSF travels. More recently, investigators have found another way of assessing glymphatic health – by measuring changes in overall brain movement. The brain is constantly moving in subtle ways, and changes in these movements may indicate disease-related changes in the glymphatic system.
Research Plan
Dr. Kyan Younes and colleagues will devote their research grant to a study of glymphatic system changes in early Alzheimer’s. For this effort, they will recruit 150 older individuals (75 with Alzheimer’s and 75 with no cognitive impairment) who have been participating in Stanford University’s Alzheimer’s Disease Research Center. First, the researchers will examine data from a variety of brain scans and cognitive tests – including tests that measure overall brain motion. They will then examine whether individuals with reduced brain motion may be more likely to show lower glymphatic activity, higher brain levels of tau and beta-amyloid and loss of memory and other cognitive functions. Next, Dr. Younes and team will conduct genetic analyses of their participants to identify genetic variations that may be associated with abnormal PVS volume, a marker of glymphatic system dysfunction. They will then examine how these genetic changes may promote the protein clumping and memory loss of early Alzheimer’s.
Impact
Dr. Younes’ study could help clarify the role of waste removal dysfunction in brain disease. It could also lead to future Alzheimer’s therapies – including genetic therapies – that target the glymphatic system.