Targeting RNA quality-control defects in tauopathies: pharmacodynamic biomarkers and therapeutic development

Tau-directed therapies can achieve biochemical target engagement without delivering consistent clinical benefit, suggesting that a key bottleneck in tauopathy development lies not only in target access, but in whether tau engagement leads to measurable recovery of disease-relevant cellular states. Recent studies increasingly link tau-associated dysfunction to RNA abnormalities in surveillance, compartmentalization and stress responses. These findings position RNA quality control as both a downstream consequence of tau pathology and a co-development layer, with potential therapeutic relevance in selected contexts. Here, we frame RNA quality control as a development-oriented layer of dysfunction in tauopathies. Within this layer, nonsense-mediated decay currently shows the strongest intervention-linked evidence, whereas nucleocytoplasmic transport and condensate reversibility are better viewed as biologically supported readout and assay-development domains. We further outline compact pharmacodynamic biomarkers and a framework for matching therapeutic modality to mechanism. By positioning RNA-state measurements as a readout layer and RNA-state correction as a potential intervention layer, this framework may help explain why biochemical tau engagement can produce heterogeneous biological responses and improve the interpretability of tau-directed therapeutic development.