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  • Perspective
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The case for rejecting the amyloid cascade hypothesis

Nature Neuroscience volume 18, pages 794–799 (2015)Cite this article

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Abstract

Alzheimer's disease (AD) is a biologically complex neurodegenerative dementia. Nearly 20 years ago, with the combination of observations from biochemistry, neuropathology and genetics, a compelling hypothesis known as the amyloid cascade hypothesis was formulated. The core of this hypothesis is that it is pathological accumulations of amyloid-β, a peptide fragment of a membrane protein called amyloid precursor protein, that act as the root cause of AD and initiate its pathogenesis. Yet, with the passage of time, growing amounts of data have accumulated that are inconsistent with the basically linear structure of this hypothesis. And while there is fear in the field over the consequences of rejecting it outright, clinging to an inaccurate disease model is the option we should fear most. This Perspective explores the proposition that we are over-reliant on amyloid to define and diagnose AD and that the time has come to face our fears and reject the amyloid cascade hypothesis.

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Figure 1: The degenerative events that ultimately produce the clinical symptoms of AD are fed by numerous deficiencies.

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Acknowledgements

The author thanks his many friends and colleagues whose spirited discussions over the years have helped sharpen the arguments raised here. Special thanks to S. Herculano-Houzel for her critical and insightful reading of an early draft of the work. Support for the writing came from The Hong Kong University of Science and Technology, the National Key Basic Research Program of China (2013CB530900), the Research Grants Council, Hong Kong Special Administrative Region (GRF660813) and the BrightFocus Foundation (A2012101).

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  1. Division of Life Science, Hong Kong University of Science and Technology, Kowloon, Hong Kong

    Karl Herrup

  2. State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Kowloon, Hong Kong

    Karl Herrup

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Herrup, K. The case for rejecting the amyloid cascade hypothesis. Nat Neurosci 18, 794–799 (2015). https://doi.org/10.1038/nn.4017

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