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2024 AD Strategic Fund: APOE Biology in Alzheimer's (ABA) (ABA)

Replacement of Peripheral APOE4 with APOE2: Effects on AD Pathology

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


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 ApoE protein. 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, 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 APOE-e4. While the exact mechanisms behind this increased risk are unclear, some studies have found that specific cells in the body may be involved.

Research Plan

Dr. Lance Johnson and colleagues received additional funding to build upon their 2022 APOE Biology in Alzheimer’s (ABA) grant to expand their work on APOE and Alzheimer’s disease. The initial award uses genetically engineered Alzheimer’s-like mice to understand the consequences of switching astrocytes from APOE-e4 to APOE-e2, such as how the switch affects changes in both astrocytes and other populations of brain cells.

For their supplemental grant, the researchers will conduct such APOE “switching” experiments in cells from two specific areas of the body: the liver and the blood vessels. They will assess how switching the cells from APOE-e4 to APOE-e2 in  Alzheimer’s-like mice will impact several biological factors related to Alzheimer’s, including metabolism (chemical changes that take place in living cells), cognitive impairment, and the build-up of dementia-related beta-amyloid protein in the brain.


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

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