A novel Alzheimer disease locus located near the gene encoding tau protein

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordAPOE ε4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ε4+ (10 352 cases and 9207 controls) and APOE ε4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ε4 status. Suggestive associations (P<1 × 10-4) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ε4+: 1250 cases and 536 controls; APOE ε4-: 718 cases and 1699 controls). Among APOE ε4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10-9). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ε4+ subjects (CR1 and CLU) or APOE ε4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10-7) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P≤1.3 × 10-8), frontal cortex (P≤1.3 × 10-9) and temporal cortex (P≤1.2 × 10-11). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10-6) and temporal cortex (P=2.6 × 10-6). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ε4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted

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

In situ neutron diffraction study of a liquid nitrogen-quenched Mg-PSZ under load: a microcrack-dominated system?

The mechanical response of liquid nitrogen-quenched 9.4 Mg-PSZ in which the orthorhombic (o) phase is the major constituent (46 wt%) was investigated using in-situ neutron diffraction during uniaxial compression. The material remains elastic below 1 GPa with a Young's modulus of~242 GPa, second highest of all zirconia-based materials and highest of all zirconia-based ceramics. Beyond 1 GPa, the material develops small plastic strains in a time-dependent manner (i.e., by room temperature creep) although the strains were generally much smaller than the unquenched material, which contains no o phase. As for standard Mg-PSZ, the creep was accompanied by a volume change usually indicative of tetragonal to monoclinic (m) phase transformation; however, the amount of m phase apparent in the neutron diffraction patterns increased only marginally. The magnitude of the volume increase could not be accounted for by the observed increase in the m phase and hence, microcracking is believed to be responsible for most of the volume change. There is some evidence for a small amount of o to m transformation at the detection limit of the phase analysis technique

Direct observation of ferroelastic domain switching in polycrystalline BaTiO3 using in situ neutron diffraction

The extent and nature of ferroelastic re-orientation in a BaTiO3 ceramic under compressive stresses up to 150 MPa were studied using strain gauges and in-situ neutron powder diffraction. At greater than or equal to 10 MPa during the first loading, the unpoled crystals shows ferroelastic re-orientation. By 80 MPa similar to 12% of the material oriented for diffraction has switched. Nearly half of the switched material reverts to its original orientation upon relaxation of the load, leaving 7% permanently switched. Successive load cycles have little further effect. It is unlikely that the ferroelasticity observed here makes a significant contribution to toughening as it saturates at relatively low stresses, such as exist only in the outer region of the process zone

Reaction kinetics in Ti3SiC2 synthesis studied by time-resolved neutron diffraction

The reactive sintering of 3Ti/SiC/C to form the ternary carbide Ti3SiC2, previously found to involve the intermediate phases TiCx and Ti5Si3Cx, was investigated by time-resolved neutron powder diffraction. The kinetics of Ti3SiC2 formation from the intermediate phases TiCx Ti5Si3Cx (x <= 1) and a small amount of free C was determined. The crystallization rate of the Ti3SiC2 phase was determined through quantitative analyses of the diffraction patterns collected at different temperatures and is initially well-described by the Mehl-Avrami-Johnson equation. The activation energy was found to be 380 +/- 10 kj/mol and the Avrami exponent 3.0 +/- 0.2. The Avrami exponent decreases to close to I when more than half of the crystallization process was completed. This indicates a change in the mechanism of Ti3SiC2 crystal growth from unrestricted two or three-dimensional growth in the a-b planes to one-dimensional growth only, due to interaction of the growing,disk-like crystals and cessation of growth in the preferred direction

Damage tolerance of Ti 3 SiC 2 to high energy iodine irradiation

The microstructure of high fluence 2 MeV I2+ irradiated Ti3SiC2 has been studied by grazing incident X-ray diffraction (GIXRD) using synchrotron radiation. The shift and broadening of the observed diffraction peaks are due to a variety of defects rangin

Interface Management between General Practitioners and Rheumatologists-Results of a Survey Defining a Concept for Future Joint Recommendations.

OBJECTIVE:To measure the views of general practitioners (GPs) and rheumatologists in a nationwide evaluation, so as to optimise their cooperation in managing patients with inflammatory rheumatic diseases. METHODS:A questionnaire covering aspects of collaboration was sent, both by mail and/or by email, to all GPs and rheumatologists in Austria. Topics covered were (i) examinations and interventions to be performed before referral, (ii) the spectrum of diseases to be referred, and (iii) the role of GPs in follow-up and continuous management of patients. RESULTS:1,229 GPs of the 4,016 GPs (31%) and 110 of the 180 rheumatologists (61%) responded to the questionnaire. In cases of suspected arthritis, 99% of the GPs and 92% of the rheumatologists recommended specific laboratory tests, and 92% and 70%, respectively, recommended X-rays of affected joints before referral. Rheumatoid arthritis and spondyloarthritis, psoriatic arthritis and connective tissue disease were unanimously seen as indications for referral to a rheumatologist. Only 12% of rheumatologists felt responsible for the treatment of hand osteoarthritis and fibromyalgia. 80% of GPs and 85% of rheumatologists were of the opinion that treatment with disease-modifying drugs should be initiated by a specialist. Subsequent drug prescription and administration by GPs was supported by a majority of GPs and rheumatologists, with a concomitant rheumatologist follow-up every three to six months. CONCLUSION:The considerable consensus between the two professional groups constitutes a solid base for future joint recommendations, with the aim to accelerate the diagnostic process and the initiation of adequate therapy