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NEURODEGENERATION

An Alzheimer’s-disease-protective APOE mutation

Nature Medicine volume 25, pages 1648–1649 (2019)Cite this article

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Homozygous APOE3-Christchurch (R136S) mutation protects a presenilin 1 (PSEN1) mutation carrier from developing Alzheimer’s disease until her seventies.

The world’s largest known family of individuals with ADAD, the Colombian PSEN1-E280A mutation carriers, comprises over 1,200 patients2. Like other PSEN1 mutations, the PSEN1-E280A mutation increases Aβ production, leading to amyloid accumulation in the brain. In this kindred, although there is some variability in age of onset and disease progression, both male and female carriers of the mutation have a remarkably fast and consistent disease course, developing mild cognitive impairment and dementia at the median ages of 44 (95% CI, 43–45) and 49 (95% CI, 49–50) years, respectively3. Identification of gene variants capable of protecting PSEN1-E280A mutation carriers from developing early-onset ADAD is of fundamental importance for better understanding AD pathogenesis and for developing strategies to treat or prevent AD. In this issue, Arboleda-Velasquez et al. report the identification of a homozygous APOE mutation, APOE3-Christchurch (R136S), that conferred strong protection against the development of ADAD in a PSEN1-E280A carrier (Fig. 1, right)4, opening a promising new avenue in AD research and therapeutics.

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Fig. 1: Effects of APOE3-R136S on Aβ and tau pathologies, neurodegeneration and cognition in PSEN1 mutation carriers, with potential underlying mechanisms.

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Authors and Affiliations

  1. Gladstone Institute of Neurological Disease, San Francisco, CA, USA

    Kelly A. Zalocusky, Maxine R. Nelson & Yadong Huang

  2. Department of Neurology, University of California, San Francisco, San Francisco, CA, USA

    Kelly A. Zalocusky & Yadong Huang

  3. Biomedical Sciences Program, University of California, San Francisco, San Francisco, CA, USA

    Maxine R. Nelson & Yadong Huang

Authors
  1. Kelly A. Zalocusky
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  2. Maxine R. Nelson
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  3. Yadong Huang
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Correspondence to Yadong Huang.

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Competing interests

Y. H. is a cofounder and scientific advisory board member of E-Scape Bio, Inc. and GABAeron, Inc. The other authors declare no competing financial interests.

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Zalocusky, K.A., Nelson, M.R. & Huang, Y. An Alzheimer’s-disease-protective APOE mutation. Nat Med 25, 1648–1649 (2019). https://doi.org/10.1038/s41591-019-0634-9

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