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

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

Oxidation contributes to low glutathione in the airways of children with cystic fibrosis

Glutathione is an important antioxidant in the lungs but its concentration is low in the airways of patients with cystic fibrosis. Whether this deficit occurs from an early age or how oxidative stress contributes to lowering glutathione is unknown. We measured glutathione, its oxidation products, myeloperoxidase, and biomarkers of hypochlorous acid in bronchoalveolar lavage from children with cystic fibrosis and disease controls using mass spectrometry and immunological techniques. The concentration of glutathione was lower in bronchoalveolar lavage from children with cystic fibrosis, whereas glutathione sulfonamide, a specific oxidation product of hypochlorous acid, was higher. Oxidised glutathione and glutathione sulfonamide correlated with myeloperoxidase and a biomarker of hypochlorous acid. The percentage of glutathione attached to proteins was higher in children with cystic fibrosis than controls. Pulmonary infections in cystic fibrosis resulted in lower levels of glutathione but higher levels of oxidised glutathione and glutathione sulfonamide in bronchoalveolar lavage. The concentration of glutathione is low in the airways of patients with cystic fibrosis from an early age. Increased oxidation of glutathione by hypochlorous acid and its attachment to proteins contribute to this deficiency. Therapies targeted against myeloperoxidase may boost antioxidant defence and slow the onset and progression of lung disease in cystic fibrosis

Sea-level related resedimentation processes on the northern slope of Little Bahama Bank (Middle Pleistocene to Holocene)

Middle Pleistocene to Holocene sediment variations observed in a 26 metre long core taken during a cruise of the RV Marion Dufresne are presented. Core MD992202 was retrieved from the northern slope of Little Bahama Bank and provides an excellent example for sedimentation processes in a mid-slope depositional environment. The sediment composition indicates sea-level related deposition processes for the past 375 000 years (marine isotope stages 1 to 11). The sediments consist of: (i) periplatform ooze (fine-grained particles of shallow-water and pelagic origin) with moderate variations in carbonate content, carbonate mineralogy and grain-size; and (ii) coarser intervals with cemented debris consisting of massive, poorly sorted, mud-supported or clast-supported deposits with an increased high-magnesium calcite content. During interglacial stages (marine isotope stages 1, 5, 7, 9 and 11) periplatform oozes (i) are characterized by higher aragonite contents, finer grain-size and higher organic contents, whereas during glacial stages (marine isotope stages 2 to 4, 6, 8 and 10), increased low-magnesium and high-magnesium calcite values, coarser grain-size and lower organic contents are recorded. These glacial to interglacial differences in mineralogy, grain-size distribution and organic content clearly show the impact of climatically controlled sea-level fluctuations on the sedimentation patterns of the northern slope of Little Bahama Bank. The coarser deposits (ii) occur mainly at the transitions from glacial to interglacial and interglacial to glacial stages, and are interpreted as redeposition events, indicating a direct link between sediment properties (changes in mineralogy, grain-size distribution, variations in organic contents) and sea-level fluctuations. Changes in hydrostatic pressure and the wave base position during sea-level changes are proposed to have triggered these large-scale sediment redepositions