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Alzheimer disease therapy—moving from amyloid-β to tau

Nature Reviews Neurology volume 9, pages 677–686 (2013)Cite this article

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Abstract

Disease-modifying treatments for Alzheimer disease (AD) have focused mainly on reducing levels of amyloid-β (Aβ) in the brain. Some compounds have achieved this goal, but none has produced clinically meaningful results. Several methodological issues relating to clinical trials of these agents might explain this failure; an additional consideration is that the amyloid cascade hypothesis—which places amyloid plaques at the heart of AD pathogenesis—does not fully integrate a large body of data relevant to the emergence of clinical AD. Importantly, amyloid deposition is not strongly correlated with cognition in multivariate analyses, unlike hyperphosphorylated tau, neurofibrillary tangles, and synaptic and neuronal loss, which are closely associated with memory deficits. Targeting tau pathology, therefore, might be more clinically effective than Aβ-directed therapies. Furthermore, numerous immunization studies in animal models indicate that reduction of intracellular levels of tau and phosphorylated tau is possible, and is associated with improved cognitive performance. Several tau-related vaccines are in advanced preclinical stages and will soon enter clinical trials. In this article, we present a critical analysis of the failure of Aβ-directed therapies, discuss limitations of the amyloid cascade hypothesis, and suggest the potential value of tau-targeted therapy for AD.

Key Points

  • The efficacy of amyloid-β (Aβ) immunization observed in animal models of Alzheimer disease (AD) is not reflected in patients with this disease

  • Immunization against Aβ in patients with mild-to-moderately severe AD reduced levels of Aβ peptides, but failed to improve cognitive function

  • Levels of the microtubule-associated protein tau, hyperphosphorylated tau, and the number of neurofibrillary tangles, synapses and neurons (but not Aβ load) correlate strongly with cognition in AD

  • These findings and results of clinical trials suggest that Aβ might not be the best therapeutic target in AD

  • Tau immunotherapy has been shown to reduce tau pathology and improve cognitive deficits in animal models of AD

  • The amyloid cascade theory of AD pathogenesis remains a useful but unproven hypothesis that should be revised to emphasize the crucial role of tau as a candidate target for AD therapy

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Figure 1: Modified amyloid cascade hypothesis schematic, emphasizing the role of tau by placing it at the centre of the cascade leading to dementia.
Figure 2: Schematic representation of tau-related processes that are potential targets for therapeutic intervention.

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  1. Department of Internal Medicine, Rehabilitation and Geriatrics, University of Geneva Hospitals, Faculty of Medicine, University of Geneva, Chemin du Pont-Bochet 3, Thonex, Geneva, CH 1226, Switzerland

    Ezio Giacobini & Gabriel Gold

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Both authors made substantial contributions to researching the data for the article, to discussions of the content, to writing the article, and to review and/or editing of the manuscript before submission.

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Correspondence to Ezio Giacobini.

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G. Gold is currently a member of an advisory board for AC Immune. E. Giacobini declares no competing interests.

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Giacobini, E., Gold, G. Alzheimer disease therapy—moving from amyloid-β to tau. Nat Rev Neurol 9, 677–686 (2013). https://doi.org/10.1038/nrneurol.2013.223

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