RESUMO
Pathological expansion of a G4C2 repeat, located in the 5' regulatory region of C9orf72, is the most common genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). C9orf72 patients have highly variable onset ages suggesting the presence of modifying factors and/or anticipation. We studied 72 Belgian index patients with FTLD, FTLD-ALS or ALS and 61 relatives with a C9orf72 repeat expansion. We assessed the effect of G4C2 expansion size on onset age, the role of anticipation and the effect of repeat size on methylation and C9orf72 promoter activity. G4C2 expansion sizes varied in blood between 45 and over 2100 repeat units with short expansions (45-78 units) present in 5.6% of 72 index patients with an expansion. Short expansions co-segregated with disease in two families. The subject with a short expansion in blood but an indication of mosaicism in brain showed the same pathology as those with a long expansion. Further, we provided evidence for an association of G4C2 expansion size with onset age (P<0.05) most likely explained by an association of methylation state of the 5' flanking CpG island and expansion size in blood (P<0.0001) and brain (P<0.05). In several informative C9orf72 parent-child transmissions, we identified earlier onset ages, increasing expansion sizes and/or increasing methylation states (P=0.0034) of the 5' CpG island, reminiscent of disease anticipation. Also, intermediate repeats (7-24 units) showed a slightly higher methylation degree (P<0.0001) and a decrease of C9orf72 promoter activity (P<0.0001) compared with normal short repeats (2-6 units). Decrease of transcriptional activity was even more prominent in the presence of small deletions flanking G4C2 (P<0.0001). Here we showed that increased methylation of CpGs in the C9orf72 promoter may explain how an increasing G4C2 size lead to loss-of-function without excluding repeat length-dependent toxic gain-of-function. These data provide insights into disease mechanisms and have important implications for diagnostic counseling and potential therapeutic approaches.
Assuntos
Esclerose Lateral Amiotrófica/genética , Proteínas/genética , Adulto , Idade de Início , Esclerose Lateral Amiotrófica/metabolismo , Bélgica , Proteína C9orf72 , Ilhas de CpG/genética , Metilação de DNA/genética , Regulação para Baixo , Epigênese Genética/genética , Epigenômica/métodos , Feminino , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/metabolismo , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , Proteínas/metabolismoRESUMO
Two multicentre genome-wide association (GWA) studies provided substantial evidence, implicating the complement receptor 1 gene (CR1) in Alzheimer disease (AD) genetic etiology. CR1 encodes a large transmembrane receptor with a crucial role in the immune complement cascade. We performed a genetic follow-up of the GWA CR1 association in a Flanders-Belgian cohort (n=1883), and investigated the effect of single-nucleotide polymorphisms (SNPs) located in the CR1 locus on AD risk and cerebrospinal fluid (CSF) biomarker levels. We obtained significant association (P(adj)<0.03; odds ratio (OR)=1.24 (95% confidence interval (CI): 1.02-1.51)) for one CR1 risk haplotype, and haplotype association was strongest in individuals carrying apolipoprotein E (APOE) É4 alleles (P(adj)<0.006; OR=1.50 (95% CI: 1.08-2.09)). Also, four SNPs correlated with increased CSF amyloid Aß1â42 levels, suggesting a role for the CR1 protein in Aß metabolism. Moreover, we quantified a low-copy repeat (LCR)-associated copy number variation (CNV) in CR1, producing different CR1 isoforms, CR1-F and CR1-S, and obtained significant association in carriers of CR1-S. We replicated the CR1 CNV association finding in a French cohort (n=2003) and calculated in the combined cohorts, an OR of 1.32; 95% CI: 1.10-1.59 (P=0.0025). Our data showed that the common AD risk association may well be explained by the presence of CR1-S increasing the number of C3b/C4b and cofactor activity sites and AD risk with 30% in CR1-S carriers. How precisely the different functional role of CR1-S in the immune complement cascade contributes to AD pathogenesis will need additional functional studies.
