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A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

An Erratum to this article was published on 13 October 2017

This article has been updated

Key Points

  • An imbalance between the production and clearance of amyloid-β (Aβ) is an early, often initiating, factor in Alzheimer disease (AD)

  • Peripheral systems are suggested to be involved in Aβ production and clearance

  • The central and peripheral pathways of Aβ metabolism communicate with each other, and work synergistically to clear Aβ from the brain

  • Increasing experimental, epidemiologic and clinical evidence suggests that AD manifestations extend beyond the brain, and that AD pathogenesis is closely associated with systemic abnormalities

  • The systemic abnormalities in patients with AD might not be secondary to the cerebral degeneration; instead, they might reflect underlying disease processes

  • A systemic view of AD provides a novel perspective for understanding the role of Aβ in AD pathogenesis and offers opportunities for the development of new treatments and diagnostic biomarkers for AD

Abstract

Alzheimer disease (AD) is the most common type of dementia, and is currently incurable; existing treatments for AD produce only a modest amelioration of symptoms. Research into this disease has conventionally focused on the CNS. However, several peripheral and systemic abnormalities are now understood to be linked to AD, and our understanding of how these alterations contribute to AD is becoming more clearly defined. This Review focuses on amyloid-β (Aβ), a major hallmark of AD. We review emerging findings of associations between systemic abnormalities and Aβ metabolism, and describe how these associations might interact with or reflect on the central pathways of Aβ production and clearance. On the basis of these findings, we propose that these abnormal systemic changes might not only develop secondary to brain dysfunction but might also affect AD progression, suggesting that the interactions between the brain and the periphery have a crucial role in the development and progression of AD. Such a systemic view of the molecular pathogenesis of AD could provide a novel perspective for understanding this disease and present new opportunities for its early diagnosis and treatment.

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Figure 1: Physiological metabolism of Aβ in the brain and periphery.
Figure 2: Systemic abnormalities in AD.

Change history

  • 13 October 2017

    In the version of this article originally published online, Figure 1 incorrectly labelled the main Aβ molecule in the peripheral pool as Aβ42 instead of Aβ40. This error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

The authors' research work is supported by the National Natural Science Foundation of China (grants 81471296 and 81625007 to Y.-J.W., and grant 81600949 to J.W.), and the Chinese Ministry of Science and Technology (grant 2016YFC1306401 to Y.-J.W.). The authors thank Dr J. Piña-Crespo and Dr H. Xu at Sanford Burnham Prebys Medical Discovery Institute, USA, for critical reading of the paper.

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Wang, J., Gu, B., Masters, C. et al. A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain. Nat Rev Neurol 13, 612–623 (2017). https://doi.org/10.1038/nrneurol.2017.111

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