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

Artículo escrito por un elevado número de autores, solo se referencian el que aparece en primer lugar, los autores pertenecientes a la UAM y el nombre del grupo de colaboración, si lo hubiereAcross 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 avenuesThis work was supported by the Michael J. Fox Foundation grant MJFF-020161 (E.M., Z.G.-O.), NIH and National Institute of Aging grants AG060747 (M.D.G.), AG066206 (Z.H.), AG066515 (Z.H., M.D.G.), the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie (grant agreement No. 890650, Y.L.G.), the Alzheimer’s Association (AARF-20-683984, M.E.B.), and the Iqbal Farrukh and Asad Jamal Fund, a grant from the EU Joint Programme—Neurodegenerative Disease Research (European Alzheimer DNA BioBank, EADB; JPND), the Japan Agency for Medical Research and Development JP21dk0207045 (T.I.), JP21dk020704 (K.O., S.N.), JP21km040550 (K.O.), the Einstein Center for Neurosciences in Berlin (S.M.Y.), the Swedish Research Council (#2018-02532, H.Z.), the European Research Council (#681712, H.Z.), and the Swedish State Support for Clinical Research (#ALFGBG-720931, H.Z.). Inserm UMR1167 is also funded by the Inserm, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine, and the French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Additional funders of individual investigators and institutions who contributed to data collection and genotyping are provided in SI Appendi

Loop diuretics association with Alzheimer’s disease risk

Objectives: To investigate whether exposure history to two common loop diuretics, bumetanide and furosemide, affects the risk of developing Alzheimer’s disease (AD) after accounting for socioeconomic status and congestive heart failure.Methods: Individuals exposed to bumetanide or furosemide were identified in the Stanford University electronic health record using the de-identified Observational Medical Outcomes Partnership platform. We matched the AD case cohort to a control cohort (1:20 case:control) on gender, race, ethnicity, and hypertension, and controlled for variables that could potentially be collinear with bumetanide exposure and/or AD diagnosis. Among individuals older than 65 years, 5,839 AD cases and 116,103 matched controls were included. A total of 1,759 patients (54 cases and 1,705 controls) were exposed to bumetanide.Results: After adjusting for socioeconomic status and other confounders, the exposure of bumetanide and furosemide was significantly associated with reduced AD risk (respectively, bumetanide odds ratio [OR] = 0.23; 95% confidence interval [CI], 0.15–0.36; p = 4.0 × 10−11; furosemide OR = 0.42; 95% CI, 0.38–0.47; p < 2.0 × 10−16).Discussion: Our study replicates in an independent sample that a history of bumetanide exposure is associated with reduced AD risk while also highlighting an association of the most common loop diuretic (furosemide) with reduced AD risk. These associations need to be additionally replicated, and the mechanism of action remains to be investigated

Influence of interlayer exchange coupling on ultrafast laser-induced magnetization reversal in ferromagnetic spin valves

In this study, we explore the influence of interlayer exchange coupling on magnetization reversal triggered by femtosecond laser pulses in ferromagnetic spin valves. Our experiments, focused on femtosecond laser-induced magnetization reversal, methodically vary the thickness of the copper (Cu) spacer layer. We identify a critical Cu thickness threshold at 2.32 nm. Above this threshold, a stable reversed magnetic domain is consistently generated upon exposure to a single laser pulse. Conversely, with a Cu spacer thinner than 2.32 nm, the observed magnetization reversal from parallel (P) to anti-parallel (AP) states occurs only under continuous laser irradiation. Once the laser is stopped, the magnetic configuration relaxes back to its initial P state, influenced by ferromagnetic exchange coupling. This research enhances our understanding of the mechanisms that drive optically induced ultrafast magnetization reversal in ferromagnetic spin valves.Comment: After resubmission. Supplemetary Materials adde

A Fast and Robust Strategy to Remove Variant-Level Artifacts in Alzheimer Disease Sequencing Project Data

Exome sequencing (ES) and genome sequencing (GS) are expected to be critical to further elucidate the missing genetic heritability of Alzheimer disease (AD) risk by identifying rare coding and/or noncoding variants that contribute to AD pathogenesis. In the United States, the Alzheimer Disease Sequencing Project (ADSP) has taken a leading role in sequencing AD-related samples at scale, with the resultant data being made publicly available to researchers to generate new insights into the genetic etiology of AD. To achieve sufficient power, the ADSP has adapted a study design where subsets of larger AD cohorts are collected and sequenced across multiple centers, using a variety of sequencing platforms. This approach may lead to variable variant quality across sequencing centers and/or platforms. In this study, we sought to implement and evaluate filters that can be applied fast to robustly remove variant-level artifacts in the ADSP data

