Validating Predicted Biological Effects of Alzheimer's Disease Associated SNPs Using CSF Biomarker Levels

Department of Biology, Brigham Young University, Provo, UT, USA.
Journal of Alzheimer's disease: JAD (Impact Factor: 4.15). 01/2010; 21(3):833-42. DOI: 10.3233/JAD-2010-091711
Source: PubMed


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.

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Available from: Petra Nowotny, Oct 01, 2015
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    • "nfluence of specific SORL1 alleles on CSF biomarkers in AD patients had conflicting results . Three studies revealed an influence of SORL1 SNP alleles on abeta in CSF ( Alexopoulos et al . , 2011 ; Guo et al . , 2012 ; Kolsch et al . , 2008 ) , whereas another study did not find any relationship between SORL1 SNP variants and abeta levels in CSF ( Kauwe et al . , 2010 ) . A study with ADNI AD patients reported a significant association between rs668387 , rs3824968 , rs1010159 , and lower abeta level in CSF ( Alexopoulos et al . , 2011 ) . Our separate analyses of the ADNI data set led to similar results , with an association between the rs3824968 - A allele and rs1010159 - G allele and lower levels o"
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    ABSTRACT: We studied the association of SORL1 single-nucleotide polymorphisms genotypes with measures of pathology in patients with probable Alzheimer's disease (AD) using an endophenotype approach. We included (1) 133 patients from the German Dementia Competence Network (71 ± 8 years; 50% females; Mini Mental State Examination [MMSE], 24 ± 3); (2) 83 patients from the Alzheimer's Disease Neuroimaging Initiative (75 ± 8 years; 45% females; MMSE, 24 ± 2); and (3) 452 patients from the Amsterdam Dementia Cohort 66 ± 8 years; 47% females; MMSE, 20 ± 5). As endophenotype markers we used cognitive tests, cerebrospinal fluid (CSF) biomarkers amyloid-beta, total tau (tau), tau phosphorylated at threonine 181, and hippocampal atrophy. We measured 19 SORL1 SNP alleles. Genotype-endophenotype associations were determined by linear regression analyses. There was an association between rs2070045-G allele and increased CSF-tau and more hippocampal atrophy. Additionally, haplotype-based analyses revealed an association between haplotype rs11218340-A/rs3824966-G/rs3824968-A and higher CSF-tau and CSF-tau phosphorylated at threonine 181. In conclusion, we found that SORL1 SNP rs2070045-G allele was related to CSF-tau and hippocampal atrophy, 2 endophenotype markers of AD, suggesting that SORL1 may be implicated in the downstream pathology in AD. Copyright © 2015 Elsevier Inc. All rights reserved.
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    • "Furthermore, significant interactions of ApoE4 with SORL1 single nucleotide polymorphisms on Aí µí»½42 cerebrospinal fluid (CSF) indicated the role that SORL1 genetic variants can have in regulating the amyloidogenic pathway [72]. Other methods have examined the relationship between small-nucleotide polymorphism loci in protein phosphatase B and calcium homeostasis modulator 1 (CALHM1), respectively , with AD quantitative biomarkers such as p-tau and Aí µí»½42 CSF or genome-wide association study with MRI brain structure degeneration localized in temporal, parietal, and hippocampal regions [73] [74] [75] [76] [77]. Histopathological aromatic dyes staining using Thioflavin S but especially Congo red is the gold standard for diagnosing amyloid plaques because it only binds aggregated í µí»½sheets [78] [79], and postmortem clinical diagnosis is still regarded as the gold standard for definitive diagnostic of AD. "
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