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Variation at APOE and STH loci and Alzheimer's disease
Lingjun Zuo, Christopher H van Dyck, Xingguang Luo, Henry R Kranzler, Bao-zhu Yang, Joel Gelernter
Behavioral and Brain Functions , 2006, DOI: 10.1186/1744-9081-2-13
Abstract: The functional polymorphisms, rs429358 and rs7412, in the APOE gene (which together define the ε2, ε3, and ε4 alleles), and the Q7R SNP in the STH gene, were genotyped in 369 patients with AD and 289 healthy European-Americans. The associations between these two genes and AD were analyzed in a case-control design.Consistent with previously reported results, the frequencies of the APOE ε4 allele, ε4/ε4 genotype and ε3/ε4 genotype were significantly higher in AD cases than controls; the ε4/ε4 genotype frequency was significantly higher in early-onset AD (EOAD) than late-onset AD (LOAD); the frequencies of the ε2 allele, ε3 allele, ε3/ε3 genotype and ε2/ε3 genotype were significantly lower in AD cases than controls. Positive likelihood ratios (LRs+) of APOE alleles and genotypes increased in a linear trend with the number of ε4 alleles and decreased in a linear trend with the number of ε2 or ε3 alleles. There was no significant difference in the STH allele and genotype frequency distributions between AD cases and controls.This study confirmed that the ε4 allele is a dose-response risk factor for AD and the ε4/ε4 genotype was associated with a significantly earlier age of onset. Moreover, we found that the ε2 allele was a dose-response protective factor for AD and the ε3 allele exerted a weaker dose-response protective effect for risk of AD compared with ε2. In a clinical setting, APOE genotyping could offer additional biological evidence of whether a subject may develop AD, but it is not robust enough to serve as an independent screening or predictive test in the diagnosis of AD. STH variation was not significantly associated with AD in our sample.Alzheimer's disease (AD) is the most common cause of dementia. It is a primary neurodegenerative cerebral disease in the elderly, characterized by two major histopathologic changes in the brain, i.e., extracellular amyloid plaques and intracellular neurofibrillary tangles [1,2].Apolipoprotein E (APOE) is one of the major chol
Screening and Evaluation of Deleterious SNPs in APOE Gene of Alzheimer’s Disease  [PDF]
Tariq Ahmad Masoodi,Sulaiman A. Al Shammari,May N. Al-Muammar,Adel A. Alhamdan
Neurology Research International , 2012, DOI: 10.1155/2012/480609
Abstract: Introduction. Apolipoprotein E (APOE) is an important risk factor for Alzheimer’s disease (AD) and is present in 30–50% of patients who develop late-onset AD. Several single-nucleotide polymorphisms (SNPs) are present in APOE gene which act as the biomarkers for exploring the genetic basis of this disease. The objective of this study is to identify deleterious nsSNPs associated with APOE gene. Methods. The SNPs were retrieved from dbSNP. Using I-Mutant, protein stability change was calculated. The potentially functional nonsynonymous (ns) SNPs and their effect on protein was predicted by PolyPhen and SIFT, respectively. FASTSNP was used for functional analysis and estimation of risk score. The functional impact on the APOE protein was evaluated by using Swiss PDB viewer and NOMAD-Ref server. Results. Six nsSNPs were found to be least stable by I-Mutant 2.0 with DDG value of >?1.0. Four nsSNPs showed a highly deleterious tolerance index score of 0.00. Nine nsSNPs were found to be probably damaging with position-specific independent counts (PSICs) score of ≥2.0. Seven nsSNPs were found to be highly polymorphic with a risk score of 3-4. The total energies and root-mean-square deviation (RMSD) values were higher for three mutant-type structures compared to the native modeled structure. Conclusion. We concluded that three nsSNPs, namely, rs11542041, rs11542040, and rs11542034, to be potentially functional polymorphic. 1. Introduction Alzheimer’s disease, the most common form of dementia in the elderly currently, affects more than five million people in the USA alone. Four leading genes (APP, PS1, PS2, and APOE) have been determined, as causative elements of this disorder. It has been seen that the mutations in APP, PS1, and PS2 cause early onset AD while APOE is the only gene that has been always marked as a risk factor for late-onset disease [1–3]. APOE is broadly considered as a crucial agent for AD and is present in 30–50% of patients who develop late-onset AD [4]. It is a circulating 34-kDa secretory protein, synthesized primarily in the liver, and functions in the periphery as a mediator of lipoprotein metabolism through the binding of APOE-containing plasma lipoprotein particles to members of the low-density lipoprotein (LDL) superfamily of receptors. Within the central nervous system (CNS), APOE is synthesized and secreted primarily by astrocytes and microglia, and its importance is underscored by the absence of most other plasma apolipoproteins in brain [5]. Additionally, brain apoE is believed to play a role in the redistribution of lipid and
