Disentangling tau: One protein, many therapeutic approaches.

The tauopathies encompass over 20 adult neurodegenerative diseases and are characterized by the dysfunction and accumulation of insoluble tau protein. Among them, Alzheimer's disease, frontotemporal dementia, and progressive supranuclear palsy collectively impact millions of patients and their families worldwide. Despite years of drug development using a variety of mechanisms of action, no therapeutic directed against tau has been approved for clinical use. This raises important questions about our current model of tau pathology and invites thoughtful consideration of our approach to nonclinical models and clinical trial design. In this article, we review what is known about the biology and genetics of tau, placing it in the context of current and failed clinical trials. We highlight potential reasons for the lack of success to date and offer suggestions for new pathways in therapeutic development. Overall, our viewpoint to the future is optimistic for this important group of neurodegenerative diseases.

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Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Adam Boxer reports a relationship with Alector LLC that includes: consulting or advisory and equity or stocks. Adam Boxer reports a relationship with Arvinas that includes: consulting or advisory and equity or stocks. Adam Boxer reports a relationship with Arkuda Therapeutics that includes: consulting or advisory and equity or stocks. Adam Boxer reports a relationship with Eli Lilly and Company that includes: consulting or advisory. Adam Boxer reports a relationship with Roche that includes: consulting or advisory. Adam Boxer reports a relationship with Merck & Co Inc that includes: consulting or advisory. Adam Boxer reports a relationship with Biogen that includes: funding grants. Adam Boxer reports a relationship with Eisai Inc that includes: funding grants. Adam Boxer reports a relationship with Regeneron Pharmaceuticals Inc that includes: funding grants. Adam Boxer reports a relationship with Janssen Pharmaceuticals Inc that includes: non-financial support. Adam Boxer reports a relationship with Denali Therapeutics Inc that includes: non-financial support. Adam Boxer reports a relationship with Oligomerix Inc that includes: consulting or advisory. Adam Boxer reports a relationship with Transposon Therapeutics Inc that includes: consulting or advisory. Adam reports a relationship with Amylyx Pharmaceuticals Inc that includes: consulting or advisory. Adam Boxer reports a relationship with Modalis that includes: consulting or advisory. Adam Boxer reports a relationship with GSK that includes: consulting or advisory. Adam Boxer has received research support from the National Institutes on Aging: NIH 1R01AG078457, U19AG063911, R01AG073482, R56AG075744, R01AG038791, RF1AG077557, R01AG071756, U24AG057437; Rainwater Charitable Foundation, Bluefield Project to Cure FTD, GHR Foundation, Alzheimer's Association, Association for Frontotemporal Degeneration, Gates Ventures, Alzheimer's Drug Discovery Foundation, UCSF Parkinson's Spectrum Disorders Center and the University of California Cures AD Program. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.