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

Boreal winter stratospheric climatology in EC-EARTH: CMIP6 version

The performance of the European Consortium Earth-system model (EC-EARTH) in the boreal winter stratosphere is comprehensively assessed for the first time, in particular its version 3.3 that contributes to CMIP6. A 100-year long simulation with prescribed climatological boundary conditions and fixed radiative forcing, representative of present-day climate, is used to evaluate the simulation of the climatological stratospheric circulation and to identify model biases. Results show that EC-EARTH has a large issue with the vertical distribution of stratospheric temperature from the tropics to mid-latitudes, seemingly linked to radiative processes of ozone, leading to a biased warm middle-upper stratosphere. Associated with this model bias, EC-EARTH simulates a stronger polar vortex at upper-stratospheric levels while the Brewer-Dobson circulation at middle/lower levels is weaker than reanalysis. The amplitude of the climatological planetary waves is overall underestimated, but the magnitude of the background wave injection from the troposphere into the stratosphere is overestimated, related to a weaker polar vortex at lower-stratospheric levels and, thus, a less effective wave filtering. This bias in the westerly flow could have a contribution from parameterized waves. The overestimation of background wave driving is maximum in early-winter, and may explain the overestimated frequency of sudden stratospheric warmings at this time, as compared to reanalysis. The spatial distribution of wave injection climatology has revealed a distinctive role of the climatological planetary waves: while large-scale waves (wavenumbers 1-2) dominate the eddy heat flux over the North Pacific, small-scale waves (wavenumbers 3-4) are responsible for the doubled-lobe structure of the eddy heat flux over Eurasia. EC-EARTH properly simulates this climatological feature, although overestimates its amplitude over central Eurasia

CD16+ monocyte subsets in patients with systemic lupus erythematosus, primary anti-phospholipid syndrome, and anti-phospholipid syndrome with lupus are associated with specific clinical/serological features of these diseases

International audienc

CD16+ monocyte subsets in patients with systemic lupus erythematosus, primary anti-phospholipid syndrome, and anti-phospholipid syndrome with lupus are associated with specific clinical/serological features of these diseases

International audienc