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

A meta-analysis of genome-wide association studies identifies multiple longevity genes

Publisher's version (útgefin grein).Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.Alexander von Humboldt-StiftungPeer Reviewe

Whiteness in and through data protection: An intersectional approach to anti-violence apps and #MeToo bots

This article analyses apps and artificial intelligence chatbots designed to offer survivors of sexual violence with emergency assistance, education, and a means to report and build evidence against perpetrators. Demonstrating how these technologies both confront and constitute forms of oppression, this analysis complicates assumptions about data protection through an intersectional feminist examination of these digital tools. In surveying different anti-violence apps, we interrogate how the racial formation of whiteness manifests in ways that can be understood as the political, representational, and structural intersectional dimensions of data protection

Unveiling White logic in criminological research: an intertextual analysis

Critical race scholars have called into question the objective neutrality upon which much positivist social science rests, arguing that it discursively masks how whiteness underpins the normative purview of research design and findings. As the scholarly securing of whiteness takes shape through explicit and discursive mechanisms, this article examines how it is manifest in criminological research through an intertextual analysis of contemporary peer-reviewed scholarship. Examining 558 articles in five recognized journals, this paper documents how blind spots towards race and racial stratification surface in criminological research, arguing that most of the articles analyzed do not simply ignore White privilege; they actively uphold it. Findings suggest that they do so through two means: first by whitewashing race, that is, disregarding how race and racism can differentially affect acts and trends of crime and deviance, and secondly, by narrowly representing race as merely explanatory variable without querying the broader power relations it marks. After discussing how these patterns reveal and uphold whiteness as a normative value, we conclude with a discussion of preliminary steps aimed at exposing and unpacking how White logic informs the field

Cashless Welfare Transfers for ‘Vulnerable’ Welfare Recipients: Law, Ethics and Vulnerability

This article aims to contribute to literature on the conceptualisation of ‘vulnerability’ and its use by neo-liberal welfare regimes to demean, stigmatize and responsibilize welfare recipients. Several conceptions of ‘vulnerability’ will be explored and utilised in the context of welfare reforms that purport to regulate social security recipients as highly risky ‘vulnerable’ subjects. However, as this article will make clear, ‘vulnerability’ is a somewhat slippery concept and one susceptible to abuse by powerful interests intent on increasing coercive surveillance, discipline and disentitlement for those designated as ‘vulnerable’. Legislation enacted ostensibly to address the ‘vulnerability’ of welfare recipients can foster intensive regulation and it must be asked who benefits most from such arrangements and the rhetoric that supports them.Full Tex

Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic

GRN mutations cause frontotemporal dementia (GRN-FTD) due to deficiency in progranulin (PGRN), a lysosomal and secreted protein with unclear function. Here, we found that Grn-/- mice exhibit a global deficiency in bis(monoacylglycero)phosphate (BMP), an endolysosomal phospholipid we identified as a pH-dependent PGRN interactor as well as a redox-sensitive enhancer of lysosomal proteolysis and lipolysis. Grn-/- brains also showed an age-dependent, secondary storage of glucocerebrosidase substrate glucosylsphingosine. We investigated a protein replacement strategy by engineering protein transport vehicle (PTV):PGRN-a recombinant protein linking PGRN to a modified Fc domain that binds human transferrin receptor for enhanced CNS biodistribution. PTV:PGRN rescued various Grn-/- phenotypes in primary murine macrophages and human iPSC-derived microglia, including oxidative stress, lysosomal dysfunction, and endomembrane damage. Peripherally delivered PTV:PGRN corrected levels of BMP, glucosylsphingosine, and disease pathology in Grn-/- CNS, including microgliosis, lipofuscinosis, and neuronal damage. PTV:PGRN thus represents a potential biotherapeutic for GRN-FTD