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


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.


  1. 1.
    Blennow K, de Leon MJ, Zetterberg H. (2006) Alzheimer’s disease. Lancet. 368:387–403.CrossRefGoogle Scholar
  2. 2.
    Selkoe DJ. (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol. Rev. 81:741–66.CrossRefGoogle Scholar
  3. 3.
    Marambaud P, Robakis NK. (2005) Genetic and molecular aspects of Alzheimer’s disease shed light on new mechanisms of transcriptional regulation. Genes Brain Behav. 4:134–46.CrossRefPubMedGoogle Scholar
  4. 4.
    Querfurth HW, LaFerla FM. (2010) Alzheimer’s disease. N. Engl. J. Med. 362:329–44.CrossRefPubMedGoogle Scholar
  5. 5.
    Lambert JC, Amouyel P. (2007) Genetic heterogeneity of Alzheimer’s disease: complexity and advances. Psychoneuroendocrinology. 32 Suppl 1: S62–70.CrossRefPubMedGoogle Scholar
  6. 6.
    Rademakers R, Rovelet-Lecrux A. (2009) Recent insights into the molecular genetics of dementia. Trends Neurosci. 32:451–61.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Lambert JC, et al. (2009) Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat. Genet. 41:1094–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Harold D, et al. (2009) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat. Genet. 41:1088–93.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE. (2007) Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat. Genet. 39:17–23.CrossRefPubMedGoogle Scholar
  10. 10.
    Hollingworth P, et al. (2011) Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat. Genet. 43:429–35.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Gomez-Isla T, et al. (1996) Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer’s disease. J. Neurosci. 16:4491–500.CrossRefPubMedGoogle Scholar
  12. 12.
    Hulette CM, et al. (1998) Neuropathological and neuropsychological changes in “normal” aging: evidence for preclinical Alzheimer disease in cognitively normal individuals. J. Neuropathol. Exp. Neurol. 57:1168–74.CrossRefPubMedGoogle Scholar
  13. 13.
    Markesbery WR, et al. (2006) Neuropathologic substrate of mild cognitive impairment. Arch. Neurol. 63:38–46.CrossRefPubMedGoogle Scholar
  14. 14.
    Morris JC, Price AL. (2001) Pathologic correlates of nondemented aging, mild cognitive impairment, and early-stage Alzheimer’s disease. J. Mol. Neurosci. 17:101–18.CrossRefPubMedGoogle Scholar
  15. 15.
    Price JL, et al. (2001) Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer disease. Arch. Neurol. 58:1395–402.CrossRefPubMedGoogle Scholar
  16. 16.
    Gottesman II, Gould TD. (2003) The endophenotype concept in psychiatry: etymology and strategic intentions. Am. J. Psychiatry. 160:636–45.CrossRefPubMedGoogle Scholar
  17. 17.
    Kauwe JS, et al. (2009) Alzheimer’s disease risk variants show association with cerebrospinal fluid amyloid beta. Neurogenetics. 10:13–7.CrossRefPubMedGoogle Scholar
  18. 18.
    De Meyer G, et al. (2010) Diagnosis-independent Alzheimer disease biomarker signature in cognitively normal elderly people. Arch. Neurol. 67:949–56.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Dubois B, et al. (2010) Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol. 9:1118–27.CrossRefPubMedGoogle Scholar
  20. 20.
    Galasko D, et al. (1998) High cerebrospinal fluid tau and low amyloid beta42 levels in the clinical diagnosis of Alzheimer disease and relation to apolipoprotein E genotype. Arch. Neurol. 55:937–45.CrossRefPubMedGoogle Scholar
  21. 21.
    Hampel H, et al. (2004) Value of CSF beta-amyloid1–42 and tau as predictors of Alzheimer’s disease in patients with mild cognitive impairment. Mol. Psychiatry. 9:705–10.CrossRefPubMedGoogle Scholar
  22. 22.
