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Serial blood and mucosal samples were characterized for 102 participants enrolled a median of 7.0 days after coronavirus disease 2019 diagnosis. Mucosal RNA was detectable for a median of 31.5 (95% confidence interval [CI], 20.5-63.5) days, with persistence ≥1 month associated with obesity (body mass index [BMI] ≥30 kg/m2; odds ratio [OR], 3.9 [95% CI, 1.2-13.8]) but not age, sex, or chronic conditions. Fifteen participants had likely reinfection; lower serum anti-spike IgG levels were associated with reinfection risk. Nearly half of participants (47%) reported symptoms lasting ≥2-3 months; persistence ≥3 months was associated with BMI ≥30 kg/m2 (OR, 4.2 [95% CI, 1.1-12.8]) and peak anti-spike and anti-nucleocapsid antibody levels.
Assuntos
Anticorpos Antivirais , COVID-19 , RNA Viral , SARS-CoV-2 , Humanos , COVID-19/imunologia , COVID-19/diagnóstico , Masculino , Feminino , SARS-CoV-2/imunologia , Pessoa de Meia-Idade , RNA Viral/sangue , Adulto , Anticorpos Antivirais/sangue , Idoso , Imunoglobulina G/sangue , Reinfecção/imunologia , Reinfecção/virologiaRESUMO
BACKGROUND: Accurate diagnosis of Alzheimer disease (AD) involving less invasive molecular procedures and at reasonable cost is an unmet medical need. We identified a serum miRNA signature for AD that is less invasive than a measure in cerebrospinal fluid. METHODS: From the Oxford Project to Investigate Memory and Aging (OPTIMA) study, 96 serum samples were profiled by a multiplex (>500 analytes) microRNA (miRNA) reverse transcription quantitative PCR analysis, including 51 controls, 32 samples from patients with AD, and 13 samples from patients with mild cognitive impairment (MCI). Clinical diagnosis of a subset of AD and the controls was confirmed by postmortem (PM) histologic examination of brain tissue. In a machine learning approach, the AD and control samples were split 70:30 as the training and test cohorts. A multivariate random forest statistical analysis was applied to construct and test a miRNA signature for AD identification. In addition, the MCI participants were included in the test cohort to assess whether the signature can identify early AD patients. RESULTS: A 12-miRNA signature for AD identification was constructed in the training cohort, demonstrating 76.0% accuracy in the independent test cohort with 90.0% sensitivity and 66.7% specificity. The signature, however, was not able to identify MCI participants. With a subset of AD and control participants with PM-confirmed diagnosis status, a separate 12-miRNA signature was constructed. Although sample size was limited, the PM-confirmed signature demonstrated improved accuracy of 85.7%, largely owing to improved specificity of 80.0% with comparable sensitivity of 88.9%. CONCLUSION: Although additional and more diverse cohorts are needed for further clinical validation of the robustness, the miRNA signature appears to be a promising blood test to diagnose AD.
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Doença de Alzheimer , Encéfalo , MicroRNA Circulante/sangue , Disfunção Cognitiva , Perfilação da Expressão Gênica/métodos , Aprendizado de Máquina , Idoso , Doença de Alzheimer/sangue , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Doença de Alzheimer/mortalidade , Autopsia/métodos , Encéfalo/metabolismo , Encéfalo/patologia , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/genética , Diagnóstico Precoce , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , TranscriptomaRESUMO
Low homocysteine levels and B vitamin treatment are reported to protect against declining cognitive health. Both B vitamins and homocysteine are involved in the production of S-adenosylmethionine, a universal methyl donor essential for the process of DNA methylation. We investigated the effect of a damaging coding variant within the DNA methyltransferase gene DNMT3L (R278G, A/G) by examining B vitamin intake, homocysteine levels, cognitive performance, and brain atrophy in individuals in the VITACOG study of mild cognitive impairment and the TwinsUK cohort. In the VITACOG study, individuals who received a 2-year treatment of B vitamins and carried the G allele showed better "visuospatial associative memory" and slower rates of brain atrophy. In the TwinsUK study, improved "visuospatial associative memory" was evident in individuals who reported regular vitamin intake and were A/A homozygotes. In silico modeling indicated that R278G disrupts protein interaction between DNMT3L and DNMT3A, affecting the DNMT3A-3L-H3 complex required for DNA methylation. These findings show that vitamin intake and genetic variation within DNMT3L interact to influence cognitive decline.
