Ketones and brain health: from metabolic rescue to metabolic flexibility

Abstract

The human brain relies predominantly on glucose under habitual dietary conditions, but this dependence is not absolute. During fasting, prolonged exercise, carbohydrate restriction or ketogenic interventions, beta-hydroxybutyrate (BHB) and acetoacetate (AcAc) become available as cerebral fuels and metabolic signals. Most literature on ketones and cognition has emphasized mild cognitive impairment (MCI), Alzheimer’s disease (AD) and other neurodegenerative disorders, where impaired cerebral glucose utilization provides a rationale for ketone-based brain-energy rescue. This Mini Review retains this evidence as proof of concept but shifts the focus toward a broader preventive hypothesis: repeated short periods of mild physiological ketosis may represent a normal component of cerebral metabolic flexibility and contribute to long-term brain health before cognitive impairment develops. This view is consistent with intermittent metabolic switching proposed recently, whereby transitions between glucose-dominant and fat/ketone-supported metabolism activate adaptive pathways involving mitochondrial function, stress resistance, autophagy, antioxidant defense and neurotrophic signaling. Mechanistically, ketones are transported into the brain through monocarboxylate transporters, oxidized by neurons and glia, and may influence histone deacetylases, redox state, neuroinflammation, BDNF-related signaling and cellular resilience. The key question may therefore be not whether sustained ketosis is superior to glucose metabolism, but whether modern lifestyles have reduced the physiological occasions on which ketones normally rise. Future studies should quantify the frequency, amplitude and metabolic context of ketone excursions induced by fasting, time-restricted eating, exercise, carbohydrate restriction, medium-chain triglycerides (MCT) intake or exogenous ketones, and relate these patterns to brain energetics and long-term cognitive trajectories.