Assuntos
Doença de Alzheimer/genética , Fator I do Complemento/metabolismo , Variações do Número de Cópias de DNA/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Complemento/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteína E4/genética , Estudos de Coortes , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Modelos Logísticos , Masculino , Metanálise como Assunto , Razão de Chances , Fragmentos de Peptídeos/líquido cefalorraquidiano , Duplicações Segmentares Genômicas , Proteínas tau/líquido cefalorraquidianoRESUMO
Several studies have reported an association of the apolipoprotein E allele epsilon 4 (APOE*4) to familial and sporadic late-onset Alzheimer's disease (LOAD). Here we report on the relationship between APOE*4 and early-onset Alzheimer's disease (EOAD) in a Dutch population-based study. The frequency of the APOE*4 allele was 2.3 times higher among EOAD cases compared to controls. Among patients, the allele frequency was 1.6 times higher in those with a positive family history than in those without. A significant increase in risk of EOAD was found for subjects homozygous for APOE*4 regardless of family history of dementia, but an increase in EOAD risk for APOE*4 heterozygotes could only be shown in subjects with a positive family history. Our study demonstrates a significant association between APOE*4 and EOAD which is modified by family history of dementia.
Assuntos
Alelos , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Adulto , Idade de Início , Idoso , Doença de Alzheimer/epidemiologia , Apolipoproteína E4 , Saúde da Família , Feminino , Frequência do Gene , Genes Dominantes , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Razão de Chances , Reação em Cadeia da Polimerase , Fatores de RiscoRESUMO
Genetic linkage studies with chromosome 21 DNA markers and mutation analysis of the beta-amyloid protein precursor gene located in 21q21.3 have indicated that early-onset Alzheimer's disease (EOAD) is a heterogeneous disorder for which at least one other chromosomal locus exists. We examined two extended histopathologically confirmed EOAD pedigrees, AD/A and AD/B, with highly informative short tandem repeat (STR) polymorphisms and found complete linkage of the disease to a (CA)n dinucleotide repeat polymorphism at locus D14S43 in 14q24.3 (Zmax = 13.25 at theta = 0.0). Using additional chromosome 14 STR polymorphisms we were able to delineate the region containing the EOAD gene to an area of, at most, 8.9 centiMorgans between D14S42 and D14S53, flanking D14S43 on both sides.
Assuntos
Doença de Alzheimer/genética , Cromossomos Humanos Par 14 , Adulto , Sequência de Bases , Mapeamento Cromossômico , Cromossomos Humanos Par 21 , DNA/genética , Feminino , Marcadores Genéticos , Humanos , Escore Lod , Masculino , Linhagem , Polimorfismo Genético , Sequências Repetitivas de Ácido NucleicoRESUMO
Several families with an early-onset form of familial Alzheimer's disease have been found to harbour mutations at a specific codon (717) of the gene for the beta-amyloid precursor protein (APP) on chromosome 21. We now report, a novel base mutation in the same exon of the APP gene which co-segregates in one family with presenile dementia and cerebral haemorrhage due to cerebral amyloid angiopathy. The mutation results in the substitution of alanine into glycine at codon 692. These results suggest that the clinically distinct entities, presenile dementia and cerebral amyloid angiopathy, can be caused by the same mutation in the APP gene.
Assuntos
Precursor de Proteína beta-Amiloide/genética , Hemorragia Cerebral/genética , Demência/genética , Adulto , Doença de Alzheimer/genética , Angiopatia Amiloide Cerebral/genética , Códon/genética , Análise Mutacional de DNA , Feminino , Ligação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Mutação PuntualRESUMO
Mutations in the gene encoding granulin (HUGO gene symbol GRN, also referred to as progranulin, PGRN), located at chromosome 17q21, were recently linked to tau-negative ubiquitin-positive frontotemporal lobar degeneration (FTLDU). Since then, 63 heterozygous mutations were identified in 163 families worldwide, all leading to loss of functional GRN, implicating a haploinsufficiency mechanism. Together, these mutations explained 5 to 10% of FTLD. The high mutation frequency, however, might still be an underestimation because not all patient samples were examined for all types of loss-of-function mutations and because several variants, including missense mutations, have a yet uncertain pathogenic significance. Although the complete phenotypic spectrum associated with GRN mutations is not yet fully characterized, it was shown that it is highly heterogeneous, suggesting the influence of modifying factors. A role of GRN in neuronal survival was suggested but the exact mechanism by which neurodegeneration and deposition of pathologic brain inclusions occur still has to be clarified.