Assuntos
Disfunção Cognitiva/etiologia , Disfunção Cognitiva/genética , DNA (Citosina-5-)-Metiltransferases/genética , Metilação de DNA/genética , Complexo Vitamínico B/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Atrofia , Encéfalo/patologia , Cognição , Disfunção Cognitiva/prevenção & controle , Disfunção Cognitiva/psicologia , Feminino , Homocisteína/efeitos adversos , Homocisteína/metabolismo , Humanos , Masculino , S-Adenosilmetionina/metabolismo , Memória EspacialRESUMO
Pre-synaptic secretion of brain-derived neurotrophic factor (BDNF) from noradrenergic neurons may protect the Alzheimer's disease (AD) brain from amyloid pathology. While the BDNF polymorphism (rs6265) is associated with faster cognitive decline and increased hippocampal atrophy, a replicable genetic association of BDNF with AD risk has yet to be demonstrated. This could be due to masking by underlying epistatic interactions between BDNF and other loci that encode proteins involved in moderating BDNF secretion (DBH and Sortilin). We performed a multi-cohort case-control association study of the BDNF, DBH, and SORT1 loci comprising 5,682 controls and 2,454 AD patients from Northern Europe (87% of samples) and Spain (13%). The BDNF locus was associated with increased AD risk (odds ratios; ORâ=â1.1-1.2, pâ=â0.005-0.3), an effect size that was consistent in the Northern European (ORâ=â1.1-1.2, pâ=â0.002-0.8) but not the smaller Spanish (ORâ=â0.8-1.6, pâ=â0.4-1.0) subset. A synergistic interaction between BDNF and sex (synergy factor; SFâ=â1.3-1.5 pâ=â0.002-0.02) translated to a greater risk of AD associated with BDNF in women (ORâ=â1.2-1.3, pâ=â0.007-0.00008) than men (ORâ=â0.9-1.0, pâ=â0.3-0.6). While the DBH polymorphism (rs1611115) was also associated with increased AD risk (ORâ=â1.1, pâ=â0.04) the synergistic interaction (SFâ=â2.2, pâ=â0.007) between BDNF (rs6265) and DBH (rs1611115) contributed greater AD risk than either gene alone, an effect that was greater in women (SFâ=â2.4, pâ=â0.04) than men (SFâ=â2.0, pâ=â0.2). These data support a complex genetic interaction at loci encoding proteins implicated in the DBH-BDNF inflammatory pathway that modifies AD risk, particularly in women.
Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Doença de Alzheimer/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Dopamina beta-Hidroxilase/genética , Epistasia Genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Loci Gênicos , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Fatores SexuaisRESUMO
Cerebral amyloid angiopathy (CAA) is of increasing clinical and research interest as the ability to detect it and its consequences by neuroimaging in living subjects has advanced. There is also increasing interest in understanding its possible role in the development of intracerebral hemorrhage, Alzheimer's disease (AD) and vascular dementia. In this article, the literature on this subject is reviewed and novel findings relating CAA to subcortical white matter damage in 224 subjects in the Oxford project to Investigate Memory and Ageing (OPTIMA) are reported. The relationship between CAA and subcortical tissue damage in the OPTIMA subjects was found to be critically dependent on ApoE genotype, there being a positive relationship between measures of CAA and subcortical small vessel disease in ApoEε4 carriers and a significant negative relationship in ApoEε2 carriers. These findings draw attention, as have many other studies, to the importance of ApoE genotype as a major risk factor not only for dementia but also for damage to blood vessels in the aging brain.
