RESUMEN
Rare mutations in AßPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AßPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.
Asunto(s)
Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , Presenilina-1/genética , Presenilina-2/genética , Proteínas tau/genética , Anciano , Anciano de 80 o más Años , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Metaanálisis como Asunto , Oportunidad RelativaRESUMEN
We sought to investigate the contribution of extended runs of homozygosity in a genome-wide association dataset of 1,955 Alzheimer's disease cases and 955 elderly screened controls genotyped for 529,205 autosomal single nucleotide polymorphisms. Tracts of homozygosity may mark regions inherited from a common ancestor and could reflect disease loci if observed more frequently in cases than controls. We found no excess of homozygous tracts in Alzheimer's disease cases compared to controls and no individual run of homozygosity showed association to Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/genética , Predisposición Genética a la Enfermedad , Homocigoto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Cromosomas Humanos Par 8/genética , Femenino , Genes/genética , Estudio de Asociación del Genoma Completo , Humanos , MasculinoRESUMEN
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)).
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Enfermedad de Alzheimer/genética , Antígenos CD/genética , Antígenos de Diferenciación Mielomonocítica/genética , Proteínas del Citoesqueleto/genética , Proteínas de la Membrana/genética , Receptor EphA1/genética , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Bases de Datos Genéticas , Femenino , Predisposición Genética a la Enfermedad , Variación Genética , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Familia de Multigenes , Polimorfismo de Nucleótido Simple , Lectina 3 Similar a Ig de Unión al Ácido SiálicoRESUMEN
BACKGROUND: Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes. METHODOLOGY: We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset. PRINCIPAL FINDINGS: We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD. SIGNIFICANCE: Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.
Asunto(s)
Enfermedad de Alzheimer/genética , Colesterol/metabolismo , Estudio de Asociación del Genoma Completo , Sistema Inmunológico/metabolismo , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Mapeo Cromosómico , Predisposición Genética a la Enfermedad/genética , Genoma Humano , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
OBJECTIVE: To determine the effects of early life education, mid life employment and later life retirement age on the age of onset (AOO) of Alzheimer's disease (AD). METHODS: Multiple regression analyses were carried out using data for 1320 probable AD cases, of which 382 were males with employment and retirement age data, using informant based information on education and employment. RESULTS: No relation was found between years of education, best qualification obtained, or employment variables in males and the AOO of AD. A significant effect of later retirement age in delaying the AOO of AD was seen in males. CONCLUSIONS: In this study no effect of education or employment was seen, although this may be due to limited variance in the study population. The significant effect of retirement age may have several explanations, the most interesting of which would be the suggestion that active employment later in life allows an individual to prolong their cognitive assets above the threshold for dementia.
Asunto(s)
Enfermedad de Alzheimer/etiología , Escolaridad , Empleo , Jubilación , Factores de Edad , Edad de Inicio , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/psicología , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis de Regresión , Factores de RiesgoRESUMEN
We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 x 10(-157)) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 x 10(-9)) and 5' to the PICALM gene (rs3851179, P = 1.9 x 10(-8)). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer's disease in the combined dataset (rs11136000, P = 8.5 x 10(-10), odds ratio = 0.86; rs3851179, P = 1.3 x 10(-9), odds ratio = 0.86).
Asunto(s)
Enfermedad de Alzheimer/genética , Clusterina/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Proteínas de Ensamble de Clatrina Monoméricas/genética , Polimorfismo de Nucleótido Simple , Cromosomas Humanos , Genoma Humano , HumanosRESUMEN
OBJECTIVES: To investigate behavioral components of Alzheimer's disease (AD) and to analyze behavioral components in relation to disease severity, apolipoprotein E genotype (APOE), sex, years of education, age at onset, and cognitive impairment. DESIGN: Cross-sectional study. SETTING: Data were collected from community-dwelling individuals and those residing in nursing homes. PARTICIPANTS: A total of 1,120 individuals meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria for late-onset probable AD. MEASUREMENTS: Behavioral symptoms were assessed using the Neuropsychiatric Inventory. First-order polychoric correlations, controlling for disease severity, between the 12 symptom domain scores were estimated, and the resulting matrix underwent principal components analysis. RESULTS: Four interpretable components were identified: behavioral dyscontrol (euphoria, disinhibition, aberrant motor behavior, and sleep and appetite disturbances), psychosis (delusions and hallucinations), mood (depression, anxiety, and apathy), and agitation (aggression and irritability). Scores on the four components were associated with severity of cognitive impairment. Higher behavioral dysfunction, agitation, and mood component scores were associated with lower age at onset. Behavioral dysfunction and mood component scores were associated with sex. None of the components were associated with age at assessment, years of education, or number of APOE epsilon4 alleles. CONCLUSION: Four behavioral components were identified that were comparable with those observed previously. Future analysis of these components will strengthen understanding of the underlying pathology of behavioral symptoms and AD.
