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

Reducing APOE4 Expression as a Therapeutic Strategy

What factors are involved in whether a gene associated with Alzheimer’s is turned “on” or “off” as a possible therapy?

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. There are several variations of the APOE gene including APOE-e2, APOE-e3 and APOE-e4. Possessing APOE-e4 increases the risk of developing Alzheimer’s, at least in some populations. Studies suggest that various population groups may be affected differently by APOE-e4. For instance, individuals of African descent who carry APOE-e4 have less risk associated with APOE-e4. 

In preliminary studies, Dr. Jeffrey Vance and his colleagues have observed that the APOE-e4 gene promoter—like a "start button" on a gene, telling the cell where to begin reading the genetic instructions to make a protein—is different in people of African descent compared to individuals of European descent. This finding suggests that individuals with an African ancestry may have a genetic factor in the APOE-e4 region that may lower their APOE-related risk for Alzheimer’s.

Research Plan

Dr. Vance and colleagues will further examine the links between regions of the APOE-e4 gene and dementia risk in different human populations. They will use a specialized type of stem cell called induced pluripotent stem cells (iPSCs). These are adult human skin cells that can be “reprogrammed” into any type of cell in the body and grown in laboratory dishes. They will reprogram the iPSCs to become brain immune cells (microglia) and will compare cells from African and European ancestry and use a new technique that combines computer analysis with a technique inside cells to figure out whether any DNA regions near the APOE gene influences whether APOE is turned “on” or “off,” and whether these DNA regions differ by ancestry.

Additionally, they will analyze the APOE-e4 gene for regions that could act as promoters (like a “start button”), enhancers (like a “gas pedal” that increases gene activation), and repressors (like a “brake pedal” that stops gene activation). They will validate any findings by deleting those parts of the gene in iPSC immune cells (microglia) and determining the impact the deletion has on whether APOE is turned “on” or “off.”

Impact

The results of this study could shed new light on the role of APOE in Alzheimer’s, including why individuals may have different associated risks with the presence of variations of APOE, and could also inform future development of therapies aimed at reducing APOE levels.