Genetic Cross-Interaction between APOE and PRNP in Sporadic Alzheimer's and Creutzfeldt-Jakob Diseases  [PDF]
Olga Calero, María J. Bullido, Jordi Clarimón, Ana Frank-García, Pablo Martínez-Martín, Alberto Lleó, María Jesús Rey, Alberto Rábano, Rafael Blesa, Teresa Gómez-Isla, Fernando Valdivieso, Jesús de Pedro-Cuesta, Isidro Ferrer, Miguel Calero
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0022090
Abstract: Alzheimer's disease (AD) and Creutzfeldt-Jakob disease (CJD) represent two distinct clinical entities belonging to a wider group, generically named as conformational disorders that share common pathophysiologic mechanisms. It is well-established that the APOE ε4 allele and homozygosity at polymorphic codon 129 in the PRNP gene are the major genetic risk factors for AD and human prion diseases, respectively. However, the roles of PRNP in AD, and APOE in CJD are controversial. In this work, we investigated for the first time, APOE and PRNP genotypes simultaneously in 474 AD and 175 sporadic CJD (sCJD) patients compared to a common control population of 335 subjects. Differences in genotype distribution between patients and control subjects were studied by logistic regression analysis using age and gender as covariates. The effect size of risk association and synergy factors were calculated using the logistic odds ratio estimates. Our data confirmed that the presence of APOE ε4 allele is associated with a higher risk of developing AD, while homozygosity at PRNP gene constitutes a risk for sCJD. Opposite, we found no association for PRNP with AD, nor for APOE with sCJD. Interestingly, when AD and sCJD patients were stratified according to their respective main risk genes (APOE for AD, and PRNP for sCJD), we found statistically significant associations for the other gene in those strata at higher previous risk. Synergy factor analysis showed a synergistic age-dependent interaction between APOE and PRNP in both AD (SF = 3.59, p = 0.027), and sCJD (SF = 7.26, p = 0.005). We propose that this statistical epistasis can partially explain divergent data from different association studies. Moreover, these results suggest that the genetic interaction between APOE and PRNP may have a biological correlate that is indicative of shared neurodegenerative pathways involved in AD and sCJD.
Influência genética sobre a doen?a de Alzheimer de início tardio
Barros, Alessandra Chiele;Lucatelli, Juliana Faggion;Maluf, Sharbel Weidner;Andrade, Fabiana Michelsen de;
Revista de Psiquiatria Clínica , 2009, DOI: 10.1590/S0101-60832009000100003
Abstract: background: late onset alzheimer's disease (load) represents the majority of cases of alzheimer's disease. objectives: to review relevant results to candidate and susceptibility genes related to load. methods: bibliographic review, starting from 1990, utilizing pubmed and scielo data banks. results: genetic polymorphisms are more relevant for load than mutations, and e*4 allele of apoe gene is the major risk factor known until now. neverthless, other genes are being investigated and data are available about the relation with load to the genes coding for apolipoprotein ci, antichymotrypsin, sigma receptor type 1, angiotensin converting enzyme, alfa 2-macroglobulin, ldl receptor related protein, interleucin 1 alfa and beta, paraoxonase, serotonin transporter and serotonin receptors. conclusions: load presents multifactorial etiology, and a broad number of genetic markers interferes with its development. they should be further pursued in the brazilian population, in which ethnic background is distinct from north-american and european populations. only with this data, a determination of the genetic risk profile will be feasible, and will improve the detection of the individuals at greater probability of developing the disease.
