Significantly increased levels of oxidized nucleic acids, proteins, and lipids have been described in the brains of subjects with Alzheimer disease (AD) and mild cognitive impairment (MCI) as well as young adults with Down syndrome, compared to age-matched controls. Therefore, it is speculated that oxidative stress (OS) and consequent cellular damage occur at an early-stage in the pathological cascade of AD. Until now, several antioxidants, mitochondrial protective agents, anti-inflammatory agents and metal chelators have been tested as possible OS-targeting therapeutics for AD. Although some of these agents have shown significant neuroprotective effects in cellular and animal models of AD, their efficacies in AD clinical trials have not been fully established. When limited efficacies of exogenous antioxidants in previous trials are taken into account, early-stage interventions aimed to activate endogenous antioxidants may be promising as OS-targeting therapeutic strategies for AD. A recent randomized controlled trial of dietary intervention for amnestic MCI is a good example of such an approach, where an OS-marker in cerebrospinal fluid is decreased and cognitive function is successfully improved by a diet with low-saturated fat and low-glycemic index. Indeed, transcriptional activators of endogenous antioxidants should be researched and tested in future clinical trials for AD.