Alzheimer’s disease is a devastating disorder that slowly destroys brain function, leading to memory loss and cognitive decline. Despite decades of research, current treatments offer only modest benefit, and most are less effective in women than in men. The goal of this project is to understand why some brain cells are especially vulnerable early in the disease and to test whether restoring a simple mineral, magnesium, can protect these cells and preserve memory.

Our earlier work mapped how different brain regions change as Alzheimer’s develops and identified the retrosplenial cortex, a key memory center, as one of the first regions to show damage. Within this area, a special group of cells called parvalbumin interneurons lose their ability to regulate brain activity. These cells are vital for keeping communication between brain regions synchronized. Using advanced molecular mapping, we discovered that these neurons show early signs of metabolic stress and impaired magnesium handling. Magnesium is essential for energy production, so this disruption could explain their early failure and the resulting breakdown in brain networks that support memory.

In this project, we will measure magnesium levels in the brain, study how magnesium-related genes change during disease, and test whether restoring magnesium levels can improve brain activity and cognition. We will also explore how protective structures around these neurons, called perineuronal nets, help maintain their health and whether reinforcing these structures can work together with magnesium to enhance resilience.

By identifying how magnesium metabolism influences brain function, this research may reveal a safe, accessible way to slow or prevent early cognitive decline. Our work aims to lay the foundation for new treatment strategies that are effective for both women and men and can be implemented before irreversible brain damage occurs.