Abstract Alzheimer’s disease (AD) and related neurodegenerative disorders are common causes of progressive cognitive decline with age. Genetic variants that influence the risk of developing AD are prevalent and could serve as a biomarker and enable the development of AD-specific approaches that protect neurologic function in the context of other age-related diseases whose co-morbidities and therapies may compound the neurologic deterioration that occurs in AD. An important and common co-morbidity in aging individuals is cancer. Using models of AD, this proposal examines the neurocognitive dysfunction that can develop after receiving cancer therapies directed to the brain, the mechanisms of which are currently poorly understood. This proposal investigates whether genetic factors associated with neurodegenerative disease predispose individuals to neurocognitive decline after brain radiation therapy. The results of this work will identify fundamental relationships between pathogenic processes underlying AD and neurologic function after cancer therapy that may then be used to develop strategies that minimize therapy-induced neurocognitive deficits in individuals with AD or at risk for AD.