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

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

Occurrence of and risk factors for electroencephalogram burst suppression during propofol-remifentanil anaesthesia.

International audienceBACKGROUND: Suppression ratio (SR) derived from bispectral index (BIS) monitoring is correlated to EEG burst suppression. It may occur during deep anaesthesia, but also in the case of metabolic or haemodynamic brain injury. The goal of the study was to describe the occurrence of SR and to determine factors associated with SR during propofol-remifentanil general anaesthesia maintenance. METHODS: We conducted a post hoc analysis of BIS recordings in consecutive patients included in two multi-centre trials, undergoing non-cardiac surgery using a dual closed-loop BIS controller allowing automated propofol-remifentanil administration. The percentage of time spent with a BIS value between 40 and 60 (T(BIS 40-60)) was measured. Two groups of patients were defined: the SR group, including patients with at least one episode of SR value >10% lasting more than 1 min, and the control group. Factors associated with SR were analysed using a stepwise multivariate analysis. RESULTS: A total of 1494 patients [age=57 (17) yr; T(BIS 40-60)=76 (17%)] were analysed and 131 (8.7%) patients constituted the SR group. The main independent factors associated with SR were advanced age [odds ratio (95% confidence interval)=4.80 (1.85-12.43) (P=0.027), 10.59 (3.76-29.81) (P80 yr, respectively], history of coronary artery disease (CAD) [2.53 (1.47-4.37) (P=0.001)] and male gender [1.57 (1.03-2.40) (P=0.03)]. CONCLUSIONS: The occurrence of SR during BIS-controlled propofol and remifentanil anaesthesia is mainly observed in elderly male patients or in patients with a history of CAD. The mechanisms underlying SR and the potential consequences for the patient's postoperative outcome remain unsolved

Workflow4Metabolomics: A collaborative research infrastructure for computational metabolomics

This work was supported by Biogenouest®, Lifegrid (Auvergne)The complex, rapidly-evolving field of computational metabolomics calls for collaborative infrastructures where the large volume of new algorithms for data preprocessing, statistical analysis and annotation can be readily integrated whatever the language, evaluated on reference datasets, and chained to build ad hoc workflows for users. We have developed Workflow4Metabolomics (W4M), the first fully open-source and collaborative online platform for computational metabolomics. W4M is a virtual research environment (VRE) built upon the Galaxy web-based platform technology. It enables ergonomic integration, exchange, and running of individual modules and workflows. Alternatively, the whole W4M framework and computational tools can be downloaded as a virtual machine for local installation. Availability: http://workflow4metabolomics.org homepage enables users to open a private account and access the infrastructure. W4M is developed and maintained by the French Bioinformatics Institute (IFB) and the French Metabolomics and Fluxomics Infrastructure (MetaboHUB)