    Mehta PD, et al. (2000) Plasma and cerebrospinal fluid levels of amyloid beta proteins 1–40 and 1–42 in Alzheimer disease. Arch. Neurol. 57:100–5.CrossRefPubMedGoogle Scholar
  23. 23.
    Motter R, et al. (1995) Reduction of beta-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer’s disease. Ann. Neurol. 38:643–8.CrossRefPubMedGoogle Scholar
  24. 24.
    Sunderland T, et al. (2003) Decreased beta-amyloid1–42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer disease. JAMA. 289:2094–103.CrossRefPubMedGoogle Scholar
  25. 25.
    Mattsson N, et al. (2009) CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA. 302:385–93.CrossRefPubMedGoogle Scholar
  26. 26.
    Fagan AM, et al. (2006) Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Ann. Neurol. 59:512–9.CrossRefPubMedGoogle Scholar
  27. 27.
    Demuro A, Parker I, Stutzmann GE. (2010) Calcium signaling and amyloid toxicity in Alzheimer disease. J. Biol. Chem. 285:12463–8.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Marambaud P, Dreses-Werringloer U, Vingtdeux V. (2009) Calcium signaling in neurodegeneration. Mol. Neurodegener. 4:20.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Supnet C, Bezprozvanny I. (2010) The dysregulation of intracellular calcium in Alzheimer disease. Cell Calcium. 47:183–9.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Green KN, LaFerla FM. (2008) Linking calcium to Abeta and Alzheimer’s disease. Neuron. 59:190–4.CrossRefPubMedGoogle Scholar
  31. 31.
    Mattson MP. (2010) ER calcium and Alzheimer’s disease: in a state of flux. Sci. Signal. 3:pe10.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Foskett JK. (2010) Inositol trisphosphate receptor Ca2+ release channels in neurological diseases. Pflugers Arch. 460:481–94.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Dreses-Werringloer U, et al. (2008) A polymorphism in CALHM1 influences Ca2+ homeostasis, Abeta levels, and Alzheimer’s disease risk. Cell. 133:1149–61.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Moreno-Ortega AJ, Ruiz-Nuno A, Garcia AG, Cano-Abad MF. (2010) Mitochondria sense with different kinetics the calcium entering into HeLa cells through calcium channels CALHM1 and mutated P86L-CALHM1. Biochem. Biophys. Res. Commun. 391:722–6.CrossRefPubMedGoogle Scholar
  35. 35.
    Gallego-Sandin S, Alonso MT, Garcia-Sancho J. (2011) Calcium homeostasis modulator 1 (CALHM1) reduces the calcium content of the endoplasmic reticulum (ER) and triggers ER stress. Biochem. J. 437:469–75.CrossRefPubMedGoogle Scholar
  36. 36.
    Boada M, et al. (2010) CALHM1 P86L polymorphism is associated with late-onset Alzheimer’s disease in a recessive model. J. Alzheimers Dis. 20:247–51.CrossRefPubMedGoogle Scholar
  37. 37.
    Cui PJ, et al. (2010) CALHM1 P86L polymorphism is a risk factor for Alzheimer’s disease in the Chinese population. J. Alzheimers Dis. 19:31–5.CrossRefPubMedGoogle Scholar
  38. 38.
    Campagne F, et al. (2008) Response: CALHM1 Association with Alzheimer’s Disease Risk. Cell. 135:994–6.CrossRefGoogle Scholar
  39. 39.
    Bertram L, et al. (2008) No association between CALHM1 and Alzheimer’s disease risk. Cell. 135:993,4; author reply 994–6.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Minster RL, Demirci FY, DeKosky ST, Kamboh MI. (2009) No association between CALHM1 variation and risk of Alzheimer disease. Hum. Mutat. 30: E566–9.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Sleegers K, et al. (2009) No association between CALHM1 and risk for Alzheimer dementia in a Belgian population. Hum. Mutat. 30: E570–4.CrossRefPubMedGoogle Scholar
  42. 42.
