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2019 Zenith Fellows Award Program (ZEN)

Identifying Protective Genetic Variants for ApoE4

Why does the APOEe4 gene affect Alzheimer’s disease risk differently in diverse populations?
 

Jeffery Vance, M.D., Ph.D.
University of Miami
Miami, FL - United States



Background

The apolipoprotein E (APOE) gene provides instructions for making the ApoE protein, a naturally occurring protein that is thought to help carry fats throughout the body. Each person has two copies of APOE in their DNA.  There are several variations of the APOE gene including APOEe2, APOEe3 and APOEe4. Possessing APOEe4 compared to the other variations increases a person’s risk of developing Alzheimer’s, and this risk is further increased in the individual who has two copies of APOEe4.
 
Studies suggest that various population groups may be affected differently by APOEe4. For instance, individuals of Asian descent who are carriers of APOEe4 have an increased risk for developing Alzheimer’s, followed by individuals of Hispanic/ Latino descent, individuals of African descent, including African Americans, who carry APOEe4 have less risk associated with APOEe4.  Although scientists do not know why these differences exist, Dr. Jeffrey Vance and his colleagues have observed that the genetic region surrounding the APOEe4 gene, and not the gene itself, has a significantly different structure in individuals of African descent, including African Americans, compared to individuals of European descent. This finding suggests that individuals with an African ancestry may have a genetic factor in the APOEe4 region that lowers their APOE-related risk for dementia.     
 

Research Plan

Dr. Vance and colleagues will further examine the links between regions of the APOEe4 gene and dementia risk in different human populations. The researchers have already used human DNA (genetic material) to find more than 500 specific differences that distinguish the APOEe4 region of the genetic materials in individuals with African or European descent. In their first experiment, Dr. Vance and his team will use specific techniques that will allow them to analyze the genetic areas surrounding the APOE gene to determine the different regions that may impact the function of APOE within cells and within an individual. The team will then use blood cells from individuals of either African or European descent who have APOEe4 and engineer them into special type of cells called induced pluripotent stem cells (iPSCs). These iPSCs will be developed into two kinds of brain cells: nerve cells (which direct brain activity) and astrocytes (which support the nerve cells). Dr. Vance’s group will then examine how these engineered cells with the APOEe4 regions from these individuals differ in their structure and function. Lastly, the results from both experiments will be combined and further analyzed to identify if there are specific genetic factors that may affect an individual’s dementia risk linked to APOEe4.
 

Impact

The results of this study could shed new light on the role of APOE in Alzheimer’s and could also inform future development of personalized medicine approaches and individual-based therapies to affect risk based on their genes.   
 

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