2022 Alzheimer's Association Research Grant to Promote Diversity (AARG-D)

Arachnoid Granulation Senescence within Blacks and Whites in Aging and AD

How might the brain’s waste removal system impact the risk and progression of Alzheimer’s in diverse populations?

Rupal Mehta, M.D.
Rush University Medical Center
Chicago, IL - United States

Background

The proteins beta-amyloid and tau accumulate to form plaques and tangles respectively, the two hallmark brain changes observed in Alzheimer's. Beta-amyloid can accumulate near brain blood vessels and these accumulations are associated with increased stiffening of the vessels. When vessels are stiffer, it can be difficult for muscle cells in the blood vessels to properly pump blood, possibly restricting blood flow throughout the brain. This process is known as “cerebral amyloid angiopathy” or CAA. CAA is thought to negatively impact brain function in two ways. One, the restriction of blood flow to the brain starves active brain cells of vital nutrients and impairs their function. Two, CAA reduces the efficiency of the brain’s waste removal system, known as the glymphatic system. Without a functional system to deliver nutrients and remove waste, brain cells may eventually die, and this contributes to cognitive decline.

The brain has a thin covering that is part of its protective barrier. Arachnoid granulations (AGs) are small protrusions of the thin covering in the brain that allow fluid found in the spaces between cells in the brain to  exit the brain into the bloodstream. 

Dr. Rupal Mehta and colleagues previously developed methods for studying AGs in human brains. Their findings suggest that AGs may have an important role in brain immune activity, waste removal, and brain resilience in aging. The research team believes that AGs may serve as centers for immune processing in the brain and that impairment of their function may impact the development and progression of brain diseases, including Alzheimer’s.

Research Plan

Dr. Mehta and colleagues will study the relationships between AG structure and function and Alzheimer’s in a diverse population. They will study brain tissue from cognitively unimpaired older adults and from individuals who had Alzheimer’s obtained from three longitudinal cohort studies: the Religious Orders  Study  (ROS), the Memory and Aging Project (MAP)  and  the  Minority Aging  Research  Study  (MARS). The researchers will use sophisticated microscopic techniques to study the structure and make-up of AGs in the brains of Black and white individuals and relate them to cognitive measures previously obtained. Dr. Mehta and colleagues will study whether AGs are associated with CAA and Alzheimer’s-related brain changes in Black and white individuals. In addition, they will determine whether AG structure and composition relates to dementia.

Impact

The results may expand the understanding of how Alzheimer’s impacts blood flow and waste removal in the brain. If successful, the findings may help identify new targets for therapies aimed at slowing the progression of Alzheimer’s and other dementias.