Assuntos
Demência/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Família , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação , Doenças Neurodegenerativas/genética , ProgranulinasRESUMO
Ubiquitin-positive, tau-negative, frontotemporal dementia (FTD) is caused by null mutations in progranulin (PGRN; HUGO gene symbol GRN), suggesting a haploinsufficiency mechanism. Since whole gene deletions also lead to the loss of a functional allele, we performed systematic quantitative analyses of PGRN in a series of 103 Belgian FTD patients. We identified in one patient (1%) a genomic deletion that was absent in 267 control individuals. The deleted segment was between 54 and 69 kb in length and comprised PGRN and two centromeric neighboring genes RPIP8 (HUGO gene symbol RUNDC3A) and SLC25A39. The patient presented clinically with typical FTD without additional symptoms, consistent with haploinsufficiency of PGRN being the only gene contributing to the disease phenotype. This study demonstrates that reduced PGRN in absence of mutant protein is sufficient to cause neurodegeneration and that previously reported PGRN mutation frequencies are underestimated.
Assuntos
Demência/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Deleção de Sequência , Idoso , Bélgica , Mapeamento Cromossômico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , ProgranulinasRESUMO
Since the first report showing that Alzheimer disease (AD) might be caused by mutations in the amyloid precursor protein gene (APP), 20 different missense mutations have been reported. The majority of early-onset AD mutations alter processing of APP increasing relative levels of Abeta42 peptide, either by increasing Abeta42 or decreasing Abeta40 peptide levels or both. In a diagnostic setting using direct sequence analysis, we identified in one patient with familial early-onset AD a novel mutation in APP (c.2172G>C), predicting a K724N substitution in the intracytosolic fragment. The mutation is located downstream of the epsilon-cleavage site of APP and is the furthermost C-terminal mutation reported to date. In vitro expression of APP K724N cDNA showed an increase in Abeta42 and a decrease in Abeta40 levels resulting in a near three-fold increase of the Abeta42/Abeta40 ratio. Further, in vivo amyloid positron emission tomography (PET) imaging revealed significantly increased cortical amyloid deposits, supporting that in human this novel APP mutation is likely causing disease.
Assuntos
Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Mutação de Sentido Incorreto , Idoso , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/diagnóstico por imagem , Precursor de Proteína beta-Amiloide/química , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Bélgica , Encéfalo/diagnóstico por imagem , Linhagem Celular , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Linhagem , Tomografia por Emissão de Pósitrons , Processamento de Proteína Pós-Traducional , Estrutura Terciária de Proteína , Análise de Sequência de ProteínaRESUMO
Malfunctioning of cyclin-dependent kinase 5 (CDK5) through aberrant proteolytic cleavage of its neuronal activators p35 and p39 is involved in neurodegeneration in Alzheimer's disease (AD) and other neurodegenerative brain diseases. By extensive genetic analysis of the genes encoding CDK5 (CDK5), p35 (CDK5R1) and p39 (CDK5R2), we excluded causal mutations in 70 familial early-onset AD patients. We performed an association study with five informative SNPs in CDK5 in two independent samples of early-onset AD patients and matched control individuals from The Netherlands and northern Sweden. Association was observed with g.149800G>C in intron 5 of CDK5, and a two times increased risk was observed in both patient samples for carriers of the C-allele. Our data are indicative for a role of the CDK5 molecular complex in the genetic etiology of early-onset AD, and suggest that a yet unknown functional variant in CDK5 or in a nearby gene might lead to increased susceptibility for early-onset AD.