Assuntos
Encéfalo/patologia , Angiopatia Amiloide Cerebral/patologia , Demência/genética , Demência/patologia , Leucoencefalopatias/patologia , Idoso , Idoso de 80 Anos ou mais , Animais , Apolipoproteínas E/genética , Angiopatia Amiloide Cerebral/complicações , Angiopatia Amiloide Cerebral/epidemiologia , Angiopatia Amiloide Cerebral/genética , Demência/complicações , Demência/epidemiologia , Demência/terapia , Feminino , Humanos , Leucoencefalopatias/genética , Estudos Longitudinais , MasculinoRESUMO
Previous mass spectrometry analysis of cerebrospinal fluid (CSF) has allowed the identification of a panel of molecular markers that are associated with Alzheimer's disease (AD). The panel comprises Amyloid beta, Apolipoprotein E, Fibrinogen alpha chain precursor, Keratin type I cytoskeletal 9, Serum albumin precursor, SPARC-like 1 protein and Tetranectin. Here we report the development and implementation of immunoassays to measure the abundance and diagnostic capacity of these putative biomarkers in matched lumbar CSF and blood plasma samples taken in life from individuals confirmed at post-mortem as suffering from AD (n = 10) and from screened 'cognitively healthy' subjects (n = 18). The inflammatory components of Alzheimer's disease were also investigated. Employment of supervised learning techniques permitted examination of the interrelated expression patterns of the putative biomarkers and identified inflammatory components, resulting in biomarker panels with a diagnostic accuracy of 87.5% and 86.7% for the plasma and CSF datasets respectively. This is extremely important as it offers an ideal high-throughput and relatively inexpensive population screening approach. It appears possible to determine the presence or absence of AD based on our biomarker panel and it seems likely that a cheap and rapid blood test for AD is feasible.
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Epistasis between interleukin-10 (IL10) and aromatase gene polymorphisms has previously been reported to modify the risk of Alzheimer's disease (AD). However, although the main effects of aromatase variants suggest a sex-specific effect in AD, there has been insufficient power to detect sex-specific epistasis between these genes to date. Here we used the cohort of 1757 AD patients and 6294 controls in the Epistasis Project. We replicated the previously reported main effects of aromatase polymorphisms in AD risk in women, for example, adjusted odds ratio of disease for rs1065778 GG=1.22 (95% confidence interval: 1.01-1.48, P=0.03). We also confirmed a reported epistatic interaction between IL10 rs1800896 and aromatase (CYP19A1) rs1062033, again only in women: adjusted synergy factor=1.94 (1.16-3.25, 0.01). Aromatase, a rate-limiting enzyme in the synthesis of estrogens, is expressed in AD-relevant brain regions ,and is downregulated during the disease. IL-10 is an anti-inflammatory cytokine. Given that estrogens have neuroprotective and anti-inflammatory activities and regulate microglial cytokine production, epistasis is biologically plausible. Diminishing serum estrogen in postmenopausal women, coupled with suboptimal brain estrogen synthesis, may contribute to the inflammatory state, that is a pathological hallmark of AD.
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Doença de Alzheimer/genética , Aromatase/genética , Interleucina-10/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/enzimologia , Estudos de Casos e Controles , Epistasia Genética , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único , Risco , Caracteres SexuaisRESUMO
Despite recent discoveries in the genetics of sporadic Alzheimer's disease, there remains substantial "hidden heritability." It is thought that some of this missing heritability may be because of gene-gene, i.e., epistatic, interactions. We examined potential epistasis between 110 candidate polymorphisms in 1757 cases of Alzheimer's disease and 6294 control subjects of the Epistasis Project, divided between a discovery and a replication dataset. We found an epistatic interaction, between rs7483 in GSTM3 and rs1111875 in the HHEX/IDE/KIF11 gene cluster, with a closely similar, significant result in both datasets. The synergy factor (SF) in the combined dataset was 1.79, 95% confidence interval [CI], 1.35-2.36; p = 0.00004. Consistent interaction was also found in 7 out of the 8 additional subsets that we examined post hoc: i.e., it was shown in both North Europe and North Spain, in both men and women, in both those with and without the ε4 allele of apolipoprotein E, and in people older than 75 years (SF, 2.27; 95% CI, 1.60-3.20; p < 0.00001), but not in those younger than 75 years (SF, 1.06; 95% CI, 0.59-1.91; p = 0.84). The association with Alzheimer's disease was purely epistatic with neither polymorphism showing an independent effect: odds ratio, 1.0; p ≥ 0.7. Indeed, each factor was associated with protection in the absence of the other factor, but with risk in its presence. In conclusion, this epistatic interaction showed a high degree of consistency when stratifying by sex, the ε4 allele of apolipoprotein E genotype, and geographic region.
