Investigating the Role of Genetic Ancestry and Mitochondrial Dysfunction in Alzheimer's Disease

The goal of our project is to investigate the relationship between mitochondrial dysfunction and Alzheimer’s pathology, and to understand if ancestry-related factors of this dysfunction help explain why some individuals show greater vulnerability to the disease than others.

Mitochondrial function plays a major role in several pathways contributing to Alzheimer’s disease (AD) risk, including both amyloid and tau. Genetic ancestry however plays a complex role in AD risk, with ancestry on nuclear and mitochondrial genes having contradictory effects. This project will resolve this contradiction and mechanistically link genetic ancestry and mitochondrial function to AD risk by investigating how discordance between mitochondrial and nuclear genetic ancestry contributes to mitochondrial dysfunction and alters AD biomarker profiles in a large, genetically diverse cohort.

This study will be the first to directly test links between genetic ancestry, mitochondrial dysfunction, and Alzheimer’s-related biomarkers. By combining high-resolution mitochondrial phenotyping with detailed genetic ancestry estimates in one of the most diverse and deeply characterized AD cohorts available, the study has the potential to open a new mechanistic window into why AD risk varies across populations.

While Alzheimer’s is a global problem, some populations have a higher risk than others of developing the disease. Our study will contribute to our understanding of why Alzheimer’s disease affects some populations more severely by revealing how genetic ancestry and mitochondrial dysfunction jointly shape biomarker levels and cognitive decline. In the long term, this knowledge can help guide the development of more precise, ancestry-informed prevention and treatment strategies that benefit everyone.