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Molecular Medicine

, Volume 17, Issue 9–10, pp 974–979 | Cite as

CALHM1 P86L Polymorphism Modulates CSF Aβ Levels in Cognitively Healthy Individuals at Risk for Alzheimer’s Disease

  • Jeremy Koppel
  • Fabien Campagne
  • Valérie Vingtdeux
  • Ute Dreses-Werringloer
  • Michael Ewers
  • Dan Rujescu
  • Harald Hampel
  • Marc L. Gordon
  • Erica Christen
  • Julien Chapuis
  • Blaine S. Greenwald
  • Peter Davies
  • Philippe Marambaud
Research Article

Abstract

The calcium homeostasis modulator 1 (CALHM1) gene codes for a novel cerebral calcium channel controlling Intracellular calcium homeostasis and amyloid-β (Aβ) peptide metabolism, a key event in the etiology of Alzheimer’s disease (AD). The P86L polymorphism in CALHM1 (rs2986017) initially was proposed to impair CALHM1 functionally and to lead to an increase in Aβ accumulation in vitro in cell lines. Recently, it was reported that CALHM1 P86L also may influence Aβ metabolism in vivo by increasing Aβ levels in human cerebrospinal fluid (CSF). Although the role of CALHM1 in AD risk remains uncertain, concordant data have now emerged showing that CALHM1 P86L is associated with an earlier age at onset of AD. Here, we have analyzed the association of CALHM1 P86L with CSF Aβ in samples from 203 AD cases and 46 young cognitively healthy individuals with a positive family history of AD. We failed to detect an association between the CALHM1 polymorphism and CSF Aβ levels in AD patients. Our data, however, revealed a significant association of CALHM1 P86L with elevated CSF Aβ42 and Aβ40 in the normal cohort at risk for AD. This work shows that CALHM1 modulates CSF Aβ levels in presymptomatic individuals, strengthening the notion that CALHM1 is involved in AD pathogenesis. These data further demonstrate the utility of endophenotype-based approaches focusing on CSF biomarkers for the identification or validation of risk factors for AD.

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Copyright information

© The Feinstein Institute for Medical Research 2011
www.feinsteininstitute.org

Authors and Affiliations

  • Jeremy Koppel
    • 1
  • Fabien Campagne
    • 2
  • Valérie Vingtdeux
    • 1
  • Ute Dreses-Werringloer
    • 1
  • Michael Ewers
    • 3
    • 4
  • Dan Rujescu
    • 5
  • Harald Hampel
    • 6
  • Marc L. Gordon
    • 1
  • Erica Christen
    • 1
  • Julien Chapuis
    • 1
  • Blaine S. Greenwald
    • 7
  • Peter Davies
    • 1
    • 8
  • Philippe Marambaud
    • 1
    • 8
  1. 1.Litwin-Zucker Research Center for the Study of Alzheimer’s DiseaseThe Feinstein Institute for Medical ResearchManhassetUSA
  2. 2.Department of Physiology and Biophysics and Institute for Computational BiomedicineWeill Medical College of Cornell UniversityNew YorkUSA
  3. 3.Department of RadiologyUniversity of San FranciscoSan FranciscoUSA
  4. 4.Veterans Administration Medical CenterSan FranciscoUSA
  5. 5.Department of PsychiatryLudwig-Maximilian UniversityMunichGermany
  6. 6.Department of Psychiatry, Psychosomatic Medicine, and PsychotherapyUniversity of FrankfurtFrankfurtGermany
  7. 7.Division of Geriatric PsychiatryThe Zucker Hillside Hospital, North Shore-LIJGlen OaksUSA
  8. 8.Department of PathologyAlbert Einstein College of MedicineBronxUSA

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