Evidence is accumulating that vaccination against a variety of different pathogens can reduce the risk of Alzheimer’s disease (AD). The vaccines now include: the Bacillus Calmette-Guérin (BCG) vaccine, a 100-year-old anti-tuberculosis vaccine; the triple vaccine of childhood (DPT); anti-tetanus or anti-diphtheria vaccination alone; anti-influenza; anti-pneumonia; and possibly anti-shingles, currently “under review.” The levels of risk reduction range from 32% to 80%, with BCG offering the best results. These studies have been retrospective, but at least three prospective randomized clinical trials now are underway in Denmark, Greece and the United States. When one considers that all attempts to treat established AD or even to slow its course have failed thus far, a major effort in “prevention” as well as “cure” seems worthwhile. Kelley et al., writing in 2015, found that in the previous five years of treating AD, the cost to the health system and families was more than the burden of cancer and cardiovascular disease together. This proposal is focused on understanding the mechanism of this immune prophylaxis, observed from a number of vaccines, but here focused on BCG. The Hebrew University group has a major program in treating superficial bladder cancer with BCG. These patients, compared with other individuals with bladder cancer treated by other means, will be followed for their cognition and other co-morbidities, and to assess in detail how their immune systems respond to the vaccine. The aim of this specific project will be to study the cell signaling processes that follow delivery of the vaccine into the bladder. A special emphasis will be on the interaction of the immune system with metabolic changes occurring in the monocyte line. These cells are known to cross the blood-brain barrier and transform to microglia, a critical cellular population that promotes neuronal health.