Neuropsychiatric Symptoms, Endophenotypes, and Syndromes in Late-Onset Alzheimer's Disease: Focus on APOE Gene  [PDF]
Francesco Panza,Davide Seripa,Grazia D'Onofrio,Vincenza Frisardi,Vincenzo Solfrizzi,Patrizia Mecocci,Alberto Pilotto
International Journal of Alzheimer's Disease , 2011, DOI: 10.4061/2011/721457
Abstract: Neuropsychiatric symptoms, previously denominated as behavioural and psychological symptoms of dementia, are common features of Alzheimer's disease (AD) and are one of the major risk factors for institutionalization. At present, the role of the apolipoprotein E (APOE) gene in the development of neuropsychiatric symptoms in AD patients is unclear. In this paper, we summarized the findings of the studies of neuropsychiatric symptoms and neuropsychiatric syndromes/endophenotypes in AD in relation to APOE genotypes, with special attention to the possible underlying mechanisms. While some studies failed to find a significant association between APOE and neuropsychiatric symptoms in late-onset AD, other studies reported a significant association between the APOE ε4 allele and an increase in agitation/aggression, hallucinations, delusions, and late-life depression or anxiety. Furthermore, some negative studies that focused on the distribution of APOE genotypes between AD patients with or without neuropsychiatric symptoms further emphasized the importance of subgrouping neuropsychiatric symptoms in distinct neuropsychiatric syndromes. Explanations for the variable findings in the existing studies included differences in patient populations, differences in the assessment of neuropsychiatric symptomatology, and possible lack of statistical power to detect associations in the negative studies. 1. Introduction Dementia and age-related cognitive disorders are reaching epidemic proportions, given the significant increase in the aging population. Alzheimer’s disease (AD), the most prevalent form of dementia [1], is a complex brain disorder that has effects on multiple cerebral systems, and characterized by relatively slow but progressive neurodegeneration and impairment in cognition, behavior, and functionality. Accurate AD epidemiological data have been recently released for the USA. The 2010 figures suggested that 5.3 million Americans have AD [2], with >26 million patients with AD worldwide, and an expected increase to more than 106 million by 2050 [3]. Neuropsychiatric symptoms, previously denominated as behavioral and psychological symptoms of dementia, are common features of AD [4, 5] and are one of the major risk factors for institutionalization [6] as well as for increasing costs both in USA and Western countries [7, 8]. Neuropsychiatric symptoms in AD include psychosis (delusions and hallucinations) as well as affective and behavioral changes such as depressive mood, anxiety, irritability/lability, apathy, euphoria, disinhibition, agitation/aggression,
KIAA1462, A Coronary Artery Disease Associated Gene, Is a Candidate Gene for Late Onset Alzheimer Disease in APOE Carriers  [PDF]
Deborah G. Murdock, Yuki Bradford, Nathalie Schnetz-Boutaud, Ping Mayo, Melissa J. Allen, Laura N. D’Aoust, Xueying Liang, Sabrina L. Mitchell, Stephan Zuchner, Gary W. Small, John R. Gilbert, Margaret A. Pericak-Vance, Jonathan L. Haines
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0082194
Abstract: Alzheimer disease (AD) is a devastating neurodegenerative disease affecting more than five million Americans. In this study, we have used updated genetic linkage data from chromosome 10 in combination with expression data from serial analysis of gene expression to choose a new set of thirteen candidate genes for genetic analysis in late onset Alzheimer disease (LOAD). Results in this study identify the KIAA1462 locus as a candidate locus for LOAD in APOE4 carriers. Two genes exist at this locus, KIAA1462, a gene associated with coronary artery disease, and “rokimi”, encoding an untranslated spliced RNA The genetic architecture at this locus suggests that the gene product important in this association is either “rokimi”, or a different isoform of KIAA1462 than the isoform that is important in cardiovascular disease. Expression data suggests that isoform f of KIAA1462 is a more attractive candidate for association with LOAD in APOE4 carriers than “rokimi” which had no detectable expression in brain.
Is MTHFR polymorphism a risk factor for Alzheimer's disease like APOE?