Assuntos
Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Glutationa Transferase/genética , Proteínas de Homeodomínio/genética , Insulisina/genética , Cinesinas/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Transcrição/genética , Idoso , Idoso de 80 Anos ou mais , Mapeamento Cromossômico , Epistasia Genética/genética , Europa (Continente)/epidemiologia , Feminino , Loci Gênicos/genética , Marcadores Genéticos/genética , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Testes Genéticos/estatística & dados numéricos , Humanos , Masculino , Prevalência , Fatores de RiscoRESUMO
OBJECTIVE: Neuroinflammation contributes to the pathogenesis of sporadic Alzheimer's disease (AD). Variations in genes relevant to inflammation may be candidate genes for AD risk. Whole-genome association studies have identified relevant new and known genes. Their combined effects do not explain 100% of the risk, genetic interactions may contribute. We investigated whether genes involved in inflammation, i.e. PPAR-α, interleukins (IL) IL- 1α, IL-1ß, IL-6, and IL-10 may interact to increase AD risk. METHODS: The Epistasis Project identifies interactions that affect the risk of AD. Genotyping of single nucleotide polymorphisms (SNPs) in PPARA, IL1A, IL1B, IL6 and IL10 was performed. Possible associations were analyzed by fitting logistic regression models with AD as outcome, controlling for centre, age, sex and presence of apolipoprotein ε4 allele (APOEε4). Adjusted synergy factors were derived from interaction terms (p<0.05 two-sided). RESULTS: We observed four significant interactions between different SNPs in PPARA and in interleukins IL1A, IL1B, IL10 that may affect AD risk. There were no significant interactions between PPARA and IL6. CONCLUSIONS: In addition to an association of the PPARA L162V polymorphism with the AD risk, we observed four significant interactions between SNPs in PPARA and SNPs in IL1A, IL1B and IL10 affecting AD risk. We prove that gene-gene interactions explain part of the heritability of AD and are to be considered when assessing the genetic risk. Necessary replications will require between 1450 and 2950 of both cases and controls, depending on the prevalence of the SNP, to have 80% power to detect the observed synergy factors.
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Iron overload may contribute to the risk of Alzheimer's disease (AD). In the Epistasis Project, with 1757 cases of AD and 6295 controls, we studied 4 variants in 2 genes of iron metabolism: hemochromatosis (HFE) C282Y and H63D, and transferrin (TF) C2 and -2G/A. We replicated the reported interaction between HFE 282Y and TF C2 in the risk of AD: synergy factor, 1.75 (95% confidence interval, 1.1-2.8, p = 0.02) in Northern Europeans. The synergy factor was 3.1 (1.4-6.9; 0.007) in subjects with the APOEε4 allele. We found another interaction, between HFE 63HH and TF -2AA, markedly modified by age. Both interactions were found mainly or only in Northern Europeans. The interaction between HFE 282Y and TF C2 has now been replicated twice, in altogether 2313 cases of AD and 7065 controls, and has also been associated with increased iron load. We therefore suggest that iron overload may be a causative factor in the development of AD. Treatment for iron overload might thus be protective in some cases.
