2023 Alzheimer’s Association Leveraging Model & Data Resources to Advance Alzheimer’s and Dementia Discovery Program (ALZDISCOVERY)
Determining the Mechanisms of Anti-Beta-Amyloid Immunotherapy on ARIA
Why do certain individuals experience harmful side effects from taking anti-amyloid treatments for Alzheimer’s?
Kate Foley, Ph.D.
Indiana University
Indianapolis, IN - United States
Background
Beta-amyloid is a sticky protein fragment that forms toxic clumps called plaques in the brain, a key hallmark of Alzheimer’s. Researchers have worked to develop antibody therapies that use the body’s own immune system to target and remove amyloid plaques. Some of these therapies have shown amyloid-clearing abilities in clinical trials and have been approved by the FDA. However, such treatments have also been shown to contribute to negative side effects known as amyloid-related imaging abnormalities (or ARIA). One type of ARIA, called ARIA-E (ARIA-Edema), is characterized by fluid accumulation in the brain and may promote changes in mental state, seizures, tremor, headache and nausea. Another type, called ARIA-H (ARIA-Hemorrhage), can promote brain blood vessel damage and brain bleeding. While the adverse effects of ARIA are understood, scientists know relatively little about how anti-amyloid treatment can lead to these side effects.
Research Plan
Dr. Kate Foley and colleagues will explore the biological mechanisms underlying ARIA-related brain damage. They will use mice genetically engineered to develop human beta-amyloid. The mice will also be engineered to express different variations of a gene called APOE: either APOE-e4, which is linked in some populations to an increased risk for both ARIA and Alzheimer’s, or APOE-e3, which is not shown to impact risk of Alzheimer’s. After administering anti-amyloid therapy to their mice, the researchers will determine how glial cells (or “helper” cells) in the brain may respond differently to amyloid treatment in animals with different forms of APOE. Specifically, they will assess whether glial cells in APOE-e4 mice become abnormally active and promote toxic brain inflammation and brain blood vessel damage. They will also genetically analyze these glial cells to determine whether specific gene varieties are responsible for their toxic responses to anti-amyloid therapy.
Impact
Results from this study could help clarify the role of APOE and glial cells in ARIA side effects. They could also lead to novel therapies that prevent such side effects in people at genetic risk for them.