Impact of SORL1 Single Nucleotide Polymorphisms on Alzheimer's Disease Cerebrospinal Fluid Markers

Article (PDF Available)inDementia and Geriatric Cognitive Disorders 32(3):164-70 · December 2011with14 Reads
DOI: 10.1159/000332017 · Source: PubMed
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 ( 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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Available from: Panagiotis Alexopoulos, Jun 08, 2015
    • "Refined clinical analyses document association of individual SNPs with distinct neuropathological features including deposition of senile plaques (SNP#8) and fibrillary tangles (SNP#10, rs11218343) [9, 25], and with loss of gray matter volume (SNP#23) [39] and hippocampal atrophy (SNP#21-26) [20] . SNPs in the 3′ haplotype block are associated with pathological alterations of AD biomarkers in cerebrospinal fluid (CSF), such as Aβ and tau [2, 24, 31, 47, 55], whereas SNP#8 [6], SNP#19 [75], and rs11218343 [64] predict longitudinal cognitive change. Interestingly, SNP#19 appears to have a gender bias impacting cognitive decline stronger in females than in males [75]. "
    [Show abstract] [Hide abstract] ABSTRACT: Alzheimer's disease (AD) represents one of the most dramatic threats to healthy aging and devising effective treatments for this devastating condition remains a major challenge in biomedical research. Much has been learned about the molecular concepts that govern proteolytic processing of the amyloid precursor protein to amyloid-β peptides (Aβ), and how accelerated accumulation of neurotoxic Aβ peptides underlies neuronal cell death in rare familial but also common sporadic forms of this disease. Out of a plethora of proposed modulators of amyloidogenic processing, one protein emerged as a key factor in AD pathology, a neuronal sorting receptor termed SORLA. Independent approaches using human genetics, clinical pathology, or exploratory studies in animal models all converge on this receptor that is now considered a central player in AD-related processes by many. This review will provide a comprehensive overview of the evidence implicating SORLA-mediated protein sorting in neurodegenerative processes, and how receptor gene variants in the human population impair functional receptor expression in sporadic but possibly also in autosomal-dominant forms of AD.
    Full-text · Article · Sep 2016
    • "When we evaluated the SNPs in the univariate models, the intronic SNP rs11218343 in SORL1 was modestly associated with higher CSF levels of tau and ptau, although the result did not sustain the correction for multiple testing. In MCI, SORL1 variants have earlier been found to be associated with (p)tau levels in CSF [49]. However, for our exploratory per-SNP analysis, our sample seems to be underpowered to detect associations between the individual genetic risk variants and the AD endophenotypes. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: We evaluated the effect of Alzheimer's disease (AD) susceptibility loci on endophenotypes closely related with AD pathology in patients with mild cognitive impairment (MCI). Methods: We selected 1730 MCI patients from four independent data sets. Weighted polygenic risk scores (PGS) were constructed of 18 non-APOE AD risk variants. In addition, we determined APOE genotype. AD endophenotypes were cognitive decline over time and cerebrospinal fluid (CSF) biomarkers (aβ, tau, ptau). Results: PGS was modestly associated with cognitive decline over time, as measured by mini-mental state examination (MMSE) (β ± SE:-0.24 ± 0.10; P = .012), and with CSF levels of tau and ptau (tau: 1.38 ± 0.36, P = 1.21 × 10(-4); ptau: 1.40 ± 0.36, P = 1.02 × 10(-4)). Conclusions: In MCI, we observed a joint effect of AD susceptibility loci on nonamyloid endophenotypes, suggesting a link of these genetic loci with neuronal degeneration in general rather than with Alzheimer-related amyloid deposition.
    Full-text · Article · Feb 2016
    • "Moreover, several mutations of the SorLA gene have been associated with AD (Rogaeva et al., 2007; Alexopoulos et al., 2011; Caglayan et al., 2014). Based on the critical phenotype previously observed in APP YG/YG mice, which resulted in premature aging and cognitive and learning deficits (Matrone et al., 2011Matrone et al., , 2012), and the potential role of SorLA as a predictive factor of neurodegeneration in AD patients (Rogaeva et al., 2007; Alexopoulos et al., 2011; Caglayan et al., 2014 ), we believe that these results strongly underscore the relevance of the correct APP binding to adaptor proteins, via Y 682 ENPTY 687 domain, as a future potential strategy to prevent neurodegeneration in vivo. "
    [Show abstract] [Hide abstract] ABSTRACT: The intracellular transport and localization of amyloid precursor protein (APP) are critical determinants of APP processing and β-amyloid peptide production, thus crucially important for the pathophysiology of Alzheimer’s disease (AD). Notably, the C-terminal Y682ENPTY687 domain of APP binds to specific adaptors controlling APP trafficking and sorting in neurons. Mutation on the Y682 residue to glycine (Y682G) leads to altered APP sorting in hippocampal neurons that favors its accumulation in intracellular compartments and the release of soluble APPα. Such alterations induce premature aging and learning and cognitive deficits in APP Y682G mutant mice (APPYG/YG). Here, we report that Y682G mutation affects formation of the APP complex with sortilin-related receptor (SorLA), resulting in endo-lysosomal dysfunctions and neuronal degeneration. Moreover, disruption of the APP/SorLA complex changes the trafficking pathway of SorLA, with its consequent increase in secretion outside neurons. Mutations in the SorLA gene are a prognostic factor in AD, and increases in SorLA levels in cerebrospinal fluid are predictive of AD in humans. These results might open new possibilities in comprehending the role played by SorLA in its interaction with APP and in the progression of neuronal degeneration. In addition, they further underline the crucial role played by Y682 residue in controlling APP trafficking in neurons.
    Full-text · Article · Mar 2015
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