Assuntos
Doença de Alzheimer/enzimologia , Doença de Alzheimer/genética , Quinases Ciclina-Dependentes/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Idoso , Quinase 5 Dependente de Ciclina , Análise Mutacional de DNA , Éxons/genética , Feminino , Frequência do Gene/genética , Testes Genéticos , Variação Genética/genética , Genótipo , Haplótipos , Humanos , Íntrons/genética , Masculino , Pessoa de Meia-Idade , Países Baixos , SuéciaRESUMO
Tau is a multifunctional protein that was originally identified as a microtubule-associated protein. In patients diagnosed with frontotemporal dementia and parkinsonism linked to chromosome 17, mutations in the gene encoding tau (MAPT) have been identified that disrupt the normal binding of tau to tubulin resulting in pathological deposits of hyperphosphorylated tau. Abnormal filamentous tau deposits have been reported as a pathological characteristic in several other neurodegenerative diseases, including frontotemporal dementia, Pick Disease, Alzheimer disease, argyrophilic grain disease, progressive supranuclear palsy, and corticobasal degeneration. In the last five years, extensive research has identified 34 different pathogenic MAPT mutations in 101 families worldwide. In vitro, cell-free and transfected cell studies have provided valuable information on tau dysfunction and transgenic mice carrying human MAPT mutations are being generated to study the influence of MAPT mutations in vivo. This mutation update describes the considerable differences in clinical and pathological presentation of patients with MAPT mutations and summarizes the effect of the different mutations on tau functioning. In addition, the role of tau as a genetic susceptibility factor is discussed, together with the genetic evidence for additional causal genes for tau-positive as well as tau-negative dementia.
Assuntos
Demência/genética , Proteínas do Tecido Nervoso/fisiologia , Tauopatias/genética , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Sequência de Aminoácidos , Animais , Cromossomos Humanos Par 17/genética , Demência/classificação , Demência/diagnóstico , Demência/epidemiologia , Demência/metabolismo , Feminino , Previsões , Heterogeneidade Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Dados de Sequência Molecular , Mutação , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Fenótipo , Isoformas de Proteínas/química , Isoformas de Proteínas/fisiologia , Relação Estrutura-Atividade , Tauopatias/diagnóstico , Tauopatias/epidemiologia , Tauopatias/metabolismo , Proteínas tauRESUMO
BACKGROUND AND PURPOSE: Carotid artery atherosclerosis is a strong predictor for future stroke. It is yet unclear whether the apolipoprotein E polymorphism (APOE) is related to atherosclerosis in the carotid arteries. The aim of the present study was to investigate the role of APOE in carotid artery atherosclerosis. METHODS: A population-based cross-sectional study was performed on 5401 subjects. Atherosclerosis was noninvasively assessed by the common carotid artery intima-media wall thickness and the presence of plaques in the carotid arteries. The relationship of the 6 APOE genotypes with these 2 indicators was studied with linear and logistic regression analysis, respectively, with adjustments for age and sex. RESULTS: Carriers of the E2E3 genotype had a thinner intima-media wall thickness (mean difference, -0.02 mm; 95% CI, -0.03 to -0.01 mm) and fewer plaques (odds ratio for >3 plaques at 6 sites, 0.6; 95% CI, 0.4 to 0.8) than the most common group, E3E3. The E4E4 group had slightly more atherosclerosis, but this was not statistically significant. Adjusting for the level of the apolipoprotein E protein (apoE) in serum or total or HDL cholesterol did not essentially change these findings. CONCLUSIONS: Our results suggest that APOE*4 is not an important risk factor for carotid artery atherosclerosis. The inverse relationship of E2E3 with carotid artery atherosclerosis seems to be independent of serum apoE and total and HDL cholesterol levels. However, the low frequency, together with the small effects, implies that any protective effect of E2E3 on carotid artery atherosclerosis is limited.
