CALHM1 P861 Polymorphism Modulates CSF Aβ Levels in Cognitively Healthy Individuals at Risk for Alzheimer's Disease

The calcium homeostasis modulator 1 (CALHM1) gene codes for a novel cerebral calcium channel controlling intracellular calcium homeostasis and amyloid-beta (A beta) 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 A beta accumulation in vitro in cell lines. Recently, it was reported that CALHM1 P86L also may influence A beta metabolism in vivo by increasing A beta 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 A beta 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 A levels in AD patients. Our data, however, revealed a significant association of CALHM1 P86L with elevated CSF A beta 42 and A beta 40 in the normal cohort at risk for AD. This work shows that CALHM1 modulates CSF A beta 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. (C) 2011 The Feinstein Institute for Medical Research, www.feinsteininstitute.org Online address: http://www.molmed.org doi: 10.2119/molmed.2011.00154