title: CALHM1 P86L polymorphism modulates CSF Aβ levels in cognitively healthy individuals at risk for Alzheimer's disease.
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.
authors.affiliation: Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Koppel
authors.forename: Fabien
authors.initials: F
authors.lastname: Campagne
authors.forename: Valérie
authors.initials: V
authors.lastname: Vingtdeux
authors.forename: Ute
authors.initials: U
authors.lastname: Dreses-Werringloer
authors.forename: Michael
authors.initials: M
authors.lastname: Ewers
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.forename: Harald
authors.initials: H
authors.lastname: Hampel
authors.forename: Marc L
authors.initials: ML
authors.lastname: Gordon
authors.forename: Erica
authors.initials: E
authors.lastname: Christen
authors.forename: Julien
authors.initials: J
authors.lastname: Chapuis
authors.forename: Blaine S
authors.initials: BS
authors.lastname: Greenwald
authors.forename: Peter
authors.initials: P
authors.lastname: Davies
authors.forename: Philippe
authors.initials: P
authors.lastname: Marambaud
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000235:genetics* / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000134:cerebrospinal fluid; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D001057:Apolipoproteins E / Q000235:genetics; D016282:Aspartic Acid Endopeptidases / Q000134:cerebrospinal fluid; D015415:Biomarkers / Q000134:cerebrospinal fluid; D015220:Calcium Channels / Q000235:genetics*; D003071:Cognition / Q000502:physiology; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D015415:Biomarkers; C530077:CALHM1 protein, human; D015220:Calcium Channels; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human