2023 AD Strategic Fund: APOE Biology in Alzheimer's (ABA) (ABA)

ApoE Lipid Transport by ABCA7 Genetic Variants

Can changes in genes responsible for the transportation of fats in the brain increase dementia risk in Black Americans?

Jamaine Davis, Ph.D.
Vanderbilt University Medical Center
Nashville, TN - United States

Background

According to the 2022 Alzheimer’s Association Facts and Figures report, Black Americans are one and a half times more likely to develop Alzheimer’s than White Americans.  It is important, therefore, to examine the factors that impact risk of Alzheimer’s in Black Americans before memory loss and other dementia-related symptoms become evident. 

Several studies have identified a gene called ABCA7 that plays a role in the production of the beta-amyloid protein and may increase an individual's risk of Alzheimer’s.  Fragments of the beta-amyloid protein can clump together and form plaques which are a hallmark brain change in Alzheimer’s. 

Recent studies suggest that ABCA7 interacts with another gene called APOE  to transport lipids (fats) in the brain. In some populations, variation of APOE and APOE-e4 is thought to be the largest genetic risk factor for Alzheimer’s. A greater understanding of this lipid transportation process may shed light on how ABCA7 and APOE work together to impact Alzheimer’s risk.

Research Plan

Dr. Jamaine Davis and colleagues will study how ABCA7 variations linked to Alzheimer’s risk interact with APOE and alter lipid transportation in the brain. They will create astrocytes (helper cells in the brain that can transport fats) using a specialized type of stem cell collected from adult human tissue called iPSCs (induced Pluripotent Stem Cells). iPSCs can be programmed to grow into any type of cell in the body, including astrocytes. In this study, astrocytes will be engineered to have variations of ABCA7 which increase risk of Alzehimer’s. These astrocytes will be exposed to different variations of APOE, including APOE-e4. The researchers will study how the ABCA7 and APOE variations interact with one another. The researchers will explore whether the protein structure may change when ABCA7 binds with each APOE variant.

Dr. Davis and colleagues will then analyze the transcriptomes (or collections of all gene readouts) and lipidomes (or collections of all lipids) in the different ABCA7 risk variants. They will then assess whether ABCA7 variants common in Black Americans have a specific genetic or lipid make-up that may promote Alzheimer’s risk.       

Impact

The results of Dr. Davis’s project could reveal how genetic changes linked to lipid transportation may impact Alzheimer’s risk in Black Americans. It could also lead to novel, targeted methods for detecting and treating Alzheimer’s in this underserved population.