2022 AD Strategic Fund: APOE Biology in Alzheimer's (ABA) (ABA)

APOE Allelic Switching to Delay or Prevent Alzheimer's Disease

How do different gene variations of APOE impact Alzheimer’s risk and how can they be modified?

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

Background

Brain cells (in particular, nerve cells) need lipids (fats) for energy and for maintaining their structure and function. The process by which fat is produced and transported to these cells is vital for the proper function of the brain. Nerve cells receive fats from “helper” brain cells called astrocytes, and this transportation process involves several proteins, including apolipoprotein E (ApoE).

The apolipoprotein E (APOE) gene provides instructions for making the ApoE protein. There are several genetic variations of APOE, including APOE-e2, APOE-e3 and APOE-e4. The variation APOE-e4 is thought, in some populations, to increase a person’s risk of developing Alzheimer’s, while APOE-e2 is believed to decrease Alzheimer’s risk. Scientists are trying to understand the exact biological mechanisms that may increase the risk of developing Alzheimer’s in individuals with the APOE-e4 genetic variation. While the exact mechanism behind this increased risk is unclear, some studies have found that astrocytes may be involved.

Research Plan

Dr. Lance Johnson and colleagues will build on previous research to study if astrocytes, which originally have the APOE-e4 variation, can improve the biological and cognitive deficits of APOE-e4 when converted to having the APOE-e2 variation instead. Using genetically engineered Alzheimer’s-like mice, the researchers will identify the consequences of switching astrocytes from APOE-e4 to APOE-e2. They will study changes in both astrocytes and other populations of brain cells, as well as changes in brain lipids and metabolism (chemical changes that take place in living cells). Next, Dr. Johnson and colleagues will determine if switching astrocytes from APOE-e4 to APOE-e2 impacts the accumulation of beta-amyloid protein (a hallmark brain change associated with Alzheimer’s) in the brains of genetically engineered Alzheimer’s-like mice. They will also study if this change impacts cognitive function in the mice.

Impact

The results of this study may shed new light on how the APOE gene impacts an individual’s risk for Alzheimer’s. The findings may also help identify novel targets for therapies that prevent or delay the onset of Alzheimer’s.