Fernandez, Liana Lisboa;Scheibe, Rosane Machado;
Arquivos de Neuro-Psiquiatria , 2005, DOI: 10.1590/S0004-282X2005000100001
Abstract: background: the role of methylenetetrahydrofolate reductase (mthfr) gene polymorphisms as risk factors for the occurence of alzheimer's disease (ad) is still controversial: objective: to verify the association between mthfr and apolipoprotein e (apoe) polymorphisms and alzheimer's disease. method: this work was conducted as a case-control study. cases included thirty patients with probable ad. controls were constituted by 29 individuals without dementia according to neuropsychological tests paired to age, sex, race and educational level. dna was isolated from peripheral leukocytes of anticoagulated venous blood. genotyping of apoe and mthfr were performed by dna amplification and digestion. the frequences of apoe and mthfr genotypes were submitted by chi-square test corrected by fisher test; the apoe genotypes, to chi-square linear tendency test and the frequences of mthfr mutant and ad, by stratificated anlysis adjust by mantel-haenszel method. results: there was significant difference about apoe4 and apoe2 in the groups. (p=0.002) the odds ratio increased exponentially with the increased number of e4 allele (c2 linear tendency test). no significant difference was detected on mthfr genotypes in both case and control groups. conclusion: the apoe4 is a risk factor and demonstrated a dose-depenent effect while apoe2 allele conferred a protection to ad. the mthfr mutation had no correlation with ad.
Novel action of apolipoprotein E (ApoE): ApoE isoform specifically inhibits lipid-particle-mediated cholesterol release from neurons
Jian-Sheng Gong, Shin-ya Morita, Mariko Kobayashi, Tetsurou Handa, Shinobu C Fujita, Katsuhiko Yanagisawa, Makoto Michikawa
Molecular Neurodegeneration , 2007, DOI: 10.1186/1750-1326-2-9
Abstract: Here we show that apoE3-HDL induced a marked cholesterol release from neurons, while apoE4-HDL induced little. To elucidate the mechanism underlying this phenomenon, we used a complex of lipid emulsion (EM) with recombinant apoE3 or apoE4 (apoE-EM) at various apoE concentrations. When a small number of apoE molecules were associated with EM, apoE3- and apoE4-EM, induced a marked cholesterol release to a level similar to that induced by EM alone. However, when apoE at given concentrations was incubated with EM, apoE3-EM induced a marked cholesterol release, while apoE4-EM induced little. Under these conditions, a greater number of apoE4 molecules were associated with EM than apoE3 molecules. When an increasing number of apoE molecules were associated with EM, both apoE3-EM and apoE4-EM induced little cholesterol release. Preincubation with β-mercaptoethanol increased the number of apoE3 molecules associated with EM similar to that of apoE4 molecules, indicating that the presence (apoE3) or absence (apoE4) of intermolecular disulfide bond formation is responsible for the association of a greater number of apoE4 molecules to EM than apoE3 molecules.These results suggest that although apoE and a lipid particle are lipid acceptors, when apoE and a lipid particle form a complex, apoE on the particle surface inhibits the lipid particle-mediated cholesterol release from cells in an apoE-concentration-dependent manner.It has been shown that the prevalence of Alzheimer's disease (AD) is associated with the polymorphisms of genes related to cholesterol metabolism, including apolipoprotein E (apoE)[1], ATP-binding cassette transporter A1 (ABCA1) [2], and CYP46, the gene encoding cholesterol 24-hydroxylase [3,4]. However, before discussing the association of altered cholesterol metabolism with AD pathogenesis, one should delineate mutual interaction between cholesterol metabolism in the circulation and that in the central nervous system across the blood-brain barrier, and also d
The COMT Val158 Met polymorphism as an associated risk factor for Alzheimer disease and mild cognitive impairment in APOE 4 carriers
Manuel Martínez, Xabier Martín, Luís Alcelay, Jessica Flores, Juan Valiente, Bego?a Juanbeltz, María Beldarraín, Josefa López, María Gonzalez-Fernández, Ana Salazar, Rocio Gandarias, Sandra Borda, Nuria Marqués, Miryam Amillano, María Zabaleta, Marian M de Pancorbo
BMC Neuroscience , 2009, DOI: 10.1186/1471-2202-10-125
