Tau Pathology in Alzheimer's Disease: Bridging Molecular Mechanisms and Targeted Therapies.

Abstract

Alzheimer's disease (AD), the leading cause of dementia, is characterized by β-amyloid (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau. While Aβ-targeting therapies have been a primary focus of drug development, their long-term efficacy remains uncertain. Emerging evidence suggests that tauopathy is more closely linked to cognitive decline, positioning tau as a promising therapeutic target. Tauopathies, a group of neurodegenerative disorders marked by tau dysfunction and aggregation, were historically attributed to a toxic gain-of-function. However, clinical trials targeting tau have yielded limited success, likely due to the heterogeneity of tau pathology, variable patient responses, and suboptimal therapeutic strategies. Here, we underline the need for a refined understanding of tau biology to develop effective interventions. Advancing precision medicine approaches and identifying optimal tau species for therapeutic intervention could transform tau-targeting therapies into a cornerstone in managing tauopathies. By integrating insights from genetics, pathology, and translational research, future efforts may overcome current challenges and unlock novel treatment avenues, ultimately improving patient outcomes.