Advanced age is the greatest risk factor for developing Alzheimer’s disease and related dementias. Evidence suggests that these diseases begin decades prior to noticeable symptoms. A better understanding of how the brain changes with age may provide clues into how/why these diseases begin and progress. We discovered that the abnormal brain cells that closely track with memory loss and disease in Alzheimer’s disease display characteristics of a stress response common to aging, called cellular senescence. Senescent cells accumulate in many tissues during aging, and contribute to disease and dysfunction. In Alzheimer’s disease brain tissue, we find that the senescent cells are neurons, the brain cells important for making, storing and retrieving memories—and many of these contain large deposits of tau protein. All neurons normally contain tau protein; however, abnormal forms of tau protein accumulate in many brain diseases. Tau aggregates, called neurofibrillary tangles, closely correlate with dementia and cell death. Similar to senescent cells, neurons with neurofibrillary tangles display signs of damage and stress, but they do not die. Also, like senescent cells, their survival comes with a tradeoff: they become toxic to surrounding healthy cells. Risk factors that increase cellular senescence in other tissues include advanced age and insulin resistance/diabetes; these risk factors also cause neurons to become senescent in the brain. We have found that regardless of the stressor, senescent neurons rely on tau to execute the stress response. Therefore, the objective of this project is to better understand how tau proteins guide neurons to become senescent in response to stress. This is important because senescent cells contribute to disease and disfunction. A better understanding of how, why and when neurons become senescent may lead to drug therapies that interrupt the toxic process. Moreover, some of these therapies may be most useful in midlife, when risk factors are evident but neurons still are healthy. This approach may reduce the risk for developing Alzheimer’s disease in later life.