Assuntos
Doença de Alzheimer/etiologia , Epistasia Genética/genética , Antígenos de Histocompatibilidade Classe I/genética , Sobrecarga de Ferro/complicações , Sobrecarga de Ferro/genética , Proteínas de Membrana/genética , Transferrina/genética , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Doença de Alzheimer/prevenção & controle , Apolipoproteína E4/genética , Feminino , Proteína da Hemocromatose , Humanos , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/terapia , Masculino , Estresse Oxidativo/genética , RiscoRESUMO
Altered glucose metabolism has been described in Alzheimer's disease (AD). We re-investigated the interaction of the insulin (INS) and the peroxisome proliferator-activated receptor alpha (PPARA) genes in AD risk in the Epistasis Project, including 1,757 AD cases and 6,294 controls. Allele frequencies of both SNPs (PPARA L162V, INS intron 0 A/T) differed between Northern Europeans and Northern Spanish. The PPARA 162LL genotype increased AD risk in Northern Europeans (p = 0.04), but not in Northern Spanish (p = 0.2). There was no association of the INS intron 0 TT genotype with AD. We observed an interaction on AD risk between PPARA 162LL and INS intron 0 TT genotypes in Northern Europeans (Synergy factor 2.5, p = 0.016), but not in Northern Spanish. We suggest that dysregulation of glucose metabolism contributes to the development of AD and might be due in part to genetic variations in INS and PPARA and their interaction especially in Northern Europeans.
Assuntos
Doença de Alzheimer/genética , Epistasia Genética , Predisposição Genética para Doença/genética , Insulina/genética , PPAR alfa/genética , Polimorfismo de Nucleotídeo Único/genética , Idoso , Idoso de 80 Anos ou mais , Apolipoproteína E4/genética , Europa (Continente) , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , MasculinoRESUMO
We have used proteomic fingerprinting to investigate diagnosis of Alzheimer's disease (AD). Samples of lumbar cerebrospinal fluid (CSF) from clinically-diagnosed AD cases (n = 33), age-matched controls (n = 20), and mild cognitive impairment (MCI) patients (n = 10) were used to obtain proteomic profiles, followed by bioinformatic analysis that generated a set of potential biomarkers in CSF samples that could discriminate AD cases from controls. The identity of the biomarker ions was determined using mass spectroscopy. The panel of seven peptide biomarker ions was able to discriminate AD patients from controls with a median accuracy of 95% (sensitivity 85%, specificity 97%). When this model was applied to an independent blind dataset from MCI patients, the intensity of signals was intermediate between the control and AD patients implying that these markers could potentially predict patients with early neurodegenerative disease. The panel were identified, in order of predictive ability, as SPARC-like 1 protein, fibrinogen alpha chain precursor, amyloid-ß, apolipoprotein E precursor, serum albumin precursor, keratin type I cytoskeletal 9, and tetranectin. The 7 ion ANN model was further validated using an independent cohort of samples, where the model was able to classify AD cases from controls with median accuracy of 84.5% (sensitivity 93.3%, specificity 75.7%). Validation by immunoassay was performed on the top three identified markers using the discovery samples and an independent sample cohort which was from postmortem confirmed AD patients (n = 17).
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Doença de Alzheimer/líquido cefalorraquidiano , Proteínas de Ligação ao Cálcio/líquido cefalorraquidiano , Proteínas da Matriz Extracelular/líquido cefalorraquidiano , Algoritmos , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Área Sob a Curva , Biomarcadores/líquido cefalorraquidiano , Estudos de Casos e Controles , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico , Estudos de Coortes , Biologia Computacional , Citoesqueleto/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Fibrinogênio/líquido cefalorraquidiano , Humanos , Masculino , Redes Neurais de Computação , Fragmentos de Peptídeos/líquido cefalorraquidiano , Mapeamento de Peptídeos/métodos , Proteômica/métodos , Escalas de Graduação Psiquiátrica , Curva ROC , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Proteínas tau/líquido cefalorraquidianoRESUMO
Vitamin D may have a role in brain function. Low levels have been frequently associated with cognitive decline and may contribute to diseases of the nervous system. The vitamin D receptor (VDR) is widely expressed in human brain. Vitamin D appears to be neuroprotective and may regulate inflammation in the brain. We examined two VDR polymorphisms, Apa1 and Taq1. We used DNA from 255 Alzheimer's disease (AD) cases and 260 cognitively screened elderly controls from the longitudinal cohort of the Oxford Project to Investigate Memory and Ageing (OPTIMA). The presence of each of the linked alleles, Apa1 T and Taq1 G, was associated with the risk of AD, particularly in people <75 years old: odds ratios ≥3.0 and p≤0.005. We also found preliminary evidence of interactions associated with AD between these polymorphisms and two other genes involved in the regulation of inflammation, interleukin-10 (IL10) and dopamine ß-hydroxylase (DBH): synergy factors ≥3.4, uncorrected p<0.05. These associations are biologically plausible and are consistent with a role for vitamin D in AD. Nevertheless, we consider this to be a hypothesis-generating study, which needs to be replicated in a larger dataset.
