The tau–microtubule axis in Alzheimer’s disease: reciprocal mechanisms, biomarker gaps, and therapeutic challenges

Microtubule dysfunction has been implicated in axonal transport failure, synaptic degeneration, and neuronal loss in Alzheimer’s disease, yet its position within the disease process remains unresolved. This critical narrative review evaluates the tau–microtubule axis across physiological, pathological, biomarker, and therapeutic contexts. Tau interacts dynamically with microtubules and regulates labile domains, motor access, severing, intracellular transport, and neuronal compartmentalization rather than acting solely as a constitutive stabilizer. In Alzheimer’s disease, abnormal post-translational modification, somatodendritic mislocalization, and aggregation alter these functions and may disrupt axonal transport, mitochondrial trafficking, and synaptic maintenance. Conversely, experimental microtubule disruption can release tau and promote its subsequent phosphorylation. These findings motivate a proposed reciprocal framework in which tau abnormalities and microtubule dysfunction may amplify one another, with potentially stage-dependent contributions from amyloid-β–tau interactions, neuroinflammation, altered tubulin modifications, and metabolic stress. Cellular and animal models support several components of this framework, but direct causal evidence in humans remains limited. Tau-lowering therapies, immunotherapies, kinase-directed interventions, and microtubule-modulating agents have shown variable outcomes, with molecular target engagement not consistently translating into clinical benefit. Current tau biomarkers measure soluble phosphorylation changes or aggregate burden but do not directly assess microtubule integrity, tau–microtubule binding, or axonal transport competence. This biomarker gap limits mechanistic interpretation of clinical trials and prevents adequate testing of whether therapeutic target engagement restores the neuronal functions that these interventions are intended to preserve.