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

Concepções da iniciação científica no ensino médio: uma proposta de pesquisa Conceptions of scientific initiation at the secondary level: a research proposal

Aborda-se, aqui, o tema da orientação acadêmica de alunos do Ensino Médio que participam do Programa de Vocação Científica (Provoc). Criado em 1986 pela Fiocruz, o Provoc consolidou-se como um modelo educacional na área de iniciação científica que ultrapassa os limites do campus de Manguinhos, no Rio de Janeiro, para difundir-se junto a outras instituições de pesquisa do país. O objetivo é propor uma análise das formas de participação de pesquisadores de renomadas instituições científicas, como orientadores de jovens que ainda não fizeram suas escolhas profissionais. A relevância estratégica desse tipo de programa institucional tem levado um grande número de pesquisadores-orientadores do Programa a refletir sobre questões e problemas, até então, abordados exclusivamente por especialistas em educação. A maioria dessas discussões resulta na formulação de propostas pedagógicas que devem ser levadas em consideração pelos atores sociais envolvidos no processo de consolidação e ampliação do Programa. Todavia, não são os resultados quantitativos, em si, que precisam ser avaliados, mas sim os argumentos que têm norteado as ações dos pesquisadores. Além da compreensão dos princípios gerais que orientaram a institucionalização do Provoc, busca-se entender como, por que e em que contextos culturais específicos se constroem as concepções da iniciação científica no Ensino Médio.<br>This work deals with the issue of the academic orientation of secondary school pupils that are taking part in the Scientific Vocation Programme (Provoc). Created in 1986 by Fiocruz, Provoc established itself as an educational model for the early stages of scientific learning. Its work in this field has gone beyond the limits of the Manguinhos campus in Rio de Janeiro and spread to a number of other research institutions in this country. The objective here is to put forward a proposal for an institutional project in which researchers from well known scientific institutions will provide guidance for those young people that have not yet made their professional choices. The strategic relevance of this type of institutional programme has encouraged a large number of the Programme's researchers-tutors to reflect upon issues and problems that - so far - had only been approached by educational experts. The ensuing discussions have often led to the formulation of pedagogical proposals that can be assessed by the very actors involved in the process of the Programme's consolidation and expansion. It is not a question of analysing the quantitative results per se, but the arguments that have guided the researchers' actions. We will be attempting to understand both the general principles that guided Provoc's institutionalisation, and how, why and in which specific cultural contexts the concepts of scientific initiation at the Secondary Level may be built

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

Characterisation of microbial attack on archaeological bone

As part of an EU funded project to investigate the factors influencing bone preservation in the archaeological record, more than 250 bones from 41 archaeological sites in five countries spanning four climatic regions were studied for diagenetic alteration. Sites were selected to cover a range of environmental conditions and archaeological contexts. Microscopic and physical (mercury intrusion porosimetry) analyses of these bones revealed that the majority (68%) had suffered microbial attack. Furthermore, significant differences were found between animal and human bone in both the state of preservation and the type of microbial attack present. These differences in preservation might result from differences in early taphonomy of the bones. © 2003 Elsevier Science Ltd. All rights reserved

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