Assuntos
Apolipoproteínas E/genética , Doenças das Artérias Carótidas/epidemiologia , Idoso , Apolipoproteínas E/sangue , Doenças das Artérias Carótidas/sangue , Doenças das Artérias Carótidas/diagnóstico , Artéria Carótida Primitiva/diagnóstico por imagem , Colesterol/sangue , HDL-Colesterol/sangue , Estudos de Coortes , Estudos Transversais , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Razão de Chances , Polimorfismo Genético , Prevalência , Túnica Íntima/diagnóstico por imagem , Túnica Média/diagnóstico por imagem , UltrassonografiaRESUMO
Genetic association has been reported between a di-allelic polymorphism in intron 8 of presenilin-1 (PSEN1) and Alzheimer's disease (AD) in some studies but not in others. In a population-based series of 102 patients with early onset AD and 118 community controls we examined whether polymorphisms in linkage disequilibrium with intron8 of PSEN1 may explain the association. In addition to the intron 8 polymorphism (P = 0.05), a promoter polymorphism (P = 0.03) and the simple tandem repeat (STR) polymorphism D14S1028 located upstream of PSEN1 (P = 0.04) were found to be marginally significantly associated to AD. When excluding PSEN1 mutation cases (n = 6), the intron 8 association was explained by linkage disequilibrium to the dominant PSEN1 mutations. In the non-mutation cases, the weak associations between the polymorphisms in the regulatory region remained. Our study suggests that a polymorphism/mutation in the promoter or regulatory region of PSEN1 rather than the polymorphism in intron 8 of PSEN1 is associated with early onset AD.
Assuntos
Idade de Início , Doença de Alzheimer/genética , Proteínas de Membrana/genética , Polimorfismo Genético/genética , Regiões Promotoras Genéticas/genética , Idoso , Estudos de Casos e Controles , Genes Reguladores/genética , Humanos , Íntrons/genética , Desequilíbrio de Ligação , Pessoa de Meia-Idade , Mutação , Presenilina-1 , Sequências de Repetição em Tandem/genéticaRESUMO
OBJECTIVES: To provide risk estimates of dementia and Alzheimer disease as a function of the apolipoprotein E (APOE) genotypes and to assess the proportion of dementia that is attributable to the APOE genotypes. DESIGN: Case-control study nested in a population-based cohort study with a mean (SD) follow-up of 2.1 (0.9) years. SETTING: General population in Rotterdam, the Netherlands. PARTICIPANTS: A total of 134 patients with incident dementia and a random sample of 997 nondemented control subjects. No participant had dementia at baseline. MAIN OUTCOME MEASURES: Odds ratios for dementia and Alzheimer disease, the fraction of dementia attributable to the APOE epsilon4 allele, and the proportion of the variance in age at the onset of dementia explained by the APOE genotypes. RESULTS: Persons with the epsilon4/4 genotype had a more than 10-fold higher risk of dementia (odds ratio, 11.2; 95% confidence interval, 3.6-35.2), and subjects with the epsilon3/4 genotype had a 1.7-fold increased risk of dementia (95% confidence interval, 1.0-2.9) as compared with persons with the epsilon3/3 genotype. The proportion of patients with dementia that is attributable to the epsilon4 allele was estimated to be 20%. The APOE genotypes explained up to 10% of the variance in age at the onset of dementia. The association between the epsilon4 allele and dementia was strongest in the youngest age category and in those with a family history of dementia. CONCLUSIONS: The APOE genotype is an important determinant of the risk of dementia. At a population level, however, other factors than the APOE genotype may play an important role in the cause of dementia.
Assuntos
Doença de Alzheimer/epidemiologia , Apolipoproteínas E/genética , Demência/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Estudos de Casos e Controles , Demência/genética , Feminino , Genótipo , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Razão de Chances , Medição de RiscoRESUMO
The APOE genotype is involved in atherosclerosis, and atherosclerosis increases the risk of dementia, in particular among carriers of the APOE-epsilon4 allele. We studied, in a population-based setting (244 dementia cases; 1,002 nondemented controls), whether APOE is associated with dementia through atherosclerosis. As neither adjusting nor stratification for atherosclerosis altered the association of APOE with dementia, our study suggests that atherosclerosis is not an intermediate factor.
