Determining the Cellular Impacts of ABCA7 Mutations in Alzheimer’s Disease

This project uses stem cell models to understand the cellular consequences of Alzheimer’s disease risk mutations in ABCA7.

Genetics plays a key role in governing Alzheimer’s disease risk, with many mutations linked to lipid biology proteins. ABCA7 is a lipid transporter and has several Alzheimer’s disease risk mutations, some found exclusively in individuals of African ancestry. However, the effects of these mutations remain unclear due to the historical lack of diverse representation in research studies. Using models of living brain cells derived from humans that harbor these mutations, I will study how modifying ABCA7 alters proteins, lipids, and cell function, paving the way for inclusive, personalized Alzheimer’s disease therapies.

This proposal is conceptually innovative in that here I am interrogating the function of understudied but highly impactful Alzheimer’s disease genetic variants in ABCA7. To gain these functional insights I am harnessing the power of induced pluripotent stem cells generated from donors of multiple genetic backgrounds to study molecular and cellular consequences of ABCA7 genetic risk using an all-human platform.

We are starting to appreciate that treatments for Alzheimer’s disease will not be one-size-fits all, and are moving towards more personalized therapeutic approaches through the identification of patient subtypes based on their genetic and molecular makeup. Since ABCA7 harbors both common and rare mutations associated with higher Alzheimer’s risk that are dependent on genetic makeup of the affected individual, results from this work will begin to explain the cellular dysfunction caused by these mutations, and possibly identify culprit cell-types and pathways to target.