    Beecham GW, Schnetz-Boutaud N, Haines JL, Pericak-Vance MA. (2009) CALHM1 polymorphism is not associated with late-onset Alzheimer disease. Ann. Hum. Genet. 73:379–81.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Nacmias B, et al. (2010) Lack of implication for CALHM1 P86L common variation in Italian patients with early and late onset Alzheimer’s disease. J. Alzheimers Dis. 20:37–41.CrossRefPubMedGoogle Scholar
  44. 44.
    Li H, et al. (2008) Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease. Arch. Neurol. 65:45–53.CrossRefPubMedGoogle Scholar
  45. 45.
    Lambert JC, et al. (2010) The CALHM1 P86L polymorphism is a genetic modifier of age at onset in Alzheimer’s disease: a meta-analysis study. J. Alzheimers Dis. 22:247–55.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Giedraitis V, et al. (2010) CALHM1 P86L polymorphism does not alter amyloid-beta or tau in cerebrospinal fluid. Neurosci. Lett. 469:265–7.CrossRefPubMedGoogle Scholar
  47. 47.
    Kauwe JS, et al. (2010) Validating predicted biological effects of Alzheimer’s disease associated SNPs using CSF biomarker levels. J. Alzheimers Dis. 21:833–42.PubMedPubMedCentralGoogle Scholar
  48. 48.
    McKhann G, et al. (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology. 34:939–44.CrossRefPubMedGoogle Scholar
  49. 49.
    Hixson JE, Vernier DT. (1990) Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J. Lipid Res. 31:545–8.PubMedGoogle Scholar
  50. 50.
    Ewers M, et al. (2011) Increased CSF-BACE1 activity associated with decreased hippocampus volume in Alzheimer’s disease. J. Alzheimers Dis. 25:373–81.CrossRefPubMedGoogle Scholar
  51. 51.
    Holsinger RM, McLean CA, Collins SJ, Masters CL, Evin G. (2004) Increased beta-Secretase activity in cerebrospinal fluid of Alzheimer’s disease subjects. Ann. Neurol. 55:898–9.CrossRefPubMedGoogle Scholar
  52. 52.
    Fagan AM, et al. (2007) Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. Arch. Neurol. 64:343–9.CrossRefPubMedGoogle Scholar
  53. 53.
    Kauwe JS, et al. (2007) Extreme cerebrospinal fluid amyloid beta levels identify family with late-onset Alzheimer’s disease presenilin 1 mutation. Ann. Neurol. 61:446–53.CrossRefPubMedGoogle Scholar
  54. 54.
    Han MR, Schellenberg GD, Wang LS, Alzheimer’s Disease Neuroimaging Initiative. (2010) Genome-wide association reveals genetic effects on human Abeta42 and tau protein levels in cerebrospinal fluids: a case control study. BMC Neurol. 10:90.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Prince JA, Zetterberg H, Andreasen N, Marcusson J, Blennow K. (2004) APOE epsilon4 allele is associated with reduced cerebrospinal fluid levels of Abeta42. Neurology. 62:2116–8.CrossRefPubMedGoogle Scholar
  56. 56.
    Sunderland T, et al. (2004) Cerebrospinal fluid beta-amyloid1–42 and tau in control subjects at risk for Alzheimer’s disease: the effect of APOE epsilon4 allele. Biol. Psychiatry. 56:670–6.CrossRefPubMedGoogle Scholar
  57. 57.
    Glodzik-Sobanska L, et al. (2009) The effects of normal aging and ApoE genotype on the levels of CSF biomarkers for Alzheimer’s disease. Neurobiol. Aging. 30:672–81.CrossRefPubMedGoogle Scholar
  58. 58.
    Vuletic S, et al. (2008) Apolipoprotein E highly correlates with AbetaPP- and tau-related markers in human cerebrospinal fluid. J. Alzheimers Dis. 15:409–17.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Miners JS, et al. (2008) Abeta-degrading enzymes in Alzheimer’s disease. Brain Pathol. 18:240–52.CrossRefPubMedGoogle Scholar
  60. 60.
    Kehoe PG, et al. (2003) Haplotypes extending across ACE are associated with Alzheimer’s disease. Hum. Mol. Genet. 12:859–67.CrossRefPubMedGoogle Scholar

Copyright information

© The Feinstein Institute for Medical Research 2011

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

Personalised recommendations