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.

Authors

Ling Yin, Ruodi Ren, Christopher Leo, Yun Lu

Published in

Pharmacological research. Pages 108439. Sep 06, 2026. Epub Sep 06, 2026.

Abstract

Tau pathology is strongly associated with neurodegeneration and clinical progression in Alzheimer's disease (AD), positioning it as an important therapeutic target. However, tau-targeted therapies have thus far demonstrated limited and inconsistent translation into meaningful clinical benefit.
To examine clinical trials of tau-targeted therapies and explore potential mechanisms underlying their translational disconnect between biological target engagement and clinical outcomes.
A structured search of PubMed, MEDLINE, Embase, Cochrane CENTRAL, and related databases was conducted to identify interventional clinical trials targeting tau pathology. Eligible studies included randomized and early-phase trials evaluating monoclonal antibodies, vaccines, antisense oligonucleotides, and small-molecule aggregation inhibitors. Findings were synthesized using a structured narrative approach due to heterogeneity in study design, disease populations, therapeutic mechanisms and clinical end points. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool.
Eleven clinical trials were included, comprising seven monoclonal antibody studies, two vaccine trials, one antisense oligonucleotide study, and one small-molecule aggregation inhibitor study. Across monoclonal antibody and vaccine programs, biomarker modulation and target engagement were observed in some studies, yet these findings did not consistently translate into meaningful reductions in cognitive or functional decline. The antisense oligonucleotide BIIB080 demonstrated substantial reductions in cerebrospinal fluid tau biomarkers, supporting biological activity and target engagement; however, clinical efficacy remains to be established. Similarly, the small-molecule aggregation inhibitor LMTM did not demonstrate consistent clinical benefit in phase 3 trials. Most studies exhibited low risk of bias or some concerns, suggesting that methodological limitations alone may not fully explain the observed translational challenges.
Tau-targeted therapies highlight a translational gap between biological activity and clinically meaningful benefit across multiple therapeutic mechanisms. Emerging evidence suggests that disease-stage timing, biomarker interpretation, tau heterogeneity, and aging-related factors may contribute to this disconnect. Future strategies will likely require earlier, and more biologically stratified intervention approaches, improved biomarker validation, and combination paradigms addressing the multifactorial complexity of neurodegenerative disease.

PMID:
42702342
Bibliographic data and abstract were imported from PubMed on 07 Sep 2026.

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