2025 AD Strategic Fund: APOE Biology in Alzheimer's (ABA) (ABA)

Uncovering the mechanism of APOE4-driven ARIA

Is there a connection between a person’s genes and whether they experience negative side effects from anti-amyloid treatments for Alzheimer’s?

Lance Johnson, Ph.D.
University of Kentucky College of Medicine
Lexington, KY - United States

Background

Genes play an important role in Alzheimer’s. The apolipoprotein E (APOE) gene provides instructions for making ApoE protein, which is thought to play a role in processing lipids (fats), metabolism, and the brain’s immune system. There are several genetic variations of APOE, including APOE-e2, APOE-e3 and APOE-e4. In some populations, the APOE-e4 variation is thought to increase a person’s risk of developing Alzheimer’s.

Beta-amyloid is a sticky protein fragment that forms toxic clumps called plaques in the brain, a key hallmark brain change in Alzheimer’s disease. Two treatments on the market, approved by the FDA, have shown amyloid-clearing abilities in clinical trials and have also been shown to contribute to negative side effects in a small number of individuals 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. Scientists know relatively little about how anti-amyloid treatment can lead to these side effects and how APOE genes might play a role in the risk of ARIA.

In preliminary studies, Dr. Lance Johnson and colleagues used genetically engineered Alzheimer’s-like mice, some with APOE-e4 gene variations and treated them with anti-amyloid antibody therapy. In those animals with APOE-e4 gene variations, the researchers saw more blood vessel damage (similar to ARIA) than mice that did not have APOE-e4 variations or APOE-e4 mice that did not receive treatment. This suggests that APOE-e4 may affect the biology that leads to increased risk of ARIA-like symptoms.

Research Plan

Dr. Lance Johnson and colleagues will develop new genetically engineered Alzheimer’s-like mice that may be more able to mimic Alzheimer’s-linked ARIA in response to anti-amyloid antibody treatment and that have APOE gene variations. They will then use these mice to assess how APOE gene variations impact the immune system’s response to amyloid antibody treatments. They will also treat some of the mice with amyloid antibodies, then use MRI to assess ARIA-like changes. Additionally, from brain samples, they will measure gene changes and immune cell activation in individuals who received treatments They hope to identify factors that may contribute to ARIA so that potential therapies could target these factors.

Impact

Results from this study may shed new light on how certain gene variations impact the risk of ARIA. The findings may also help identify novel targets for therapies that could help prevent ARIA.