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

Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. panos.alexopoulos @
Dementia and Geriatric Cognitive Disorders (Impact Factor: 3.55). 12/2011; 32(3):164-70. 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
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    • "The APOE ε4 allele shows strong and replicable association with cerebrospinal fluid Aβ42 and tau levels in several studies. Significant associations between variants in CLU, MS4A4A, and SORL1 and cerebrospinal Aβ42 levels [91, 150] and between variants in CLU, PICALM, and CR1 and cerebrospinal tau levels have been reported [148, 151, 152]. The recent success of these approaches to both characterize newly discovered AD risk variants and identify novel risk variants suggests that the use of endophenotypes is an important part of the ongoing effort to solve the genetic architecture of AD. "
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    ABSTRACT: Alzheimer's disease is the most common form of dementia and is the only top 10 cause of death in the United States that lacks disease-altering treatments. It is a complex disorder with environmental and genetic components. There are two major types of Alzheimer's disease, early onset and the more common late onset. The genetics of early-onset Alzheimer's disease are largely understood with variants in three different genes leading to disease. In contrast, while several common alleles associated with late-onset Alzheimer's disease, including APOE, have been identified using association studies, the genetics of late-onset Alzheimer's disease are not fully understood. Here we review the known genetics of early- and late-onset Alzheimer's disease.
    07/2013; 2013(5054):254954. DOI:10.1155/2013/254954
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    • "SORL1, a neuronal sorting receptor gene on chromosome 11, was found to be genetically associated with LOAD in multiple sample sets [5]. There have been recent reports that SORL1 variants might influence not only the expression of this gene [11] [12] [13] but also the CSF A␤ 42 level in LOAD patients [14] [15] [16]. SORL1 knockout mice carrying both the PSEN1 (exon 9 deletion) and APP (Swedish, K595M/N596L) pathogenic mutations exhibited increased production and accumulation of A␤ [17]. "
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    ABSTRACT: SORL1 was shown to be genetically associated with late-onset Alzheimer's disease (LOAD) in a large-scale genome-wide association study (GWAS) involving clinically verified subjects. Here, we attempted to replicate the association of SORL1 in Japanese neuropathologically characterized brain donor subjects (LOAD, 213; control, 370) through a single-nucleotide polymorphism (SNP)-based genetic study involving 19 SNPs: 11 SNPs were selected from the initial study reported by Rogaeva et al. (2007), and the other eight were from our GWAS. Among these SNPs, five exhibited a significant association with LOAD after multiple test correction (p < 2.63E-03 [ = 0.05/19]), which was supported by means of multiple logistic regression analysis with adjustment for age, gender, and carrier status of the APOE ε4 allele. Three of these SNPs (rs985421, rs12364988 [Rogaeva's SNP 7], and rs4598682) were encompassed by a 5' linkage disequilibrium (LD) region, and the remaining two (rs3781834 and rs3781836) by a 3' LD region. Strong LD among SNPs was observed within each LD region, implying that there are two genomic regions showing association with LOAD in SORL1. Case-control haplotype analysis demonstrated that some haplotypes are associated with LOAD in both LD regions. Our replication study strongly supports the preceding evidence that SORL1 is likely one of the genes associated with LOAD.
    Journal of Alzheimer's disease: JAD 03/2013; 35(2). DOI:10.3233/JAD-122395 · 4.15 Impact Factor
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    • "Expression of ApoE4 gene with smallnucleotide polymorphism could synergistically interact with at least PICALM and, thus providing insight into their own mechanism of regulation, and serve as a diagnostic tool to predict the development of AD in nondement subjects [70] [71]. 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]. "
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    ABSTRACT: Sporadic Alzheimer's disease (AD) is an emerging chronic illness characterized by a progressive pleiotropic pathophysiological mode of actions triggered during the senescence process and affecting the elderly worldwide. The complex molecular mechanisms of AD not only are supported by cholinergic, beta-amyloid, and tau theories but also have a genetic basis that accounts for the difference in symptomatology processes activation among human population which will evolve into divergent neuropathological features underlying cognitive and behaviour alterations. Distinct immune system tolerance could also influence divergent responses among AD patients treated by immunotherapy. The complexity in nature increases when taken together the genetic/immune tolerance with the patient's brain reserve and with neuropathological evolution from early till advance AD clinical stages. The most promising diagnostic strategies in today's world would consist in performing high diagnostic accuracy of combined modality imaging technologies using beta-amyloid 42 peptide-cerebrospinal fluid (CSF) positron emission tomography (PET), Pittsburgh compound B-PET, fluorodeoxyglucose-PET, total and phosphorylated tau-CSF, and volumetric magnetic resonance imaging hippocampus biomarkers for criteria evaluation and validation. Early diagnosis is the challenge task that needs to look first at plausible mechanisms of actions behind therapies, and combining them would allow for the development of efficient AD treatment in a near future.
    The Scientific World Journal 02/2013; 2013(1):589308. DOI:10.1155/2013/589308 · 1.73 Impact Factor
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