10 research outputs found

    New insights into the genetic etiology of Alzheimer's disease and related dementias

    Get PDF
    Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE Δ4 allele

    Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

    Get PDF
    Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased AÎČ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

    La calidad de las informaciones profesionales de que disponen los adolescentes

    No full text
    Estudiar la calidad de las informaciones de que disponen los adolescentes de 14-15 años sobre aspectos de las profesiones tales como ingresos, salidas, posibilidades de encuentros, aspectos que pueden jugar un rol central en la determinaciĂłn de las preferencias profesionales. 735 adolescentes españoles (de la provincia de Guadalajara) que cursan octavo de EGB, año 1988-89, repartidos en 6 grupos en funciĂłn del sexo, la categorĂ­a socio-cultural de los padres y del hĂĄbitat (rural o urbano). Cada alumno contesta 4 cuestionarios diferentes elegidos al azar de los 11. Se dispone para cada dimensiĂłn de un cuestionario-escala obtenido por la agregaciĂłn de respuestas de 30 expertos-orientadores escolares. Las designaciones hechas por cada alumno se comparan con las designaciones medias realizadas por los expertos sobre los cuestionarios correspondientes. Una serie de once cuestionarios de profesiones, cada uno de ellos comporta una consigna de las siguientes dimensiones: prestigio, salario, promociĂłn, salidas, intelectual-manual, iniciativa-rutina, molestias-diversiĂłn, masculinidad-feminidad, encuentros-aislamiento, interior-exterior y accesibilidad. Se realizan dos series de anĂĄlisis de varianza mĂșltiples cuyos planos son sexo, hĂĄbitat, 2x2 para la primera serie y sexo por medio socio-profesional de las madres, 2x2, para la segunda. Aparecen efectos ligados al sexo en las dimensiones molestias-diversiĂłn, intelectual-manual y encuentros-aislamientos. En la primera, los chicos estĂĄn mejor informados que las chicas, en las otras dos dimensiones es a la inversa. TambiĂ©n aparecen efectos ligados al medio-socio-econĂłmico, sobre las dimensiones molestias-diversiĂłn y promociĂłn. En los dos casos los adolescentes de medio socio-econĂłmico mĂĄs favorecido estĂĄn mejor informados que los de medio socio-econĂłmico menos favorecido. Se da interacciĂłn significativa entre medio-socio-econĂłmico y sexo con respecto a la dimensiĂłn interior-exterior. Parece importante recomendar un esfuerzo particular de informaciĂłn de los adolescentes sobre las dimensiones que peor conocen: salidas, molestias-diversiĂłn, iniciativa-rutina y posibilidades de promociĂłn. En contraposiciĂłn, no parece necesario diferenciar este esfuerzo en funciĂłn del sexo, del hĂĄbitat o medio de origen, aunque han sido observadas diferencias, estas no son tan amplias para justificar una complejizaciĂłn del dispositivo de informaciĂłn.Ministerio EducaciĂłn CIDEBiblioteca de EducaciĂłn del Ministerio de EducaciĂłn, Cultura y Deporte; Calle San AgustĂ­n, 5 - 3 Planta; 28014 Madrid; Tel. +34917748000; Fax +34917748026; [email protected]

    Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

    Get PDF
    Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease

    Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

    No full text
    Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease. © 2021, The Author(s)

    Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

    No full text
    Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease. © 2021, The Author(s)

    El tiempo de la archivĂ­stica: un estudio de sus espacios de racionalidad histĂłrica

    No full text

    New insights into the genetic etiology of Alzheimer’s disease and related dementias

    No full text
    Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE Δ4 allele. © 2022, The Author(s)
    corecore