Summary. Over 5 million Americans suffer from Alzheimer’s disease (AD) and related dementias (ADRD). AD is an irreversible, incurable brain disorder, is the sixth leading cause of death in the U.S., and accounts for as much as 60 to 70% of all forms of dementia. While genetic mutations account for a small proportion of AD and ADRDs, the most common risk factor for dementia is prior central nervous system (CNS) injury. Notably, traumatic brain injury (TBI) can accelerate the onset of AD/ADRD, and increases AD risk by 2.3 - 4.5-fold. Thus, TBI is a significant risk factor for the development of AD and ADRDs, and there are currently no effective treatments for AD or ADRDs. Identifying novel therapeutic mechanisms and targets, is a critical preclinical and clinical need. The complex hallmark brain changes that occur in AD include the appearance of abnormal clumps in the brain, known as amyloid plaques, and tangled bundles of fibers, called neurofibrillary or tau tangles. Inflammation and neuroinflammation are thought to play a major role in plaques and tangles, and in numerous other aspects of AD pathogenesis. Interestingly, TBI induces inflammatory responses that have been shown to exacerbate: AD pathology, neuropathology and neurobehavioral deficits. An immune response can be considered to be non-specific, or specific, and both have been implicated in AD/ and ADRDs. We have found that targeting a protein called CD74, a component of both the non-specific (aka innate immune system) and specific immune response (aka adaptive immune system), is neuroprotective after a TBI, and prevents cognitive decline after TBI. We propose that inhibiting CD74 after TBI will impede the development of AD-related inflammation, neuroinflammation, neuropathology and neurobehavioral deficits. This work is a natural extension of our currently funded proposal, in that we are already manipulating CD74 to determine mechanisms of post-traumatic inflammation, neuroinflammation and neurobehavioral decline. Here, we incorporate 5XFAD mice, and AD-specific outcome measures to determine if targeting CD74 after TBI prevents detrimental neurobehavioral, neuropathological, and immune/neuroimmune outcomes in the context of AD. We have assembled a research team dedicated to successful completion of these important experiments, and each member possesses expertise that is uniquely suited to make the sum of the parts greater than the sum of the whole.