2024 Alzheimer's Association Research Fellowship to Promote Diversity (AARF-D)

Identifying mechanisms of an African-specific locus protective for AD

Could a genetic variant of an Alzheimer’s risk gene be protective against developing Alzheimer’s?

Luciana Bertholim Nasciben, Ph.D.
Miller School of Medicine of the University of Miami
Miami, FL - United States

Background

The apolipoprotein E (APOE) gene provides instructions for making ApoE, a protein believed to help carry fats throughout the body. There are several genetic variations of APOE, including APOE-e2, APOE-e3 and APOE-e4. Studies have shown that individuals who possess APOE-e4 have an increased risk for developing Alzheimer’s, compared to individuals with other APOE variants, but the mechanisms linking APOE-e4 and Alzheimer’s risk is not yet understood.

Research suggests that APOE-e4 carriers with various racial and ethnic backgrounds may have differences in their risk of developing Alzheimer’s. Specifically, APOE-e4 carriers of African ancestry may be protected from developing Alzheimer’s while APOE-e4 carriers of European ancestry are at greater risk. In preliminary studies, Dr. Luciana Nasciben and colleagues have identified an allele (or a specific variant) of the APOE-e4 gene, called rs_10423769, in individuals of African ancestry that may decrease one’s Alzheimer’s risk.

Research Plan

Building on their initial findings, Dr. Nasciben and team aim to identify the mechanisms by which rs_10423769 is protective against developing Alzheimer’s. Using sophisticated gene editing and sequencing techniques, they will first identify the specific DNA sequence of rs_10423769 that is protective against Alzheimer’s and how this sequence differs from the common APOE-e4 variant. The researchers will then measure the levels of APOE mRNA (another type of genetic material that acts as the messenger between DNA and the protein it provides instructions for making) in brain tissue from individuals with the protective rs_10423769 variant, and examine whether APOE mRNA vary between individuals of African or European ancestry.

Impact

Results of this study could increase our understanding of how APOE-e4 contributes to Alzheimer’s risk. If successful, the findings may serve as the foundation for developing novel gene therapies that target APOE-e4 in Alzheimer’s.