Oxidative imbalance is one of the earliest manifestations of Alzheimer disease (AD) actually preceding the classic pathology of amyloid β deposits and neurofibrillary tangles. Clinical trials examining antioxidant modulation by a number of global interventions show efficacy, while simple supplementation has limited benefit suggesting complexity of multiple contributing factors. In this review, we highlight new insights regarding novel approaches to understanding and treating AD based on holistic views of oxidative balance including diet.