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Tau-targeting therapies for Alzheimer disease

Nature Reviews Neurology volume 14, pages 399–415 (2018)Cite this article

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Abstract

Alzheimer disease (AD) is the most common form of dementia. Pathologically, AD is characterized by amyloid plaques and neurofibrillary tangles in the brain, with associated loss of synapses and neurons, resulting in cognitive deficits and eventually dementia. Amyloid-β (Aβ) peptide and tau protein are the primary components of the plaques and tangles, respectively. In the decades since Aβ and tau were identified, development of therapies for AD has primarily focused on Aβ, but tau has received more attention in recent years, in part because of the failure of various Aβ-targeting treatments in clinical trials. In this article, we review the current status of tau-targeting therapies for AD. Initially, potential anti-tau therapies were based mainly on inhibition of kinases or tau aggregation, or on stabilization of microtubules, but most of these approaches have been discontinued because of toxicity and/or lack of efficacy. Currently, the majority of tau-targeting therapies in clinical trials are immunotherapies, which have shown promise in numerous preclinical studies. Given that tau pathology correlates better with cognitive impairments than do Aβ lesions, targeting of tau is expected to be more effective than Aβ clearance once the clinical symptoms are evident. With future improvements in diagnostics, these two hallmarks of the disease might be targeted prophylactically.

Key points

  • Therapies for Alzheimer disease in clinical trials are gradually shifting from amyloid-β (Aβ)-targeting to tau-targeting approaches.

  • Early anti-tau therapies were based mainly on inhibition of kinases or tau aggregation, or on stabilization of microtubules, but most of these approaches have been discontinued because of toxicity and/or lack of efficacy.

  • Most of the tau-targeting approaches that are currently in clinical trials are immunotherapies.

  • Tau is likely to be a better target than Aβ once cognitive deficits manifest because the tau burden correlates better with clinical impairments than does the Aβ burden.

  • Eventually, with continued improvements in diagnostics, both Aβ and tau are likely to be targeted prophylactically for clearance.

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Fig. 1: The defining pathological hallmarks of Alzheimer disease.
Fig. 2: Tau-related therapeutic targets.
Fig. 3: Proposed modes of action of anti-tau antibodies.
Fig. 4: Current status of clinical trials of drugs that target tau pathology.

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Acknowledgements

E.M.S. was supported by NIH grants R01 NS077239 and R01 AG032611 and a pilot grant from the Michael J. Fox Foundation. E.E.C. was supported by a grant from the Alzheimer’s Association.

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Authors and Affiliations

  1. Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY, USA

    Erin E. Congdon & Einar M. Sigurdsson

  2. Department of Psychiatry, New York University School of Medicine, New York, NY, USA

    Einar M. Sigurdsson

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  1. Erin E. Congdon
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Both authors researched data for the article, made substantial contributions to discussion of the content, wrote the article, developed the figures and tables and reviewed and edited the manuscript before submission.

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Correspondence to Einar M. Sigurdsson.

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Competing interests

E.M.S. is an inventor on various patents on immunotherapies and related diagnostics that are assigned to New York University. Some of those focusing on the tau protein are licensed to and are being co-developed with H. Lundbeck A/S. E.E.C. declares no competing interests.

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Congdon, E.E., Sigurdsson, E.M. Tau-targeting therapies for Alzheimer disease. Nat Rev Neurol 14, 399–415 (2018). https://doi.org/10.1038/s41582-018-0013-z

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