The case for rejecting the amyloid cascade hypothesis

Karl Herrup

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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.

Read the full article on Readcube for free here.

And see our post on a counter-point Perspective by Erik Musiek and David Holtzman here.

Nat Neurosci. 2015 Jun;18(6):794-9. doi: 10.1038/nn.4017.

Go to the profile of Tim Spencer

Tim Spencer

Senior Editor, Nature Neuroscience

Tim Spencer received his PhD from the City University of New York, where he studied the signaling mechanisms which underlie the promotion of axonal growth and regeneration following injury in the laboratory of Marie Filbin. He then moved to the laboratory of Chris Henderson at Columbia University, where he examined molecular markers of postnatal motor neuron maturation and elements of neurodegenerative diseases such as ALS and SMA. His research interests include neuronal development and maturation, axonal guidance and models of neuronal disease and dysfunction. Tim joined the editorial team of Nature Neuroscience in March of 2011, where he handles many of the manuscripts on neural development and neurogenesis, neurodegeneration, neuroinflammation and neuroimmune interactions, myelination/remyelination, molecular and cellular pathways, and "brain cancer" (glioblastoma, etc.).


Go to the profile of Douglas F Watt
Douglas F Watt over 4 years ago

Let me just say that Drs. Herrup, Musiek and Holtzman have all done an excellent job in presenting the case against as well as for the amyloid hypothesis. These two papers represent two of the very best summaries for and against the amyloid hypothesis in the vast and sprawling literature on Alzheimer’s disease, and Nature Neuroscience should be commended for graciously provided these as open source. I recommend that interested parties (students, clinicians and researchers) read both papers thoroughly, as thoughtful treatments of this important problem of etiology.

Ultimately, while Musiek and Holtzman’s erudition and sophistication in repackaging and attempting to salvage the amyloid hypothesis is impressive, no one can adequately explain either the long-appreciated temporal and spatial disconnection between the two classic markers of plaques and tangles, or the equally large temporal and spatial disconnect between amyloid plaque and neurodegeneration and cognitive decline. This suggests that other primary cofactors in neurodegeneration must be in the mix. And ultimately, the linear ‘feedforward’ image in the amyloid cascade hypothesis – as pointed out by Dr. Herrup and admitted by Musiek and Holtzman – fails to square with the now enormous evidence that virtually every cellular phenotype of aging appears to contribute mechanistically to neurodegeneration (and to the other phenotypes!). This includes not simply declining autophagy and proteostasis (increasing junk protein and its clearance failure), but virtually every other cellular/molecular process that has been linked to aging and its diseases: mitochondrial dysfunction, declining genomic integrity and increasing genetic damage, increasing inflammation (termed ‘inflammaging’), oxidative stress, cellular senescence, the disordering of cell cycling and apoptosis, bioenergetic dysfunction and increasing insulin resistance. Not only are all of these processes involved in virtually all the diseases of aging, but they all have significant positive feedback in relationship to most of the other cellular phenotypes of aging. This suggests not an linear ‘amyloid cascade’ but rather a complex recursion between these intrinsic properties of aging organisms, where positive feedback between many if not most of these processes may first create and then progressively amplify the brain’s movement towards neurodegeneration, as a rut from which it cannot escape, ensuring ultimate brain failure.

The other basic problem with the amyloid hypothesis is that it fails completely to address the now large body evidence that neurodegeneration and cognitive decline is associated with increasing levels of CNS inflammation, and that increasing inflammation, increasing tangling, and deteriorating functioning all appear to be tightly conjoined. We already know that chronic inflammation in every other organ system – kidney, heart, liver, and lung to name four others – is inevitably associated with end-stage organ disease and inevitable organ failure. What makes us think that the brain is any different? When chronic inflammation fails to remove its source or trigger (clearly the case in AD, and where the triggers may extend beyond just amyloid deposition), the end result is inevitable organ failure.

If this forum provides impetus to both clinicians and researchers to rethink other targets beyond removing amyloid, particularly inflammation, mitochondrial dysfunction, bioenergetic dysfunction and insulin resistance, disordering of cell cycling and apoptosis, this hopefully will move us in the direction of much more multi-targeted treatment, and less reliance on monotherapy, based on the outdated concept of simple single factor causes for diseases of aging. 20+ years of theoretical dominance by the amyloid cascade hypothesis have yielded zero disease modifying therapies. It’s time to move on, and time to accept that this may be a disease without a single cause, but where all the phenotypes of aging may contribute and may be exacerbated and accelerated by their significant and mutual positive feedback. Given the impending tsunami of AD in the pipeline in Western societies, time is short. Improving and updating our theory is urgently needed to actually create a truly disease-modifying group of therapies, and where different stages will likely have different targets and treatments.