Proteomics to Study Racial Disparities in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) disproportionately affects African American/Black adults, leading to disparities in relation to non-Hispanic White adults. Though many factors such as socioeconomic factors and comorbidities are known to contribute to these disparities, the underlying molecular mechanisms remain unknown. Proteomics enables the study of thousands of proteins in biological samples such as cell lysates and postmortem brain tissue and was applied in this work to address this knowledge gap. Structural and proteomics analyses of cell models revealed that a mutation in the phospholipid-transporting ATPase ABCA7 (ABCA7) gene, associated with AD in African American/Black adults, had a subtle impact on the cellular proteome and lipid-binding abilities of ABCA7. Previous proteomics studies of postmortem brain tissue in AD have included primarily non-Hispanic White adults and have lacked racial/ethnic diversity. Proteomics analyses of postmortem brain tissue from two distinct cohorts consisting of African American/Black and non-Hispanic White adults who were cognitively normal (CN) or diagnosed with AD revealed many novel differentially-expressed proteins in AD, likely due to the diversity of these cohorts and the brain regions studied. Furthermore, these analyses also identified a subset of proteins that changed only in one racial group and not the other in AD. Machine learning models based on existing brain proteomics datasets were used to test how well these datasets performed when applied to datasets that included African American/Black adults. This work emphasizes the need for diversity in AD studies to better understand AD pathogenesis at the molecular level across racial groups, and furthermore to understand potential strategies to reduce racial disparities in AD.