Alzheimer’s disease (AD) does not equally affect all parts of the brain. Regions such as the entorhinal cortex and hippocampus are damaged early, while others, like the midbrain, remain relatively spared. The reasons for this selective vulnerability are not well understood.
In this project, we will create a human stem cell–based model that mimics different brain regions. This will allow us to study how brain cells respond to the hallmarks of AD, including amyloid beta and tau buildup. We will focus on two major factors that may shape regional vulnerability: genetic background, particularly the APOE gene (with APOE4 increasing risk and APOE3-Christchurch offering protection), and the activity of the immune system in the brain. Using our model, we will test how neurons and astrocytes from vulnerable versus resistant regions respond to disease features, and how interactions with immune cells, especially T cells, worsen or prevent damage. Finally, we will explore whether blocking specific immune signals can protect against the loss of brain cells. These studies will shed light on why certain brain regions are more vulnerable in AD and may guide the development of more precise treatment strategies tailored to a person’s genetics and stage of disease.
