The repeated failure of amyloid therapies highlights a core misunderstanding of Alzheimer's disease (AD) origins. A new metabolic paradigm now positions impaired brain metabolism—not protein accumulation—as the central, early driver. Key evidence shows cerebral glucose hypometabolism emerges decades before symptoms, linked to brain insulin resistance (“type 3 diabetes”) and mitochondrial dysfunction. The APOE ε4 allele worsens lipid defects thereby, accelerating the progression of AD pathology. These disruptions—alongside gut–brain axis issues—create a self-reinforcing cycle that fuels amyloid β (Aβ), tau, neuroinflammation, and synaptic loss. This framework integrates with the neuron-centric model, explaining disease heterogeneity and the inadequacy of single-target drugs. This review particularly highlights the metabolic perspective in AD, underscoring the need for a radical therapeutic shift: from late stage protein clearance strategies to early, multimodal interventions that restore metabolic homeostasis and disrupt the entire pathogenic continuum. © 2026 The Author(s)