Ketogenic diet and ketone body metabolism in Alzheimer’s disease: mechanisms, clinical evidence, and emerging perspectives

Alzheimer’s disease (AD), the most common neurodegenerative disorder, is associated with progressive cognitive impairment, β-amyloid (Aβ) aggregation, and tau hyperphosphorylation, while currently available treatments provide only partial symptomatic relief or modestly slow disease progression. Cerebral glucose hypometabolism and neuronal energy deficiency can occur early in AD, making metabolic dysfunction a potential therapeutic target. The ketogenic diet (KD) restricts carbohydrate intake to stimulate hepatic ketogenesis and increase the availability of ketone bodies; its principal circulating metabolite, β-hydroxybutyrate (BHB), may influence AD-related processes through metabolic, epigenetic, and immunomodulatory pathways. This review summarizes proposed mechanisms and clinical evidence for ketogenic dietary interventions and exogenous ketone strategies in AD and mild cognitive impairment (MCI). BHB may provide an alternative oxidative substrate, influence mitochondrial and autophagy-related signaling, serve as a substrate for β-hydroxybutyrylation (Kbhb), inhibit selected histone deacetylases (HDACs), and modulate inflammatory pathways involving GPR109A and the NLRP3 inflammasome. These mechanisms are supported mainly by preclinical studies and have not been jointly validated in clinical trials. Human studies remain limited by small samples, heterogeneous interventions, short follow-up, and variable blinding and adherence. We therefore discuss safety, methodological limitations, and priorities for biomarker-informed clinical studies, while emphasizing that the clinical relevance of the proposed mechanisms remains to be established.