Unlike peripheral organs, the brain and the cells within are very sensitive to inflammation, therefore any immune response must be tightly controlled. However, during neurodegenerative disease, there is a build-up of proteins such as Amyloid- (A) that bind innate immune receptors on microglia, the principal immune cell in the brain. Over time, this results in widespread and chronic microglial-mediated inflammation, as the A-induced stimulation persists without resolution. We have found an important role for microglia-mediated inflammation as a driver of Alzheimer’s disease and dementia. In recent years, it has become clear that on immune stimulation, many cells quickly change their use of nutrients, which can control their inflammatory effector function. The goal of our lab is to understand how microglial use of substrates and metabolites can influence their cellular function via metabolic or epigenetic regulation, ultimately leading to neurodegeneration. We are particularly interested in understanding how environmental factors like diet can contribute to these neurodegenerative pathways by providing additional innate immune stimuli and driving metabolic signaling changes. We make use of preclinical models and clinical samples to address our questions. A major goal of the McManus lab is to use these insights to identify novel immune-targeted therapies that could provide better, patient-specific options for individuals with Alzheimer’s disease and dementia.