Evidence supports a pathogenic role for free radical injury to brain in Alzheimer's disease; however, clinical trial results are only mildly encouraging. Examining brains from The Adult Changes in Thought study offers a unique perspective. Selectively increased free radical damage to cerebral cortex was associated with Alzheimer's disease, microvascular brain injury, and current smoking, but not with antioxidant supplement usage. Our results support suppression of free radical injury to brain as a therapeutic target for Alzheimer's disease and microvascular brain injury; however, future clinical trials should consider other antioxidants or doses than those identified in our study.