NAD+ plays a fundamental role in life and health, including in brain resilience. Preclinical and clinical studies show an age-dependent reduction of NAD+ which is exacerbated in multiple neurodegenerative diseases, including Alzheimer’s disease; conversely, NAD+ augmentation ameliorates memory loss in Alzheimer-like animal models, stimulating multiple on-going clinical trials for this disease. Mechanistically, NAD+ maintains brain resilience via multiple approaches, including stimulating mitochondrial autophagy (termed mitophagy). We hypothesize an NAD+-mitophagy axis in brain health maintenance.