Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks : The GR@ACE project

Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series

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

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 ε4 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

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 Aβ42. 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

Tejiendo historias, Convento do Beato, Universidad, Fábrica cerealis, Lisboa, Portugal : PFG septiembre, 2017, Tribunal 6.06

El punto de partida de este proyecto habla del diálogo entre las capas de la historia, entendiéndola como un lienzo mil veces vuelto a dibujar y reinterpretado por todo el que tuvo la suerte de poder formar parte, dejando constancia de cómo lo espacios hablan por ellos mismos y siempre tienen una historia que contar. En un enclave privilegiado de la ciudad lisboeta, el Convento do Beato pudo formar parte de muchas de los acontecimientos que dibujaron el curso de la historia, a orillas del rio Tajo. En lo que por el siglo XV eran terrenos de cultivo y partiendo de una pequeña ermita en honor a Sao Bento, la reina Doña Isabel tras recibir como regalo de bodas la Abadia de Alcobaça, ordena construir un hospicio para los “Bons Homens de Vilar”. La muerte prematura de Doña Isabel hace que Afonso V continúe las obras y para enaltecer a su difunta esposa amplia el conjunto para la creación del Convento de Sao Bento de Xabregas, que es autorizado por el Papa Pío II en 1461. Las obras concluyen en 1697, sobreviviendo al terremoto de 1755 sin sufrir daños estructurales. En 1834 el templo es profanado transformando una de las alas del edificio en Hospital Real Militar, siendo el fin del uso conventual. Tras un incendio que inutilizó las instalaciones del Hospital, el edificio es comprado por Joao do Brito, quien comienza a utilizar las instalaciones del convento para fines industriales, durante la primera etapa del uso fabril se instala en la iglesia una fábrica de malta, emergiendo del altar mayor dos grandes chimeneas pertenecientes a la máquina de vapor e instalando el molino en las antiguas cocinas del convento. La marca “Nacional” que nace en estas instalaciones y para la que la reina María I de Portugal autoriza el uso de este nombre, se convierte en una de las marcas principales a nivel nacional, y con repercusión en el mercado internacional. Esta gran demanda hizo indispensable la construcción de nuevas instalaciones y la utilización de mayor maquinaria para rentabilizar el proceso. Se construyen tres grandes edificios cada uno de ellos ligado a una etapa del proceso, el edificio de “Limpiadores”, el edificio del “Molino Austro-húngaro” y el edificio de los “Ensacadores”. Hoy en día el conjunto industrial se encuentra en desuso en su gran mayoría (el conjunto formado por los tres edificios anteriormente citados), sin embargo el Convento do Beato ha sido recientemente rehabilitado y se usa como lugar de celebraciones de eventos, gestionado por la propia Fábrica Cerealis. Y es aquí donde se sitúa el punto de partida, un conjunto de una calidad arquitectónica bastante subrayable, con importancia a nivel nacional y con una gran memoria histórica, que ha marcado el devenir del barrio y que resume de una forma clara la historia de la ciudad, cae en el olvido aún estando el conjunto reconocido y protegido patrimonialmente. Los fundamentales, que dotaban de unidad al conjunto y explicaban la convivencia de periodos de historia tan distintos en un espacio tan reducido. Actualmente la empresa tiene previsto la rehabilitación del conjunto fabril para hacer viviendas, un uso inusual para este tipo de edificio industriales. Desde el proyecto se pone en crítica esta decisión abogando por un uso público que involucre a toda la ciudad y que permita a sus habitantes recordar y disfrutar de un conjunto industrial tan maravilloso evitando que caiga en el olvido. Se propone el uso de estas instalaciones como Facultad de Ingeniería de los Alimentos y Grado en Nutrición y Dietética Humana, ambos con un nexo de unión “la alimentación”.Universidad de Sevilla. Grado en Arquitectur

Ruta de arquitectura: romanticismo nórdico

Esta guía es fruto del viaje de estudios realizado del 26 de abril al 3 de mayo de 2015. Actividad recogida en el Proyecto docente de la asignatura de Proyectos 8, grupos 4.03 y 4.04. Curso 2014-2015. AULA TALLER F. Departamento de Proyectos Arquitectónicos. E.T.S. de Arquitectura de Sevilla. Universidad de Sevilla. La arquitectura de los países escandinavos constituye un apartado singular de alto interés en el panorama cultural del siglo XX y debe observarse en relación a sus países vecinos, Finlandia y Dinamarca. Se mezclan y suceden generaciones: en Finlandia, Alvar Aalto, Erik Brygman, Heiki y Kaija Siren o Reima Pietilä; en Suecia, Gunnar Asplund y Sigurd Lewerentz junto a Sven Markelius, anteceden a las figuras de Ralph Erskine o de Peter Celsing; en Dinamarca serán Arne Jacobsen y posteriormente Jorn Utzon; en Noruega, Sverre Fhen para la buena práctica arquitectónica y Christian Norberg–Schulz para la construcción de nuevas teorías. El romanticismo nórdico había surgido a principios del siglo XX como otros movimientos de pre–vanguardia, en oposición a la situación academicista heredada del siglo XIX. Esta situación de tránsito define un contexto propio en Suecia que será reconocible en el pensamiento y en las arquitecturas que construyeran Lewerentz y sobre todo Asplund.This guide is the result of the study tour made from 26 April to 3 May 2015. Activity included in the Teaching Project of Project 8, groups 4.03 and 4.04. 2014-2015 school year. AT-F. Department of Architectural Projects. Higher Technical School of Architecture. University of Seville. The architecture of the Scandinavian countries is a unique case of high interest in the cultural scene of the twentieth century and must be observed in relation to its neighboring countries, Finland and Denmark. They mix and happen generations: in Finland, Alvar Aalto, Erik Brygman, Heiki and Kaija Siren or Reima Pietilä; in Sweden, Gunnar Asplund and Sigurd Lewerentz with Sven Markelius, precede the figures of Ralph Erskine) or Peter Celsing; in Denmark will be Arne Jacobsen and later Jorn Utzon; in Norway, Sverre Fhen for good architectural practice and Christian Norberg-Schulz for the construction of new theories. Nordic romanticism had emerged in the early twentieth century as other pre-vanguard movements, as opposition to the academic situation inherited from the nineteenth century.Universidad de Sevill

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

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

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

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 ε4 allele

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

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 ε4 allele