From target engagement to translational disconnect: A systematic review and narrative synthesis of direct tau-targeted clinical trials in Alzheimer's disease and primary tauopathies.
Pharmacol ResSep 6, 2026 (epub)
Clinical ResearchNeurology
Ling Yin, Ruodi Ren, Christopher Leo et al.
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In 30 seconds
This systematic review examined 11 clinical trials of tau-targeted therapies in Alzheimer's disease and primary tauopathies. Despite some studies showing biomarker modulation, there was no consistent translation into meaningful cognitive or functional improvements. The review highlights the translational disconnect between biological target engagement and clinical outcomes.
Key findings
- Biomarker modulation was observed in some monoclonal antibody and vaccine studies, but did not lead to significant cognitive improvements.
- The antisense oligonucleotide BIIB080 showed substantial reductions in cerebrospinal fluid tau biomarkers, indicating biological activity.
- The small-molecule aggregation inhibitor LMTM failed to demonstrate consistent clinical benefit in phase 3 trials.
- Most studies had low risk of bias, suggesting methodological issues alone do not explain the translational challenges.
Why it matters
Understanding the translational disconnect in tau-targeted therapies is crucial for developing effective treatments for Alzheimer's disease. Insights from this review may inform future research directions and therapeutic strategies.