Mineralogical and geochemical analysis of Fe-phases in drill-cores from the Triassic Stuttgart Formation at Ketzin CO₂ storage site before CO₂ arrival

Reactive iron (Fe) oxides and sheet silicate-bound Fe in reservoir rocks may affect the subsurface storage of CO2 through several processes by changing the capacity to buffer the acidification by CO2 and the permeability of the reservoir rock: (1) the reduction of three-valent Fe in anoxic environments can lead to an increase in pH, (2) under sulphidic conditions, Fe may drive sulphur cycling and lead to the formation of pyrite, and (3) the leaching of Fe from sheet silicates may affect silicate diagenesis. In order to evaluate the importance of Fe-reduction on the CO2 reservoir, we analysed the Fe geochemistry in drill-cores from the Triassic Stuttgart Formation (Schilfsandstein) recovered from the monitoring well at the CO2 test injection site near Ketzin, Germany. The reservoir rock is a porous, poorly to moderately cohesive fluvial sandstone containing up to 2–4 wt% reactive Fe. Based on a sequential extraction, most Fe falls into the dithionite-extractable Fe-fraction and Fe bound to sheet silicates, whereby some Fe in the dithionite-extractable Fe-fraction may have been leached from illite and smectite. Illite and smectite were detected in core samples by X-ray diffraction and confirmed as the main Fe-containing mineral phases by X-ray absorption spectroscopy. Chlorite is also present, but likely does not contribute much to the high amount of Fe in the silicate-bound fraction. The organic carbon content of the reservoir rock is extremely low (<0.3 wt%), thus likely limiting microbial Fe-reduction or sulphate reduction despite relatively high concentrations of reactive Fe-mineral phases in the reservoir rock and sulphate in the reservoir fluid. Both processes could, however, be fuelled by organic matter that is mobilized by the flow of supercritical CO2 or introduced with the drilling fluid. Over long time periods, a potential way of liberating additional reactive Fe could occur through weathering of silicates due to acidification by CO2

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

Genetic studies of frontotemporal dementia : With particular emphasis on the tau gene

Frontotemporal dementia (FTD) is next to Alzheimer's disease one of the common causes of early onset progressive dementia. FTD is mainly characterized by personality changes such as disinhibition, although there are large clinical and neuoropathological variations among the cases. The disorder is partly hereditary and three genomic regions have been linked to familial forms of the disease. The work presented in this thesis aimed at identifying genetic factors that directly or indirectly cause FTD, by investigating families with dominant inheritance patterns, as well as clinic-based FTD cases. Particular focus has been directed to the gene for the microtubule associated protein tau, which seems to have a pivotal role in several neurodegenerative disorders known as tauopathies. In the initial study, linkage analysis was performed to two specified regions on chromosome 3 and 17 in a Swedish family with early-onset rapidly progressive FTD. Linkage was identified to chromosome 17q21 with a maximum two-point LOD score of 2.76 at 0=0 for the marker D17S806. Sequencing of the tau gene localized on chromosome 17q21 failed to identify any mutations segregating with the disease in this family. Many other FTD families with shared clinical and neuropathological features were independently linked to an overlapping region on chromosome 17q21 and the disorder was collectively given the term Fromotemporal Dementia and Parkinsonism linked to chromosome 17 (FTDP-17). In collaboration with other groups we characterized the FTDP-17 candidate region in order to identify the gene causing the disease. A physical- and transcript map was constructed by assembling a contig of genomic clones and by positioning known genes and EST clusters on this physical map. Nineteen known genes and a number of ESTs were localized to the candidate region. Furthermore, seven novel genes were identified by exon-trapping and isolated in their full-length sequences. A number of genes mapped to the region were investigated for mutations. However, no mutations segregating in the FTDP- 17 families were identified. Hence, we extended the sequencing of the most obvious candidate, the tau gene, to a large number of families and to extended regions of the gene. Three missense mutations, G272V, P301L and R406W, were identified in the regions of tau that associates with microtubules. In addition, three intronic mutations 3' of the exon 10 5' splice site were observed. Other groups independently confirmed these results, as tau missense and 5' splice mutations now are identified as the major cause of FTDP- 17. The frequency of tau mutations was investigated in a Swedish clinic-based FTD population, although no additional tau mutations were found. Thus, tau mutations were rare among Swedish FTD cases and other genetic and/or environmental components must be operating. Consequently, we aimed at investigating such genetic factors, using two different approaches. Possible defects of the tau gene as larger deletions or alteration of splicing was investigated in a Swedish FTDP-17 family, where no tau mutations previously had been found. However, using methods such as Southern blot and RT-PCR, no pathological changes were observed. Furthermore, we investigated the presence of mutations in six other candidate genes on chromosome 17q2 1: gamma-tubulin, glial fibrillary acid protein (GFAP), human VH- I related dual specificity phosphatase (VHR), rap2-interacting protein 8 (RPIP8), P35, and the recently identified FTDCG1. However, no pathological changes were found in any of the genes. In a second approach, we investigated the apolipoprotein E (APOE) genotype distribution in the clinic-based FTD population. This study showed that the APOE epsilon4 allele was overrepresented among FID cases. Furthermore, cerebrospinal fluid (CSF) levels of the tau protein were measured in this population and found to be significantly increased in a subset of the cases. In conclusion, the findings of missense and 5' splice mutations in the tau gene in FTDP- 17 families reported by us and other groups, was a major breakthrough in dementia research as it showed that tau can have a pivotal role in neurodegeneration. However, tau mutations are not present in all FTDP- 17 families, and were found to be a rare cause of FTD among clinical cases. Extended investigation of tau and sequencing of other genes resulted in negative findings. Thus, it remains to continue the search for additional causes of FTD to get further insight into the pathogenesis of neurodegeneration. We also conclude that positive results regarding APOE epsilon4 association and increased levels of CSF tau gives further evidence for a common pathogenic pathway in the disease processes for several tauopathies such as AD and FTD, with both tau and APOE being a link between the different disorders