Tau Protein Aggregation Inhibitors—Therapeutic Strategy for Concurrent Tau and Amyloid Aggregation Inhibition

Tau protein, a microtubule-associated protein widely distributed in the central nervous system, aggregates abnormally and forms neurofibrillary tangles in neurodegenerative diseases. Particularly in Alzheimer's disease, pathological tau protein aggregates disrupt the structure and function of neurons, triggering other neurodegenerative-related processes such as neuroinflammation and amyloid plaque formation, and finally leading to neuronal death. Several classes of drugs targeting neurofibrillary tangles have recently been studied, with tau protein aggregation inhibitors as a key research direction. In the context of emerging therapeutic perspectives, this review aims to provide an updated, practical overview of currently available tau protein aggregation inhibitors and future research directions. The first part of the manuscript highlights the pathophysiological basics of tau protein aggregation and tau-related changes in neurodegenerative disorders, with a focus on Alzheimer's disease pathology. Subsequently, the most relevant classes of drugs that inhibit tau protein aggregation, including small-molecule inhibitors and natural compounds, are presented, with examples from recent clinical trials. Finally, beyond summarizing established classes of tau aggregation inhibitors, this review places particular emphasis on emerging and comparatively underexplored compounds with dual activity against both tau and amyloid-β pathology. The originality and novelty of this work arise from the systematical analysis of recent preclinical and clinical evidence with a translational, practice-oriented perspective, highlighting mechanistic convergence, repurposing opportunities, and therapeutic combinations that may better reflect the multifactorial nature of neurodegenerative diseases. Thus, this work provides a forward-looking framework for future drug development and identifies promising candidates that may shape the next generation of disease-modifying therapies.