Abstract: A total of 223 MCI patients, 345 AD and 253 healthy controls were analyzed. Clinical criteria and neuropsychological tests were used to establish diagnostic groups.The DNA Bank of the University of the Basque Country (UPV-EHU) (Spain) determined COMT Val158 Met and APOE genotypes using real time polymerase chain reaction (rtPCR) and polymerase chain reaction (PCR), and restriction fragment length polymorphism (RFLPs), respectively. Multinomial logistic regression models were used to determine the risk of AD and MCI.Neither COMT alleles nor genotypes were independent risk factors for AD or MCI. The high activity genotypes (GG and AG) showed a synergistic effect with APOE ε4 allele, increasing the risk of AD (OR = 5.96, 95%CI 2.74-12.94, p < 0.001 and OR = 6.71, 95%CI 3.36-13.41, p < 0.001 respectivily). In AD patients this effect was greater in women.In MCI patients such as synergistic effect was only found between AG and APOE ε4 allele (OR = 3.21 95%CI 1.56-6.63, p = 0.02) and was greater in men (OR = 5.88 95%CI 1.69-20.42, p < 0.01).COMT (Val158 Met) polymorphism is not an independent risk factor for AD or MCI, but shows a synergistic effect with APOE ε4 allele that proves greater in women with AD.Genetic, metabolic and environmental factors play a role in Alzheimer's disease (AD). The APOE ε4 allele is the strongest genetic risk factor for sporadic forms of AD [1]. However, the APOE gene explains only a fraction of the genetic risk associated with AD, and it is possible that other genes or metabolic factors may modify the APOE ε4 effect to initiate the pathogenesis of AD. One of these candidate genes is the COMT (Catechol-O methyltransferase) gene [2].COMT is located on chromosome 22. It has 6 exons, spans 27 kb and encodes a protein of 271 amino acids. There is a single functional nucleotide polymorphism (SNP) on exon 4 of the COMT gene: rs4680. This SNP is characterised by low allele A activity (ATG/methionine) and a (high activity) allele G (GTG/valine) in codo
Genetic Loci Associated with Alzheimer’s Disease and Cerebrospinal Fluid Biomarkers in a Finnish Case-Control Cohort  [PDF]
Lyzel S. Elias-Sonnenschein, Seppo Helisalmi, Teemu Natunen, Anette Hall, Teemu Paajanen, Sanna-Kaisa Herukka, Marjo Laitinen, Anne M. Remes, Anne M. Koivisto, Kari M. Mattila, Terho Lehtim?ki, Frans R. J. Verhey, Pieter Jelle Visser, Hilkka Soininen, Mikko Hiltunen
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0059676
Abstract: Objectives To understand the relation between risk genes for Alzheimer’s disease (AD) and their influence on biomarkers for AD, we examined the association of AD in the Finnish cohort with single nucleotide polymorphisms (SNPs) from top AlzGene loci, genome-wide association studies (GWAS), and candidate gene studies; and tested the correlation between these SNPs and AD markers Aβ1–42, total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF). Methods We tested 25 SNPs for genetic association with clinical AD in our cohort comprised of 890 AD patients and 701-age matched healthy controls using logistic regression. For the correlational study with biomarkers, we tested 36 SNPs in a subset of 222 AD patients with available CSF using mixed models. Statistical analyses were adjusted for age, gender and APOE status. False discovery rate for multiple testing was applied. All participants were from academic hospital and research institutions in Finland. Results APOE-ε4, CLU rs11136000, and MS4A4A rs2304933 correlated with significantly decreased Aβ1–42 (corrected p<0.05). At an uncorrected p<0.05, PPP3R1 rs1868402 and MAPT rs2435211 were related with increased t-tau; while SORL1 rs73595277 and MAPT rs16940758, with increased p-tau. Only TOMM40 rs2075650 showed association with clinical AD after adjusting for APOE-ε4 (p = 0.007), but not after multiple test correction (p>0.05). Conclusions We provide evidence that APOE-ε4, CLU and MS4A4A, which have been identified in GWAS to be associated with AD, also significantly reduced CSF Aβ1–42 in AD. None of the other AlzGene and GWAS loci showed significant effects on CSF tau. The effects of other SNPs on CSF biomarkers and clinical AD diagnosis did not reach statistical significance. Our findings suggest that APOE-ε4, CLU and MS4A4A influence both AD risk and CSF Aβ1–42.
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