Article

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: 3.61). 01/2010; 21(3):833-42. DOI: 10.3233/JAD-2010-091711
Source: PubMed

ABSTRACT 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.

Full-text

Available from: Petra Nowotny, Jun 11, 2015
0 Followers
 · 
137 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: One of the most important neurodegenerative diseases of our time is Alzheimer's disease, which mainly affects the elderly population. The accumulation of β-amyloid and tau protein in the brain tissue is the most characteristic pathomechanical event of the disease, later causing neuronal cell death. Setting up an accurate diagnosis of Alzheimer's disease has essentially changed recently, since besides psychometry, neurochemical and neuroimaging examinations are also gaining greater importance in the clinical routine. Thanks to the widening of diagnostic methods, in the future the disease could be recognised even during the preclinical phase. The most remarkable source of brain-derived compounds is the cerebrospinal fluid. Although obtaining cerebrospinal fluid is greatly unpleasant, it poses a low risk and is frequently used as part of the diagnostic procedure. The assay of cerebrospinal fluid means the identification of the level of β-amyloid(1-42), tau and phospho-tau and their ratio, but to get more specific and sensitive investigations there is intensive research work both on the utility of their combination and on finding even more specific biomarkers. This review gives a summary of the biomarkers that are being used and being researched for the diagnostic tests of both familial and sporadic forms of Alzheimer's disease. Other notable sources of neurochemical compounds are the serum and the plasma, however, the identification of their biomarkers is under preclinical examinations. Unfortunately neither the validation of these markers nor the consistent acceptance of the experimental results is possible due to the wide range of protocols in international research. The importance of biomarkers in the development of potential drug candidates is also discussed.
    Neuropsychopharmacologia Hungarica: a Magyar Pszichofarmakológiai Egyesület lapja = official journal of the Hungarian Association of Psychopharmacology 09/2012; 14(3):165-76.
  • Source
    [Show abstract] [Hide abstract]
    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.
    Neurobiology of Aging 12/2014; 36(3). DOI:10.1016/j.neurobiolaging.2014.12.007 · 4.85 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: CALHM1 is a plasma membrane voltage-gated Ca2+-permeable ion channel that controls amyloid-β (Aβ) metabolism and is potentially involved in the onset of Alzheimer's disease (AD). Recently, Rubio-Moscardo et al. (PLoS One (2013) 8: e74203) reported the identification of two CALHM1 variants, G330D and R154H, in early-onset AD (EOAD) patients. The authors provided evidence that these two human variants were rare and resulted in a complete loss of CALHM1 function. Recent publicly available large-scale exome sequencing data confirmed that R154H is a rare CALHM1 variant (minor allele frequency (MAF) = 0.015%), but that G330D is not (MAF = 3.5% in an African American cohort). Here, we show that both CALHM1 variants exhibited gating and permeation properties indistinguishable from wild-type CALHM1 when expressed in Xenopus oocytes. While there was also no effect of the G330D mutation on Ca2+ uptake by CALHM1 in transfected mammalian cells, the R154H mutation was associated with defects in the control by CALHM1 of both Ca2+ uptake and Aβ levels in this cell system. Together, our data show that the frequent CALHM1 G330D variant has no obvious functional consequences and is therefore unlikely to contribute to EOAD. Our data also demonstrate that the rare R154H variant interferes with CALHM1 control of cytosolic Ca2+ and Aβ accumulation. While these results strengthen the notion that CALHM1 influences Aβ metabolism, further investigation will be required to determine whether CALHM1 R154H, or other natural variants in CALHM1, is/are associated with EOAD.
    PLoS ONE 11/2014; 9(11):e112484. DOI:10.1371/journal.pone.0112484 · 3.53 Impact Factor