Assuntos
Apolipoproteínas E/genética , Arteriosclerose/genética , Arteriosclerose/psicologia , Demência/genética , Idoso , Alelos , Feminino , Genótipo , Humanos , Masculino , Valores de ReferênciaRESUMO
BACKGROUND: Whereas several authors recently reported a positive association between the alpha2-macroglobulin gene (A2M) and late-onset AD (LOAD), others were unable to replicate these findings. Early-onset AD (EOAD) is defined as onset age <65 years. Virtually all patients with LOAD are >65 years of age. OBJECTIVE: To evaluate the role of A2M in AD, the authors conducted a population-based study of EOAD and LOAD as well as a meta-analysis of all studies conducted to date. METHODS: Patients with EOAD (n = 100) were derived from a population-based study in four northern provinces of the Netherlands and the area of metropolitan Rotterdam. Patients with LOAD (n = 344) were drawn from the Rotterdam Study, a population-based prospective study on residents aged 55 years and over of a Rotterdam suburb in the Netherlands. Two polymorphisms were studied, A2M-I/D and A2M-Ile1000Val, in relation to the APOE epsilon4 allele (APOE*4). RESULTS: No genotypic or allelic association was found for either polymorphism in the population-based series of patients with LOAD. In patients with EOAD without APOE*4, a significant increase of carriers of A2M-1000Val was found. The meta-analysis of available published case-control data on these polymorphisms in white and mixed ethnic populations yielded no significant differences between cases and controls. Pooling the Asian studies conducted to date showed a significant decrease in the frequency of A2M-D among patients. CONCLUSIONS: These results suggest that A2M is not genetically associated with LOAD in white patients or mixed populations as found in the United States. In these populations A2M does not have clinical relevance. From a scientific perspective, the findings on EOAD and Asian patients require replication and further research in the A2M region.
Assuntos
Doença de Alzheimer/genética , alfa-Macroglobulinas/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Metanálise como Assunto , Estudos Multicêntricos como Assunto , Polimorfismo Genético/genética , Estudos Prospectivos , Fatores de RiscoRESUMO
Nearly all mutations in the presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid beta precursor protein (APP) genes lead to early-onset Alzheimer disease (EOAD, onset age at or before 65 years). In order to assess the genetic contribution of these genes in a series of Colombian AD cases, we performed a systematic mutation analysis in 11 autosomal dominant, 23 familial, and 42 sporadic AD patients (34% with age of onset < or = 65 years). No APP missense mutations were identified. In three autosomal dominant cases (27.2%), two different PSEN1 missense mutations were identified. Both PSEN1 mutations are missense mutations that occurred in early-onset autosomal AD cases: an I143T mutation in one case (onset age 30 years) and an E280A mutation in two other cases (onset ages 35 and 42 years). In addition, a novel PSEN1 V94M mutation was present in one early-onset AD case without known family history (onset age 53 years) and absent in 53 controls. The E318G polymorphism was present in five AD cases and absent in controls. In PSEN2, two different silent mutations were detected, including one not reported elsewhere (P129). The majority of the Colombian AD cases, predominantly late-onset, were negative for PSEN and APP mutations.
