Simple SummaryRadiation therapy-related brain damage with neurocognitive impairment is a common long-term side effect in cancer survivors and significantly impairs the quality of life. Increasing evidence indicates the increased vulnerability of the developing brain to the neurotoxic effects of ionizing radiation (IR). In this review, historical and current clinical evidence on the age dependency of radiation-induced neurocognitive dysfunction is summarized. Moreover, recent research developments regarding the mechanistic causes for this age-related extent of brain damage following IR exposure are presented.AbstractCranial radiotherapy is a known risk factor for neurocognitive impairment in cancer survivors. Although radiation-induced cognitive dysfunction is observed in patients of all ages, children seem to be more vulnerable than adults to suffering age-related deficits in neurocognitive skills. So far, the underlying mechanisms by which IR negatively influences brain functions as well as the reasons for the profound age dependency are still insufficiently known. We performed a comprehensive Pubmed-based literature search to identify original research articles that reported on age dependency of neurocognitive dysfunction following cranial IR exposure. Numerous clinical trials in childhood cancer survivors indicate that the severity of radiation-induced cognitive dysfunction is clearly dependent on age at IR exposure. These clinical findings were related to the current state of experimental research providing important insights into the age dependency of radiation-induced brain injury and the development of neurocognitive impairment. Research in pre-clinical rodent models demonstrates age-dependent effects of IR exposure on hippocampal neurogenesis, radiation-induced neurovascular damage and neuroinflammation.