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Can tauopathy shake the amyloid cascade hypothesis?

Nature Reviews Neurology volume 9, page 356 (2013)Cite this article

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In an article in the February 2013 issue of this journal (Alzheimer disease: Aβ-independent processes—rethinking preclinical AD. Nat. Rev. Neurol. 9, 123–124; 2013),1 Gaël Chételat discusses the roles of tau and amyloid in Alzheimer disease (AD) pathology. The article was based around the findings of a 2013 publication by Knopman et al.2 that reported neuronal injury in the absence of substantial amyloid burden. After two decades of chasing evidence for the amyloid hypothesis of AD, and after the recent disappointments in immunotherapy trials, it is imperative that alternative hypotheses are considered and actively pursued. New models are emerging that present opportunities for therapeutic research. The amyloid hypothesis was again questioned in the article by Chételat.1 'Amyloid-β (Aβ)-independent process' is an exciting concept, but is there enough evidence to warrant a rethinking of the amyloid cascade hypothesis?

The concept that amyloid pathology occurs upstream of neurodegeneration by tau has been the cornerstone of the amyloid hypothesis. In autopsy studies, however, tau pathology has been observed before marked Aβ deposition. In a study of brains from young individuals (between 4 and 29 years of age), Braak and Del Tredici observed pre-tangles that were positive for AT8 (an anti-tau monoclonal antibody) as early as the first decade of life.3 Notably, many genetic tauopathies are not associated with significant dementia.4 Presence of tau from the first decade of life to old age in the absence of dementia could indicate, therefore, that tau is a marker of ageing.

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  1. Department of Neurology, Postgraduate Institute of Medical Education and Research, 160012, Chandigarh, India

    Venugopalan Y. Vishnu

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  1. Venugopalan Y. Vishnu
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Vishnu, V. Can tauopathy shake the amyloid cascade hypothesis?. Nat Rev Neurol 9, 356 (2013). https://doi.org/10.1038/nrneurol.2013.21-c1

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