Insulin resistance and obesity: Drivers of energy crisis for Alzheimer's disease.

Alzheimer's disease (AD) is increasingly recognized as a disorder driven not only by classical neuropathological hallmarks but also by profound disturbances in brain energy metabolism. Growing evidence points to insulin resistance and obesity as major contributors to this metabolic crisis, linking peripheral metabolic dysfunction to central neurodegenerative processes. This chapter explores AD in the light of bioenergetic failure, highlighting the epidemiological and mechanistic connections between impaired insulin signaling, excess adiposity, and cognitive decline. The chapter further highlights how obesity-related inflammation, adipokine imbalance, and gut-brain axis dysregulation accelerates central insulin resistance and neuronal vulnerability. Evidence for glucose hypometabolism, mitochondrial failure, and disrupted astrocyte-neuron metabolic coupling in AD is reviewed, positioning amyloid and tau pathology as downstream consequences of sustained energy insufficiency. Finally, emerging therapeutic strategies aimed at restoring metabolic balance ranging from insulin-based interventions to lifestyle and mitochondria-targeted approaches are discussed, underscoring the potential of metabolic restoration as a disease-modifying strategy in Alzheimer's disease.