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Doença de Alzheimer/genética , Receptores de Calcitriol/genética , Alelos , Apolipoproteínas E/genética , Estudos de Coortes , DNA/genética , Dopamina beta-Hidroxilase/genética , Humanos , Inflamação/genética , Interleucina-10/genética , Razão de Chances , Reação em Cadeia da Polimerase , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , RiscoRESUMO
We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).
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Transportadores de Cassetes de Ligação de ATP/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Doença de Alzheimer/genética , Antígenos CD/genética , Antígenos de Diferenciação Mielomonocítica/genética , Proteínas do Citoesqueleto/genética , Proteínas de Membrana/genética , Receptor EphA1/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Bases de Dados Genéticas , Feminino , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Família Multigênica , Polimorfismo de Nucleotídeo Único , Lectina 3 Semelhante a Ig de Ligação ao Ácido SiálicoRESUMO
A key pathological feature of late-onset Alzheimer's disease (LOAD) is the abnormal extracellular accumulation of the amyloid-ß (Aß) peptide. Thus, altered Aß degradation could be a major contributor to the development of LOAD. Variants in the gene encoding the Aß-degrading enzyme, angiotensin-1 converting enzyme (ACE) therefore represent plausible candidates for association with LOAD pathology and risk. Following Alzgene meta-analyses of all published case-control studies, the ACE variants rs4291 and rs1800764 showed significant association with LOAD risk. Furthermore ACE haplotypes are associated with both plasma ACE levels and LOAD risk. We tested three ACE variants (rs4291, rs4343, and rs1800764) for association with LOAD in ten Caucasian case-control populations (n = 8,212). No association was found using multiple logistic models (all p > 0.09). We found no population heterogeneity (all p > 0.38) or evidence for association with LOAD risk following meta-analysis of the ten populations for rs4343 (OR = 1.00), rs4291 (OR = 0.97), or rs1800764 (OR = 0.99). Although we found no haplotypic association in our complete dataset (p = 0.51), a significant global haplotypic p-value was observed in one population (p = 0.007) due to an association of the H3 haplotype (OR = 0.72, p = 0.02) and a trend towards an association of H4 (OR = 1.38, p = 0.09) and H7 (OR = 2.07, p = 0.08) although these did not survive Bonferroni correction. Previously reported associations of ACE variants with LOAD will be diminished following this study. At best, ACE variants have modest effect sizes, which are likely part of a complex interaction between genetic, phenotypic and pharmacological effects that would be undetected in traditional case-control studies.
