The immune system protects against infectious diseases and is actively involved in noninfectious disease processes, including neurodegenerative illnesses like Alzheimer’s disease (AD). When working effectively, the immune system may prevent neurodegenerative disease, but the immune system also can become disarrayed with age and disease progression and promote further decline. We are investigating the repurposing of a vaccine against tuberculosis—the BCG vaccine—given its association with decreased incidence of AD (based on studies of individuals receiving this treatment for bladder cancer). This vaccine has been found to benefit human health beyond protection against tuberculosis, including positive outcomes in those patients with type 1 diabetes and several forms of cancer, through processes linked to the vaccine’s effect on the immune system. We are performing a series of clinical trials using the BCG vaccine in older adults with and without dementia to identify early evidence supporting a possible clinical benefit against Alzheimer’s disease. Our priority for this proposal is to understand how a vaccine might impact the immune system interacting with the brain (distinct from the immune system circulating in our blood). Our studies carefully look at these central nervous system immune cells to identify whether they function differently after vaccination. The project has important implications for future studies of immune-related treatments for Alzheimer’s disease, due to this rare opportunity to study the immune cells that surround and support the brain—not at one timepoint, but at up to three timepoints of cell collections over one year.