Impact of SORL1 Single Nucleotide Polymorphisms on Alzheimer's Disease Cerebrospinal Fluid Markers
ABSTRACT Recently, genetic variants of the neuronal sortilin-related receptor with A-type repeats (SORL1, also called LR11 or sorLA) have emerged as risk factors for the development of Alzheimer's disease (AD).
In this study, SORL1 gene polymorphisms, which have been shown to be related to AD, were analyzed for associations with cerebrospinal fluid (CSF) amyloid beta1-42 (Aβ(1-42)), phosphorylated tau181, and total tau levels in a non-Hispanic Caucasian sample, which encompassed 100 cognitively healthy elderly individuals, 166 patients with mild cognitive impairment, and 87 patients with probable AD. The data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (www.loni.ucla.edu/ADNI). Moreover, the impact of gene-gene interactions between SORL1 single nucleotide polymorphisms (SNPs) and the apolipoprotein E (APOE) ε4 allele, the major genetic risk factor for sporadic AD, on Aβ(1-42) concentrations was investigated.
Significant associations between CSF Aβ(1-42) levels and the SORL1 SNPs 23 (rs3824968) and 24 (rs2282649) were detected in the AD group. The latter association became marginally statistically insignificant after Bonferroni correction for multiple comparisons. Carriers of the SORL1 SNP24 T allele and the SNP23 A allele both had lower CSF Aβ(1-42) concentrations than non-carriers of these alleles. The analysis of the impact of interactions between APOE ε4 allele and SORL1 SNPs on CSF Aβ(1-42) levels unraveled significant influences of APOE.
Our findings provide further support for the notion that SORL1 genetic variants are related to AD pathology, probably by regulating the amyloid cascade.
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ABSTRACT: Mild Alzheimer's disease (AD) is usually difficult to differentiate from other dementias or mild cognitive impairment (MCI). The aim of our study is to evaluate the clinical importance of cerebrospinal fluid (CSF) β-amyloid 42 (Aβ42) in MCI, AD and other dementias, more specifically: frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), Parkinson's disease (PD) with dementia (PDD) and vascular dementia (VaD). Fifty eligible articles were identified by search of databases including PubMed, EMBASE, Elsevier, Springer Link and the Cochrane Library, from January 1990 to May 2014. The random effects model was used to calculate the standardized mean difference (SMD) with corresponding 95% CI by STATA 9.0 software. The subgroup analyses were made on the method (ELISA, xMAP). We found that CSF Aβ42 concentrations were significantly lower in AD compared to MCI (SMD: -0.68, 95% CI: [-0.80, -0.56], z=11.34, P<0.001), FTD (SMD: -1.09, 95% CI: [-1.41, -0.76], z=6.62, P<0.001), PDD (SMD: -0.75, 95% CI: [-1.39, -0.10], z=2.27, P=0.023), VaD (SMD: -0.95, 95% CI: [-1.30, -0.61], z=5.43, P<0.001). In addition, compared to DLB, Aβ42 concentrations are moderately lower in AD (SMD: -0.27, 95% CI: [-0.51, -0.03], z=2.20, P=0.028). Results from this meta-analysis hinted that CSF Aβ42 is a good biomarker for discriminating Alzheimer's disease from other dementias and MCI.Journal of the Neurological Sciences 07/2014; 345(1-2). DOI:10.1016/j.jns.2014.07.015 · 2.26 Impact Factor
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ABSTRACT: Methanol (MeOH) is considered to be a poison in humans because of the alcohol dehydrogenase (ADH)-mediated conversion of MeOH to formaldehyde (FA), which is toxic. Our recent genome-wide analysis of the mouse brain demonstrated that an increase in endogenous MeOH after ADH inhibition led to a significant increase in the plasma MeOH concentration and a modification of mRNA synthesis. These findings suggest endogenous MeOH involvement in homeostasis regulation by controlling mRNA levels. Here, we demonstrate directly that study volunteers displayed increasing concentrations of MeOH and FA in their blood plasma when consuming citrus pectin, ethanol and red wine. A microarray analysis of white blood cells (WBC) from volunteers after pectin intake showed various responses for 30 significantly differentially regulated mRNAs, most of which were somehow involved in the pathogenesis of Alzheimer's disease (AD). There was also a decreased synthesis of hemoglobin mRNA, HBA and HBB, the presence of which in WBC RNA was not a result of red blood cells contamination because erythrocyte-specific marker genes were not significantly expressed. A qRT-PCR analysis of volunteer WBCs after pectin and red wine intake confirmed the complicated relationship between the plasma MeOH content and the mRNA accumulation of both genes that were previously identified, namely, GAPDH and SNX27, and genes revealed in this study, including MME, SORL1, DDIT4, HBA and HBB. We hypothesized that human plasma MeOH has an impact on the WBC mRNA levels of genes involved in cell signaling.PLoS ONE 07/2014; 9(7):e102837. DOI:10.1371/journal.pone.0102837 · 3.53 Impact Factor
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ABSTRACT: The amyloid cascade hypothesis posits that deposition of the amyloid β (Aβ) peptide in the brain is a key event in the initiation of Alzheimer's disease (AD). Nonetheless, it now seems increasingly unlikely that amyloid toxicity is the cause of sporadic AD, which leads to cognitive decline. Here, using accelerated-senescence nontransgenic OXYS rats, we confirmed that aggregation of Aβ is a later event in AD-like pathology. We showed that an age-dependent increase in the levels of Aβ1-42 and extracellular Aβ deposits in the brain of OXYS rats occur later than do synaptic losses, neuronal cell death, mitochondrial structural abnormalities, and hyperphosphorylation of the tau protein. We identified the variants of the genes that are strongly associated with the risk of either late-onset or early-onset AD, including App, Apoe4, Bace1, Psen1, Psen2, and Picalm. We found that in OXYS rats nonsynonymous SNPs were located only in the genes Casp3 and Sorl1. Thus, we present proof that OXYS rats may be a model of sporadic AD. It is possible that multiple age-associated pathological processes may precede the toxic amyloid accumulation, which in turn triggers the final stage of the sporadic form of AD and becomes a hallmark event of the disease.Oncotarget 12/2014; · 6.63 Impact Factor