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Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Predisposição Genética para Doença/genética , Peptidil Dipeptidase A/genética , Polimorfismo de Nucleotídeo Único/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Apolipoproteínas E/genética , Estudos de Casos e Controles , Europa (Continente)/epidemiologia , Feminino , Frequência do Gene , Genótipo , Humanos , Modelos Logísticos , Masculino , Metanálise como Assunto , América do Norte/epidemiologia , Razão de Chances , Fatores de Risco , População Branca/genéticaRESUMO
BACKGROUND: The loss of noradrenergic neurones of the locus coeruleus is a major feature of Alzheimer's disease (AD). Dopamine ß-hydroxylase (DBH) catalyses the conversion of dopamine to noradrenaline. Interactions have been reported between the low-activity -1021T allele (rs1611115) of DBH and polymorphisms of the pro-inflammatory cytokine genes, IL1A and IL6, contributing to the risk of AD. We therefore examined the associations with AD of the DBH -1021T allele and of the above interactions in the Epistasis Project, with 1757 cases of AD and 6294 elderly controls. METHODS: We genotyped eight single nucleotide polymorphisms (SNPs) in the three genes, DBH, IL1A and IL6. We used logistic regression models and synergy factor analysis to examine potential interactions and associations with AD. RESULTS: We found that the presence of the -1021T allele was associated with AD: odds ratio = 1.2 (95% confidence interval: 1.06-1.4, p = 0.005). This association was nearly restricted to men < 75 years old: odds ratio = 2.2 (1.4-3.3, 0.0004). We also found an interaction between the presence of DBH -1021T and the -889TT genotype (rs1800587) of IL1A: synergy factor = 1.9 (1.2-3.1, 0.005). All these results were consistent between North Europe and North Spain. CONCLUSIONS: Extensive, previous evidence (reviewed here) indicates an important role for noradrenaline in the control of inflammation in the brain. Thus, the -1021T allele with presumed low activity may be associated with misregulation of inflammation, which could contribute to the onset of AD. We suggest that such misregulation is the predominant mechanism of the association we report here.
Assuntos
Doença de Alzheimer/genética , Dopamina beta-Hidroxilase/genética , Epistasia Genética/genética , Polimorfismo de Nucleotídeo Único , Idoso , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/patologia , Europa (Continente) , Feminino , Genótipo , Humanos , Interleucina-1alfa/genética , Interleucina-6/genética , Locus Cerúleo/patologia , Masculino , Neurônios/patologia , Razão de Chances , Fatores de Risco , EspanhaRESUMO
BACKGROUND: The insulin-degrading enzyme gene (IDE) is a strong functional and positional candidate for late onset Alzheimer's disease (LOAD). METHODOLOGY/PRINCIPAL FINDINGS: We examined conserved regions of IDE and its 10 kb flanks in 269 AD cases and 252 controls thereby identifying 17 putative functional polymorphisms. These variants formed eleven haplotypes that were tagged with ten variants. Four of these showed significant association with IDE transcript levels in samples from 194 LOAD cerebella. The strongest, rs6583817, which has not previously been reported, showed unequivocal association (p = 1.5x10(-8), fold-increase = 2.12,); the eleven haplotypes were also significantly associated with transcript levels (global p = 0.003). Using an in vitro dual luciferase reporter assay, we found that rs6583817 increases reporter gene expression in Be(2)-C (p = 0.006) and HepG2 (p = 0.02) cell lines. Furthermore, using data from a recent genome-wide association study of two Croatian isolated populations (n = 1,879), we identified a proxy for rs6583817 that associated significantly with decreased plasma Abeta40 levels (ss = -0.124, p = 0.011) and total measured plasma Abeta levels (b = -0.130, p = 0.009). Finally, rs6583817 was associated with decreased risk of LOAD in 3,891 AD cases and 3,605 controls. (OR = 0.87, p = 0.03), and the eleven IDE haplotypes (global p = 0.02) also showed significant association. CONCLUSIONS: Thus, a previously unreported variant unequivocally associated with increased IDE expression was also associated with reduced plasma Abeta40 and decreased LOAD susceptibility. Genetic association between LOAD and IDE has been difficult to replicate. Our findings suggest that targeted testing of expression SNPs (eSNPs) strongly associated with altered transcript levels in autopsy brain samples may be a powerful way to identify genetic associations with LOAD that would otherwise be difficult to detect.
