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The amyloid cascade is not the only pathway to AD

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

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In my original News & Views article (Alzheimer disease: Aβ-independent processes—rethinking preclinical AD. Nat. Rev. Neurol. 9, 123–124; 2013),1 I discussed contradictions between the conclusion made by Knopman et al.2—namely, that the initial appearance of brain-injury biomarkers in preclinical Alzheimer disease (AD) may not depend on β-amyloidosis—and the current dominant view of the sequence of biomarkers in AD. Following a letter from V. Y. Vishnu (Can tauopathy shake the amyloid cascade hypothesis? Nat. Rev. Neurol. doi:10.1038/nrneurol.2013.21-c1)3 in which he mentions a paper by Jack et al.4 that revisits the biomarker model, I would like to make some comments and clarifications.

Jack et al.4 insist on the distinction between the neuropathological processes and the biomarkers, which I agree is important. Knopman et al.2 suggest that, from a neuroimaging-based-biomarker perspective, neurodegeneration can appear before amyloid-β (Aβ) deposition. However, these biomarkers represent only the visible part of the AD 'iceberg'; inferences regarding the 'immersed' part (that is, the physiopathological mechanisms) should be made cautiously. Such inferences are supported by autopsy studies,5 leading Jack and colleagues4 to propose a model in which tauopathy is the first pathophysiological process in AD. However, Jack et al.4 consider that, on neuroimaging, Aβ deposition is always visible before tau-mediated neuronal injury. I argue for a more flexible scenario in which tau-related injury can appear before Aβ, even at the biomarker level.

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References

  1. Chételat, G. Alzheimer disease: Aβ-independent processes—rethinking preclinical AD. Nat. Rev. Neurol. 9, 123–124 (2013).

    Article  Google Scholar 

  2. Knopman, D. S. et al. Neuronal injury biomarkers are not dependent on β-amyloid in normal elderly. Ann. Neurol. http://dx.doi.org/10.1002/ana.23816.

  3. Vishnu, V. Y. Can tauopathy shake the amyloid cascade hypothesis? Nat. Rev. Neurol. http://dx.doi.org/10.1038/nrneurol.2013.21-c1.

  4. Jack, C. R. Jr et al. Tracking the pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 12, 207–216 (2013).

    Article  CAS  Google Scholar 

  5. Braak, H. & Braak, E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol. Aging 18, 351–357 (1997).

    Article  CAS  Google Scholar 

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  1. INSERM, U1077, CHU Avenue de la Côte de Nacre, CS 30001, Caen Cedex 9, 14033, France

    Gaël Chételat

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  1. Gaël Chételat
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Chételat, G. The amyloid cascade is not the only pathway to AD. Nat Rev Neurol 9, 356 (2013). https://doi.org/10.1038/nrneurol.2013.21-c2

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