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.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the presence of senile plaques in different brain regions of the neocortex and hippocampus [1,2]
The apolipoprotein E (APOE) ε4 allele has been found to predict in some [55,56], but not all studies [57,58], changes in cerebrospinal fluid (CSF) Aβ concentrations in non-demented individuals, potentially as an early marker of evolving disease. Another example is the gene coding for angiotensin-converting enzyme (ACE), a protease involved in Aβ degradation [59], for which a haplotype associated with an increased risk of AD has been reported in association with elevated levels of CSF Aβ [60]
An association was observed between the calcium homeostasis modulator 1 (CALHM1) P86L polymorphism and elevated levels of CSF Aβ42 and Aβ40 in a small sample of young, cognitively healthy individuals with a positive family history for AD
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the presence of senile plaques in different brain regions of the neocortex and hippocampus [1,2]. There is clear evidence that genetic variation strongly influences the risk of developing sporadic AD, the only robust and unequivocally identified AD risk factor is the ε4 allele of the apolipoprotein E (APOE) gene [5,6]. Meta-analyses and genome-wide association studies, have revealed recently that multiple independent loci show significant association with AD risk, indicating that other genes are involved in the disease etiology [7,8,9,10]. Future interventions may be targeted to those at increased risk, before clinical symptoms are manifested. The use of protein biomarkers from cerebrospinal fluid (CSF) as quantitative endophenotypes may be a helpful tool for identifying individuals at risk for AD and for providing an unparalleled opportunity to increase the power
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