Interestingly, the power of our case-control study was sufficiently large to detect an odds ratio (OR) of 2 or larger, as reported by Cruchaga et al.3. Since the association reported by Cruchaga et ...al.3 was mainly for late-onset Alzheimer's disease and was stronger in cases with a positive family history3, we stratified our samples according to: (1) age at onset (that is, #65 or .65 years); and (2) family history (defined as the presence of at least one self-reported dementia case in the family). Notably, our findings do not concur with those of the accompanying paper by van der Lee et al.13 who reported a significant association for p.Val232Met in their meta-analysis of six independent samples (1,914 non-familial Alzheimer's disease patients and 8,021controls).
Recent large-scale genetic studies of late-onset Alzheimer's disease have identified risk variants in CALHM1, GAB2, and SORL1. The mechanisms by which these genes might modulate risk are not ...definitively known. CALHM1 and SORL1 may alter amyloid-β (Aβ) levels and GAB2 may influence phosphorylation of the tau protein. In this study we have analyzed disease associated genetic variants in each of these genes for association with cerebrospinal fluid (CSF) Aβ or tau levels in 602 samples from two independent CSF series. We failed to detect association between CSF Aβ42 levels and single nucleotide polymorphisms in SORL1 despite substantial statistical power to detect association. While we also failed to detect association between variants in GAB2 and CSF tau levels, power to detect this association was limited. Finally, our data suggest that the minor allele of rs2986017, in CALHM1, is marginally associated with CSF Aβ42 levels. This association is consistent with previous reports that this non-synonymous coding substitution results in increased Aβ levels in vitro and provides support for an Aβ-related mechanism for modulating risk for Alzheimer's disease.