Assuntos
Doença de Alzheimer/genética , Proteínas/genética , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/epidemiologia , Sequência de Aminoácidos , Substituição de Aminoácidos , Precursor de Proteína beta-Amiloide/genética , Sequência de Bases , Colômbia/epidemiologia , DNA/química , DNA/genética , Análise Mutacional de DNA , Feminino , Frequência do Gene , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Mutação , Mutação Puntual , Polimorfismo de Fragmento de Restrição , Polimorfismo Conformacional de Fita Simples , Presenilina-1 , Presenilina-2RESUMO
The apolipoprotein E (APOE) gene is involved in lipid transport. A common polymorphism in this gene with the APOE*2, APOE*3, and APOE*4 alleles influences plasma levels of apolipoprotein E and cholesterol. Besides its role in lipid transport, the APOE*4 allele is a genetic risk factor for Alzheimer disease (AD). Recently, a polymorphism in the APOE promoter region was found to be involved in plasma apolipoprotein E levels and was found associated with AD. We studied the effect of this -491A/T promoter polymorphism on plasma apolipoprotein E levels and risk for AD in a population-based case-control study. We found that there was a modest but statistically significant effect of the -491A/T polymorphism on plasma apolipoprotein E levels independent of the APOE genotype. The lowest plasma levels were measured for the AA genotype, highest levels for the TT genotype, and intermediate levels for the heterozygotes. There was a small effect of the -491 AA genotype on AD risk that disappeared after adjusting for APOE genotypes. Our data suggest that the -491A/T polymorphism has an APOE genotype-independent effect on plasma apolipoprotein E levels but no APOE-independent effect on AD risk.
Assuntos
Doença de Alzheimer/genética , Apolipoproteínas E/genética , Polimorfismo de Nucleotídeo Único , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença de Alzheimer/sangue , Apolipoproteínas E/sangue , DNA/genética , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Regiões Promotoras Genéticas/genética , Fatores de RiscoRESUMO
We describe a patient who was clinically diagnosed with familial early-onset Alzheimer disease (AD) carrying both the E318G substitution in presenilin 1 (PSEN1) and an insertion of 7 octapeptide coding repeats in the prion protein gene (PRNP). Neuropathological examination revealed elongated cerebellar prion protein deposits in the absence of AD pathology. Further analysis of other family members showed that the Creutzfeldt-Jakob disease phenotype in this family was caused solely by the PRNP insertion. This observation is consistent with our previous finding that PSEN1 E318G is not causally related to AD.
Assuntos
Síndrome de Creutzfeldt-Jakob/genética , Elementos de DNA Transponíveis , Proteínas de Membrana/genética , Mutação de Sentido Incorreto/genética , Príons/genética , Adulto , Substituição de Aminoácidos , Encéfalo/patologia , Síndrome de Creutzfeldt-Jakob/patologia , Feminino , Humanos , Masculino , Meninges/patologia , Linhagem , Presenilina-1RESUMO
We have previously reported a significant association between early-onset Alzheimer's disease (EOAD) and an allele in the promoter of presenilin 1 (PSEN1) significantly decreasing PSEN1 expression in vitro. For late-onset Alzheimer's disease (LOAD), numerous studies have reported inconsistent associations with a PSEN1 intronic polymorphism. We therefore hypothesized that linkage disequilibrium between the intronic PSEN1 polymorphism and the functional promoter polymorphism might explain the conflicting reports in LOAD. We analysed both variations in 356 LOAD patients and 230 controls in a population-based case-control study. In addition, we re-analysed all published literature on the PSEN1 intronic polymorphism in a meta-analysis. No significant association was found with the PSEN1 intronic or promoter polymorphism in our case-control sample. In the meta-analysis no major differences between patients and controls were found for the PSEN1 intronic variation. Together, our results do not support a major role for variable expression of PSEN1 in LOAD.
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Predisposição Genética para Doença , Proteínas de Membrana/biossíntese , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Proteínas de Membrana/análise , Polimorfismo Genético , Presenilina-1 , Fatores de RiscoRESUMO
The APOE*4 allele of the apolipoprotein E gene increases the risk of Alzheimer's disease (AD), but whether it also affects the course of the disease is controversial. However, all studies on this issue until now have been based on patients at various stages of disease. In the present population-based study, 97 patients were included at a similar stage, i.e., before the onset of symptoms, and followed for up to 5 years. We found that the APOE*4 allele is not a strong determinant of survival in AD. As change in cognitive function and severity of dementia are similar for AD patients with and without APOE*4, our study suggests that progression of AD is not related to the APOE*4 allele.