Alternate-day Fasting Improves Cognitive and Brain Energy Deficits by Promoting Ketone Metabolism in the 3xtg Mouse Model of Alzheimer's Disease

Alzheimer's disease (AD) is characterized by disorders in brain energy. The lack of sufficient energy for nerve function leads to cognitive dysfunction and massive neuronal loss in AD. Ketone bodies are an alternative to glucose as a source of energy in the brain, and alternate-day fasting (ADF) promotes the production of the ketone body β-hydroxybutyric acid (βOHB). In this study, 7-month-old male WT mice and 3xTg mice underwent dietary control for 20 weeks. We found that ADF increased circulating βOHB concentrations in 3xTg mice, improved cognitive function, reduced anxiety-like behaviors, improved hippocampal synaptic plasticity, and reduced neuronal loss, Aβ oligomers and tau hyperphosphorylation. In addition, ADF improved mitochondrial bioenergetic function by promoting brain ketone metabolism and rescued brain energy deficits in 3xTg mice. A safety evaluation showed that ADF improved exercise endurance and liver and kidney function in 3xTg mice without negatively affecting muscle motor and heart functions. This study provides a theoretical basis and strong support for the application of ADF as a non-drug strategy for preventing and treating brain energy defects in the early stage of AD.