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

Dating the topography through thermochronology: Application of Pecube code to inverted vertical profile in the eastern Sila Massif, southern Italy

none4noneOlivetti, Valerio; Balestrieri, Maria Laura; Faccenna, Claudio; Stuart, Fin M.Olivetti, Valerio; Balestrieri, Maria Laura; Faccenna, Claudio; Stuart, Fin M

Space history of the High Possil and Strathmore meteorites from Ne and Ar isotopes

The High Possil and Strathmore L6 chondrites fell in Scotland in 1804 and 1917 respectively. Unravelling their cosmic-ray exposure (CRE) ages provides crucial information about when they were ejected from the parent body, how they were delivered to Earth and is ultimately important for understanding the dynamics of small bodies in the solar system. Here we use new measurements of the Ne and Ar isotopic composition to determine CRE ages of both meteorites. Duplicated cosmogenic 21Ne and 38Ar concentrations yield CRE ages of 44.6 ± 4.6 Ma for High Possil and 15.4 ± 1.3 Ma for Strathmore. These coincide with well-established peaks in the ejection record for the L6 chondrites. They yield 40Ar gas retention ages in excess of 3.15 Ga, which is consistent with both meteorites originating at depth within the parent body at the time of asteroidal break-up.Thematic collection: This article is part of the Early Career Research collection available at: https://www.lyellcollection.org/cc/SJG-early-career-researc

Picrite-basalt associated to Ethiopian-Yemeni CFB and their relevance to mantle plume processes

The Oligocene Northern Ethiopian-Yemeni LIP, represented by a CFB plateau extending ca. 700 km in diameter, is characterized by a well-defined zonal arrangement with increasing plume-related physico-chemical features of erupted magmas, such as thermal regime, incompatible element enrichment and specific Sr-Nd-Pb-He isotopic fingerprint, from the periphery to the central plateau area [1]. Two CFB volcanic piles in the Lalibela district (Northern Ethiopia, ca. 2 km thick) and in the Manakhah section (Northern Yemeni plateau, ca. 1 km thick) which erupted close to the Oligocene Afar plume axis, are similarly characterized by very high-Titransitional basalts and picrites (HT2, [1] [2]) that account for ca. 13% (40,000 km3) of the total Ethiopian-Yemeni CFB lavas. These magmas are characterized, in addition to the extremely high TiO2content (3-6 wt%) by a high MgO content (mostly between 8 and 18 wt%), and show striking compositional analogies with those from the Karoo province and the Siberian meimechites [3] [4]. Petrological modelling based on whole rock FeO-MgO and Ol composition [5] indicates that some of picrites (MgO 16-17 wt%) are near-primary magmas with olivine phenoscrysts up to Fo 90.4. Calculation shows that the primary melts have picrite composition MgO 19.8-20.7 wt% and were generated by polybaric melting in the pressure range 3-4 GPa at a potential temperature of 1570°C. Together with high-MgO lavas from Hawaii and Gorgona, these are the highest temperatures of any OIB and LIP lavas. The available data suggest that HT2 magma sources necessarily require the involvement of specific high-Ti (and Fe) deep-seated sublithospheric components which were entrained and remobilized by the rising plume. References: [1] Beccaluva et al. (2009), J. Petrol. 50, 1377-1403. [2] Beccaluva et al. (2011), GSA Sp. Paper 478, 77-104. [3] Ellam & Cox (1991), Earth Planet. Sci. Lett. 105, 330-342. [4] Heinonen et al.(2014), Earth Planet. Sci. Lett.394, 229-241. [5] Herzberg et al. (2007), Geochem. Geophys. Geosyst. 8, doi:10.1029GC001390

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease

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

Author Correction: Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing (Nature Genetics, (2019), 51, 3, (414-430), 10.1038/s41588-019-0358-2)

An amendment to this paper has been published and can be accessed via a link at the top of the paper