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

Multicentre randomised controlled trial comparing Bankart repair with remplissage and Latarjet procedure in shoulder instability with subcritical bone loss (STABLE): study protocol

Introduction Recurrent shoulder dislocations often cause attrition of the labrum and progressive loss of the anterior bony contour of the glenoid. Treatment options for this pathology involve either soft tissue repair or bony augmentation procedure. The optimal management for patients with shoulder instability with subcritical bone loss remains unknown and current clinical practice is highly varied.Methods and analysis The Shoulder instability Trial comparing Arthroscopic stabilisation Benefits compared with Latarjet procedure Evaluation (STABLE) is an ongoing multicentre, randomised controlled trial of 114 patients diagnosed with recurrent anterior shoulder instability and subcritical glenoid bone loss (10%–20%, measured on 3D CT using circle of best fit technique). Patients are randomised either arthroscopic capsuloligamentous repair (Bankart repair+remplissage) or open or arthroscopic coracoid transfer (Latarjet procedure). The primary outcome of this trial will be the between-group difference in the change from baseline to 24 months postintervention in Western Ontario Shoulder Instability Index scores. Secondary outcomes include: (1) rates of recurrent shoulder dislocations and symptoms of instability up to 24 months’ postsurgery; (2) clinical outcomes measured by American Shoulder and Elbow Society score, Shoulder Activity Scale, EQ-5D and Patient Satisfaction Scale; (3) physical examination (range of motion, stability); (4) return to previous level of activity/sport; (5) rate of shoulder-related complications and serious adverse events.Ethics and dissemination This protocol has been reviewed and approved by the Hamilton Integrated Research Ethics Board (HiREB; project number 15998) prior to commencement of the trial. Results from the study will be submitted for publication in a peer-reviewed journal regardless of whether there are statistically significant findings.Trial registration number NCT05705479; this study was prospectively registered on clinicaltrials.gov

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