2023 Alzheimer’s Association Leveraging Model & Data Resources to Advance Alzheimer’s and Dementia Discovery Program (ALZDISCOVERY)
Impact of APOE on Cerebrovascular Aging
How do aging and a dementia-related gene variation promote brain blood flow loss that may lead to Alzheimer’s?
Ashley Walker, Ph.D.
University of Oregon
Eugene, OR - United States
Background
Blood vessels in the brain provide nerve cells with oxygen-rich blood that is necessary for the cells’ ability to function properly. Inadequate blood flow can damage and eventually kill cells anywhere in the body, but the brain is especially vulnerable. Studies show that loss of brain blood vessel (or cerebrovascular) function may also represent an early brain change in dementia. These vascular changes may be associated with nerve cell damage and death observed in Alzheimer’s or other dementia.
Several factors may play a role in cerebrovascular dysfunction, including aging and genetics. As people age, for example, small blood vessels called “arterioles” stiffen and lose their ability to “move” properly. Healthy arterioles constantly dilate and contract allowing blood to flow. But arteriole stiffening may hinder the dilation process, called vasodilation, and hinder adequate blood flow. Studies also suggest that having APOE-e4, a gene variation linked to increased Alzheimer’s risk in some populations, may also promote one’s risk for reduced cerebrovascular health.
Research Plan
Dr. Ashley Walker and colleagues will examine how APOE-e4 and aging impact brain blood vessel function and promote early Alzheimer’s disease. They will employ a new method of studying older brain arterioles ex vivo, or outside the body of an organism. Their method involves removing individual arterioles from the brains of older mice. Then, after inserting tiny glass tubes into the blood vessels to test how well they can dilate and contract.
The researchers will use their new technique to measure arteriole stiffness and loss of function in older mice with and without the APOE-e4 gene. Specifically, they will examine whether arterioles from older mice with APOE-e4 show reduced vasodilation compared with arterioles from mice without APOE-e4. Next, Dr. Walker’s team will use other techniques to examine whether APOE-e4 promotes structures inside cells called mitochondria (the powerhouse of energy for the cells) to become dysfunctional in older mice. They will then explore how brain cell damage called oxidative stress, which results from mitochondrial dysfunction, may impact cerebrovascular health and cognitive decline (such as memory loss) in older mice with APOE-e4.
Impact
Dr. Walker’s project could shed new light on the genetic mechanisms underlying blood flow loss in dementia. It could also lead to novel treatments for dementia that target mitochondria.