Intermittent fasting and neuroprotection in Alzheimer's disease: metabolic mechanisms, cellular signaling, and brain-peripheral crosstalk.

Intermittent fasting (IF) promotes a metabolic switch characterized by reduced glucose and insulin availability along with increased lipolysis and ketone body production, particularly β-hydroxybutyrate (βOHB). In the brain, IF enhances metabolic flexibility by facilitating ketone utilization and supporting the astrocyte-neuron lactate shuttle (ANLS), partially compensating for cerebral glucose hypometabolism which is commonly observed in Alzheimer's disease (AD). Beyond bioenergetics, IF activates autophagy and inhibits mTOR signaling, promoting protein clearance and cellular homeostasis. Neuroinflammation is also attenuated with IF through the modulation of microglial activation. IF further induces increased levels of brain-derived neurotrophic factor (BDNF), thereby supporting synaptic plasticity and neuronal resilience. At the systemic level, IF enhances brain-peripheral crosstalk by improving adipose tissue function (e.g., leptin sensitivity and adipokine balance) and stimulating skeletal muscle-derived myokine signaling, which collectively influence brain metabolism and inflammation. These integrated mechanisms converge to reduce amyloid-β accumulation, tau pathology, and neuroinflammation, ultimately improving synaptic function and cognitive outcomes, as evidenced by preclinical rodent models and emerging clinical studies.