Assuntos
Doença de Alzheimer/enzimologia , Peptídeos beta-Amiloides/genética , Insulisina/genética , RNA Mensageiro/genética , Doença de Alzheimer/genética , Estudos de Casos e Controles , HumanosRESUMO
Associations have been reported of aromatase polymorphisms with Alzheimer's disease (AD). We studied nine polymorphisms in 207 cases of AD, 23 cases of mild cognitive impairment (MCI) and 233 controls, all from the OPTIMA cohort. We replicated two reported associations and found others. Our findings were consistent between AD and MCI. Further, our results were sex-specific, i.e. there were significant interactions between certain polymorphisms and gender, and the associations with AD were almost entirely in women. Aromatase catalyses the conversion of androgens to estrogens. It is expressed in the human brain. In the hippocampus, it is upregulated in postmenopausal women and is lowered in AD. These sex-specific results are therefore plausible. However, our results now need to be replicated in a larger dataset.
Assuntos
Doença de Alzheimer/genética , Aromatase/genética , Idoso , Idoso de 80 Anos ou mais , Transtornos Cognitivos/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Mutação INDEL , Desequilíbrio de Ligação , Estudos Longitudinais , Masculino , Repetições de Microssatélites , Polimorfismo de Nucleotídeo Único , Fatores SexuaisRESUMO
BACKGROUND: Chronic inflammation is a characteristic of Alzheimer's disease (AD). An interaction associated with the risk of AD has been reported between polymorphisms in the regulatory regions of the genes for the pro-inflammatory cytokine, interleukin-6 (IL-6, gene: IL6), and the anti-inflammatory cytokine, interleukin-10 (IL-10, gene: IL10). METHODS: We examined this interaction in the Epistasis Project, a collaboration of 7 AD research groups, contributing DNA samples from 1,757 cases of AD and 6,295 controls. RESULTS: We replicated the interaction. For IL6 rs2069837 AA x IL10 rs1800871 CC, the synergy factor (SF) was 1.63 (95% confidence interval: 1.10-2.41, p = 0.01), controlling for centre, age, gender and apolipoprotein E epsilon4 (APOEepsilon4) genotype. Our results are consistent between North Europe (SF = 1.7, p = 0.03) and North Spain (SF = 2.0, p = 0.09). Further replication may require a meta-analysis. However, association due to linkage disequilibrium with other polymorphisms in the regulatory regions of these genes cannot be excluded. CONCLUSION: We suggest that dysregulation of both IL-6 and IL-10 in some elderly people, due in part to genetic variations in the two genes, contributes to the development of AD. Thus, inflammation facilitates the onset of sporadic AD.
Assuntos
Doença de Alzheimer/genética , Encefalite/genética , Epistasia Genética/genética , Predisposição Genética para Doença/genética , Interleucina-10/genética , Interleucina-6/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/imunologia , Doença de Alzheimer/fisiopatologia , Encéfalo/imunologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Química Encefálica/genética , Química Encefálica/imunologia , Análise Mutacional de DNA , Encefalite/imunologia , Encefalite/fisiopatologia , Feminino , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Testes Genéticos , Genótipo , Humanos , Masculino , Polimorfismo Genético/genética , Fatores de RiscoRESUMO
Mutations in amyloid precursor protein (APP) and presenilin (PSEN) genes are known to cause familial early-onset Alzheimer's disease (AD), which account for around 5% of AD cases. Genetic associations for the remaining "sporadic" cases, other than the risks associated with the apolipoprotein (APOE) epsilon4 allele are currently not fully established. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in PSEN1 are associated with a modified risk for sporadic AD or a modified disease phenotype. Eight tag SNPs were identified using linkage disequilibrium (LD) data from the International HapMap project providing coverage of the entire PSEN1 gene. These SNPs were investigated for AD susceptibility in a case-control haplotype association study (N=714) and for genotype-specific effects on cognitive performance in AD patients (N=169) using non-linear mixed effects modelling. Replication of a mild associated-risk of an intronic PSEN1 polymorphism with AD was achieved (P=0.03). No other single SNPs or haplotypes were associated with AD risk. However, 3 SNPs were associated with an altered rate of cognitive decline underlining their role as genetic modifiers of disease.