Alzheimer’s disease is the most common cause of dementia, impacting memory, thinking and behavior. It affects an estimated 32 million people worldwide, with one in 10 people older than 65 and nearly a third of people older than 85 having the disease. Alzheimer’s disease severely impacts a person’s ability to carry out basic daily activities, inflicting both an enormous personal and societal burden, with the total cost in the United States estimated to be $355 billion in 2021. Treatment options remain limited, however, because our understanding of Alzheimer’s disease is incomplete. Alzheimer’s disease causes dementia because the brain cells called neurons die off, causing the brain to shrink. These neurons are thought to die because of runaway inflammation in the brain. We recently discovered that the skull contains a rich repertoire of immune cells that normally supply the brain’s borders but that can move to the brain itself when it is damaged. These skull-derived immune cells also receive signals from the brain, meaning they are poised to respond to changes in brain health. Over the last two years, we were able to demonstrate that both the skull and blood provide immune cells to the brain in Alzheimer’s disease, and overall, their contribution is detrimental to brain health. We also found a molecular marker that we can use to specifically target and manipulate skull-derived cells. Using this molecular handle, we are planning to assess over the next two years whether skull- vs. blood-derived cells play different roles and whether we can boost one population over the other to slow the progression of Alzheimer’s disease.