Reframing Alzheimer's Disease Through a Redox-Metabolic Framework

Alzheimer's disease (AD) has been conceptualised as a proteinopathy driven by amyloid-β plaques and hyperphosphorylated tau neurofibrillary tangles. AD should not be understood as exclusively a proteinopathy or a metabolic/redox disorder, but as a network of interacting processes in which metabolic dysfunction, mitochondrial impairment, redox dysregulation, amyloid-β, tau, neuroinflammation, metal dyshomeostasis, and regulated cell death reinforce one another. This review examines AD through a redox-metabolic framework integrating cerebral glucose metabolism, insulin signalling, mitochondrial bioenergetics, metal homeostasis, and regulated cell death. We discuss how glucose hypometabolism, impaired oxidative phosphorylation, and weakened antioxidant defences may promote reactive oxygen species production and self-reinforcing oxidative and metabolic dysfunction. We examine interactions with amyloid-β and tau pathology, glial immunometabolism, gut-brain signalling, neuroinflammation, and metal-mediated toxicity. Advances in multi-omics, blood-based metabolomic and lipidomic biomarkers, and imaging may enable earlier biological stratification. Therapeutic strategies targeting mitochondria, NRF2 signalling, metabolic dysfunction, metal dyshomeostasis, and regulated oxidative cell death are evaluated based on current evidence and their potential complementarity with amyloid-directed therapies. Although temporal relationships remain unresolved, redox-metabolic dysfunction may represent an early determinant and amplifier of neuronal vulnerability. Evidence for lecanemab and donanemab supports an integrative rather than replacement model of AD treatment. This framework may facilitate earlier diagnosis, patient stratification, and complementary disease-modifying interventions.