Tau phosphorylation in Alzheimer’s disease: emerging mechanisms, network interactions, and therapeutic implications

<jats:title>Abstract</jats:title> <jats:p>While amyloid-β (Aβ) has historically dominated the research landscape of Alzheimer’s disease (AD), the limited clinical success of Aβ-centric therapies has redirected focus toward tau pathology, which correlates more robustly with cognitive deterioration and synaptic dysfunction. Transcending the traditional linear pathological model, this review reframes tau phosphorylation as a dynamic hub within a multi-scale regulatory network. We first synthesize recent breakthroughs in molecular mechanisms, detailing how the kinase-phosphatase equilibrium, cross-regulation of diverse post-translational modifications (PTMs), nuclear envelope damage, iron metabolism and ferroptosis collectively drive the transition from soluble tau species to neurofibrillary tangles (NFTs). Beyond neuronal boundaries, we elucidate how pathological tau orchestrates systemic neurotoxicity by synergizing with Aβ deposition to trigger neuroinflammation, blood-brain barrier breakdown, and gut-brain axis dysregulation. Finally, we bridge these mechanistic insights with translational advancements, evaluating next-generation biofluid biomarkers and innovative therapeutic modalities—ranging from small-molecule inhibitors to Dephosphorylation-Targeting Chimeras (DEPTACs)—currently under clinical investigation. This integrated perspective offers a holistic framework for understanding AD pathogenesis and provides a roadmap for the development of precision medicine strategies targeting the tau interactome.</jats:p>