Extending the scope and understanding of all-optical magnetization switching in Gd-based alloys by controlling the underlying temperature transients

We use the thickness of Cu layers to control all-optical switching of magnetization in adjacent Gd$_{24}$(Fe$_9$0Co$_{10}$)$_{76}$ films. While increasing the Cu thickness from 5 to 900nm has no effect on the switching threshold, it significantly enlarges the fluence and pulse duration at which multiple domains emerge. Having shown that thermally activated multi-domain formation limits the maximum fluence and pulse duration for controlled switching, we demonstrate that continuous magnetization reversal precedes multi-domain formation in Gd$_{18}$Dy$_4$Co$_{78}$ films excited with fluences slightly larger than the multi-domain threshold

Single laser pulse induced magnetization switching in in-plane magnetized GdCo alloys

The discovery of all-optical ultra-fast deterministic magnetization switching has opened up new possibilities for manipulating magnetization in devices using femtosecond laser pulses. Previous studies on single pulse all-optical helicity-independent switching (AO-HIS) have mainly focused on perpendicularly magnetized thin films. This work presents a comprehensive study on AO-HIS for in-plane magnetized GdxCo100-x thin films. Deterministic single femtosecond laser pulse toggle magnetization switching is demonstrated in a wider concentration range (x=10% to 25%) compared to the perpendicularly magnetized counterparts with GdCo thicknesses up to 30 nm. The switching time strongly depends on the GdxCo100-x concentration, with lower Gd concentration exhibiting shorter switching times (less than 500 fs). Our findings in this geometry provide insights into the underlying mechanisms governing single pulse AO-HIS, which challenge existing theoretical predictions. Moreover, in-plane magnetized GdxCo100-x thin films offer extended potential for opto-spintronic applications compared to their perpendicular magnetized counterparts.Comment: 19 pages, 4 figure

Criteria to observe single-shot all-optical switching in Gd-based ferrimagnetic alloys

Single-shot all-optical helicity-independent switching (AO-HIS) induced by a femto-second laser pulse has been mainly reported in Gadolinium based rare earth-transition metal (RE-TM) alloys such as GdFeCo or GdCo, but the mechanism leading to magnetization switching is a hotly debated topic. Here, we elaborate on a large number of GdyRE1-x-yCox (RE = Dy, Tb, Ho) alloys to tune various magnetic parameters in order to define what the criteria are for observing AO-HIS in such systems. The state diagrams show that two laser fluences thresholds must be considered:the fluence which induces the single laser pulse switching (FSwitch) and the fluence at which the material breaks into a multi-domain state (FMulti). Those two fluences are shown to behave very differently as a function of the material properties and the laser pulse duration. Taking into account the parameters defining the conditions for which multi-domain states are created and considering only the angular momentum transfer from the Gd sublattice to the rest of the system explains in large our experimental results. The importance of the compensation in the ferrimagnetic alloys is also discussed. We believe the defined criteria will be an important tool for designing new ultra-fast spintronic devices based on all optical switching

Pour un accompagnement global en pension de famille : l’apport des capabilités d’Identité-Logement

Face à l’augmentation constante du nombre de personnes sans domicile en France, le « Plan Logement d'abord 2018-2022 » s’appuie sur les résultats du modèle « Housing First » (HF) pour proposer des solutions de logement pérennes. Il s'agit notamment de pensions de famille qui offrent un logement permanent aux personnes en situation de grande précarité, avec un accompagnement adapté. Si le modèle initial (HF) destiné à un public atteint de troubles psychiques propose un accompagnement orienté vers le rétablissement, l’accompagnement en pension de famille destiné à un public plus large, il nécessite d’être pensé autrement. Par une étude de cas menée en pension de famille, cet article présente une philosophie d’intervention différente où l’accompagnement prendrait appui sur l’approche par les capabilités et sur le concept d’Identité-logement, ouvrant la voie au pragmatisme critique.Faced with the ever-increasing number of homeless people in France, the "Housing First Plan 2018-2022" builds on the results of the "Housing First" (HF) model to propose sustainable solutions. These include boarding houses that provide permanent accommodation for people in very precarious situations, with appropriate support. While the Housing First (HF) model for people with mental health problems offers recovery-oriented support, support in boarding houses for a wider public needs to be considered differently. Through a case study in a boarding house, this article presents a different philosophy of intervention where the support would be based on the capability approach and on the concept of Home-identity, opening the way to critical pragmatism

Anterolateral Ligament Reconstruction Does Not Delay Functional Recovery, Rehabilitation, and Return to Sport After Anterior Cruciate Ligament Reconstruction: A Matched-Pair Analysis From the SANTI (Scientific ACL Network International) Study Group.

