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Alzheimer's disease is a progressive, incurable neurodegenerative disease targeting specific neuronal populations within the brain while neighboring neurons appear unaffected. The focus for defining mechanisms has therefore been on the pathogenesis in affected neuronal populations and developing intervention strategies to prevent their cell death. However, there is growing recognition of the importance of glial cells in the development of pathology. Determining exactly how glial cells are involved in the disease process and the susceptibility of the aging brain provides unprecedented challenges. The present review examines recent studies attempting to unravel the glial response during the course of disease and how this action may dictate the outcome of neurodegeneration. The importance of regional heterogeneity of glial cells within the CNS during healthy aging and disease is examined to understand how the glial cells may contribute to neuronal susceptibility or resilience during the neurodegenerative process.-Alibhai, J. D., Diack, A. B., Manson, J. C. Unravelling the glial response in the pathogenesis of Alzheimer's disease.