NEXT-100 Technical Design Report (TDR). Executive Summary

In this Technical Design Report (TDR) we describe the NEXT-100 detector that will search for neutrinoless double beta decay (bbonu) in Xe-136 at the Laboratorio Subterraneo de Canfranc (LSC), in Spain. The document formalizes the design presented in our Conceptual Design Report (CDR): an electroluminescence time projection chamber, with separate readout planes for calorimetry and tracking, located, respectively, behind cathode and anode. The detector is designed to hold a maximum of about 150 kg of xenon at 15 bar, or 100 kg at 10 bar. This option builds in the capability to increase the total isotope mass by 50% while keeping the operating pressure at a manageable level. The readout plane performing the energy measurement is composed of Hamamatsu R11410-10 photomultipliers, specially designed for operation in low-background, xenon-based detectors. Each individual PMT will be isolated from the gas by an individual, pressure resistant enclosure and will be coupled to the sensitive volume through a sapphire window. The tracking plane consists in an array of Hamamatsu S10362-11-050P MPPCs used as tracking pixels. They will be arranged in square boards holding 64 sensors (8 times8) with a 1-cm pitch. The inner walls of the TPC, the sapphire windows and the boards holding the MPPCs will be coated with tetraphenyl butadiene (TPB), a wavelength shifter, to improve the light collection.Comment: 32 pages, 22 figures, 5 table

Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer’s Disease Aetiopathogenesis in Men

Mosaic loss of chromosome Y (mLOY) is a common ageing-related somatic event and has been previously associated with Alzheimer’s disease (AD). However, mLOY estimation from genotype microarray data only reflects the mLOY degree of subjects at the moment of DNA sampling. Therefore, mLOY phenotype associations with AD can be severely age-confounded in the context of genome-wide association studies. Here, we applied Mendelian randomisation to construct an age-independent mLOY polygenic risk score (mloy-PRS) using 114 autosomal variants. The mloy-PRS instrument was associated with an 80% increase in mLOY risk per standard deviation unit (p = 4.22 × 10−20) and was orthogonal with age. We found that a higher genetic risk for mLOY was associated with faster progression to AD in men with mild cognitive impairment (hazard ratio (HR) = 1.23, p = 0.01). Importantly, mloy-PRS had no effect on AD conversion or risk in the female group, suggesting that these associations are caused by the inherent loss of the Y chromosome. Additionally, the blood mLOY phenotype in men was associated with increased cerebrospinal fluid levels of total tau and phosphorylated tau181 in subjects with mild cognitive impairment and dementia. Our results strongly suggest that mLOY is involved in AD pathogenesis.P.G.-G. (Pablo García-González) is supported by CIBERNED employment plan CNV-304-PRF-866. CIBERNED is integrated into ISCIII (Instituto de Salud Carlos III). I.d.R is supported by a national grant from the Instituto de Salud Carlos III FI20/00215. A.C. (Amanda Cano) acknowledges the support of the Spanish Ministry of Science, Innovation, and Universities under the grant Juan de la Cierva (FJC2018-036012-I). M.B. (Mercé Boada) and A.R. (Agustín Ruiz) are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240, and PI19/01301. The Genome Research @ Fundació ACE project (GR@ACE) is supported by Grifols SA, Fundación bancaria “La Caixa”, Fundació ACE, and CIBERNED. Acción Estratégica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)—Subdirección General de Evaluación—and the Fondo Europeo de Desarrollo Regional (FEDER—“Una manera de hacer Europa”). Genotyping of the ACE MCI-EADB samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW project number 733051061). This work was supported by a grant (European Alzheimer DNA BioBank, EADB) from the EU Joint Program—Neurodegenerative Disease Research (JPND). Partial funding for open access charge: Universidad de Málag

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

Genomic Characterization of Host Factors Related to SARS-CoV-2 Infection in People with Dementia and Control Populations: The GR@ACE/DEGESCO Study

Emerging studies have suggested several chromosomal regions as potential host genetic factors involved in the susceptibility to SARS-CoV-2 infection and disease outcome. We nested a COVID-19 genome-wide association study using the GR@ACE/DEGESCO study, searching for susceptibility factors associated with COVID-19 disease. To this end, we compared 221 COVID-19 confirmed cases with 17,035 individuals in whom the COVID-19 disease status was unknown. Then, we performed a meta-analysis with the publicly available data from the COVID-19 Host Genetics Initiative. Because the APOE locus has been suggested as a potential modifier of COVID-19 disease, we added sensitivity analyses stratifying by dementia status or by disease severity. We confirmed the existence of the 3p21.31 region (LZTFL1, SLC6A20) implicated in the susceptibility to SARS-CoV-2 infection and TYK2 gene might be involved in COVID-19 severity. Nevertheless, no statistically significant association was observed in the COVID-19 fatal outcome or in the stratified analyses (dementia-only and non-dementia strata) for the APOE locus not supporting its involvement in SARS-CoV-2 pathobiology or COVID-19 prognosis

SiPMs coated with TPB : coating protocol and characterization for NEXT

Silicon photomultipliers (SiPM) are the photon detectors chosen for the tracking readout in NEXT, a neutrinoless {\beta}{\beta} decay experiment which uses a high pressure gaseous xenon time projection chamber (TPC). The reconstruction of event track and topology in this gaseous detector is a key handle for background rejection. Among the commercially available sensors that can be used for tracking, SiPMs offer important advantages, mainly high gain, ruggedness, cost-effectiveness and radio-purity. Their main drawback, however, is their non sensitivity in the emission spectrum of the xenon scintillation (peak at 175 nm). This is overcome by coating these sensors with the organic wavelength shifter tetraphenyl butadienne (TPB). In this paper we describe the protocol developed for coating the SiPMs with TPB and the measurements performed for characterizing the coatings as well as the performance of the coated sensors in the UV-VUV range.Comment: Submitted to the Journal of Instrumentation on december 26th 201

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

Description and commissioning of NEXT-MM prototype: first results from operation in a Xenon-Trimethylamine gas mixture

A technical description of NEXT-MM and its commissioning and first performance is reported. Having an active volume of similar to 35 cm drift x 28 cm diameter, it constitutes the largest Micromegas-read TPC operated in Xenon ever constructed, made by a sectorial arrangement of the 4 largest single wafers manufactured with the Microbulk technique to date. It is equipped with a suitably pixelized readout and with a sufficiently large sensitive volume (similar to 23 l) so as to contain long (similar to 20 cm) electron tracks. First results obtained at 1 bar for Xenon and Trymethylamine (Xe-(2%) TMA) mixture are presented. The TPC can accurately reconstruct extended background tracks. An encouraging full-width half-maximum of 11.6% was obtained for similar to 29 keV gammas without resorting to any data post-processing

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