PurposeTo determine whether the addition of an anterolateral ligament reconstruction (ALLR) resulted in delayed functional recovery (based on the Knee Santy Athletic Return to Sport [K-STARTS] score) at 6 months after anterior cruciate ligament reconstruction (ACLR).MethodsA retrospective analysis of prospectively collected data from consecutive patients who underwent an ACLR between September 2017 and December 2020 was conducted. Patients who received an isolated hamstring autograft (isolated ACLR group) were propensity matched in a 1:1 ratio to patients who received a hamstring autograft ACLR combined with an ALLR (ACLR-ALLR group). Outcome measures included the Tegner Activity Scale and the K-STARTS test-a validated composite return-to-sports test (including the Anterior Cruciate Ligament-Return to Sport After Injury scale, Qualitative Assessment of Single-Leg Landing tool, limb symmetry index, and ability to change direction using the Modified Illinois Change of Direction Test).ResultsThe study included 111 matched pairs. At 6 months postoperatively, there were no significant differences between groups in the overall K-STARTS score (65.4 for isolated ACLR vs 61.2 for ACLR-ALLR, P = .087) or the Tegner Activity Scale score (3.7 for isolated ACLR vs 3.8 for ACLR-ALLR, P = .45). In addition, an evaluation of the subscales of the K-STARTS score revealed no disadvantage across the domains of neuromuscular control, limb symmetry index, agility, or psychological readiness to return to sport when an ALLR was performed.ConclusionsThe addition of ALLR at the time of ACLR does not delay functional recovery. Specifically, at 6 months postoperatively, there was no disadvantage in patients undergoing ALLR-ACLR, when compared with those undergoing isolated ACLR, with respect to neuromuscular control, limb symmetry indices (hop tests), agility, or psychological readiness to return to sport.Level of evidenceLevel III, retrospective comparative study

Proteo-genomics of soluble TREM2 in cerebrospinal fluid provides novel insights and identifies novel modulators for Alzheimer's disease

Triggering receptor expressed on myeloid cells 2 (TREM2) plays a critical role in microglial activation, survival, and apoptosis, as well as in Alzheimer's disease (AD) pathogenesis. We previously reported the MS4A locus as a key modulator for soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF). To identify additional novel genetic modifiers of sTREM2, we performed the largest genome-wide association study (GWAS) and identified four loci for CSF sTREM2 in 3,350 individuals of European ancestry. Through multi-ethnic fine mapping, we identified two independent missense variants (p.M178V in MS4A4A and p.A112T in MS4A6A) that drive the association in MS4A locus and showed an epistatic effect for sTREM2 levels and AD risk. The novel TREM2 locus on chr 6 contains two rare missense variants (rs75932628 p.R47H, P=7.16×10; rs142232675 p.D87N, P=2.71×10) associated with sTREM2 and AD risk. The third novel locus in the TGFBR2 and RBMS3 gene region (rs73823326, P=3.86×10) included a regulatory variant with a microglia-specific chromatin loop for the promoter of TGFBR2. Using cell-based assays we demonstrate that overexpression and knock-down of TGFBR2, but not RBMS3, leads to significant changes of sTREM2. The last novel locus is located on the APOE region (rs11666329, P=2.52×10), but we demonstrated that this signal was independent of APOE genotype. This signal colocalized with cis-eQTL of NECTIN2 in the brain cortex and cis-pQTL of NECTIN2 in CSF. Overexpression of NECTIN2 led to an increase of sTREM2 supporting the genetic findings. To our knowledge, this is the largest study to date aimed at identifying genetic modifiers of CSF sTREM2. This study provided novel insights into the MS4A and TREM2 loci, two well-known AD risk genes, and identified TGFBR2 and NECTIN2 as additional modulators involved in TREM2 biology