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

Glaciation across the Oligocene-Miocene boundary in southern McMurdo Sound, Antarctica: new chronology from the CIROS-1 drill hole

Few Palaeogene and Neogene sediment cores from the Antarctic continental margin have been dated with sufficient precision to enable establishment of direct linkages between glacial events on the Antarctic continent and marked events in deep-sea [delta]18O records. As a result, much of our knowledge of the gradual, but stepwise, shift from 'greenhouse' climates of the Cretaceous to the 'ice-house' climates of the Quaternary is inferred from well-dated and more continuously deposited deep-sea sediments. In this study, we present new magnetostratigraphic results from the CIROS-1 drill core from McMurdo Sound, Antarctica, along with a reinterpretation of a published diatom biostratigraphic zonation that is constrained by correlation to a high-precision age model from the nearby CRP-2/2A drill core. Our results suggest that most of the upper 350 m of the CIROS-1 drill core represents rapid sediment accumulation during a short time interval spanning the Oligocene-Miocene boundary. Chronostratigraphic control is precise enough to enable correlation of this interval of glacimarine sedimentation with the Mi-1 deep-sea [delta]18O event, which confirms that the Mi-1 event was related to a major expansion of Antarctic ice. A major unconformity at 366 m in the CIROS-1 drill core, which is widely observed in regional seismic reflection studies, represents 9 Myr of missing time. This unconformity can be traced offshore into the Ross Sea using seismic stratigraphy and is interpreted to indicate significant East Antarctic ice sheet development during the Mi-1 glaciation. The stratigraphic expression of this ~400-kyr glacial event is evidently multiphase and complex in the Victoria Land Basin, probably because it was punctuated by higher-frequency orbitally induced glacial oscillations. The presence of Nothofagidites pollen throughout the CIROS-1 drill core and the presence of a Nothofagus (Southern beech) leaf within the early Miocene portion of the core indicate that Antarctic mean summer temperatures did not decrease below 5[deg]C throughout the Mi-1 glaciation. These temperatures are significantly warmer than present-day mean summer temperatures at sea level in McMurdo Sound. The persistence of a Nothofagus forest in coastal southern Victoria Land throughout this time interval suggests that the present state of deep refrigeration was not reached until some time after the Mi-1 glaciatio

Magnetostratigraphic calibration of Southern Ocean diatom datums from the Eocene-Oligocene of Kerguelen Plateau (Ocean Drilling Program sites 744 and 748)

Ocean Drilling Program holes 744A and 748B represent key sections for calibration of Southern Ocean Eocene-Oligocene biostratigraphic zonations. Sites 744 and 748 were above the carbonate compensation depth throughout this time interval and contain good planktonic foraminiferal, calcareous nannofossil, and diatom biostratigraphic records. In particular, the Southern Ocean diatom biostratigraphic zonation for the Oligocene critically hinges on calibration of these two holes. Previous low-resolution magnetostratigraphic studies at these sites were hampered by limited sampling and technical difficulties, which prompted our high-resolution reinvestigation of the magnetostratigraphy. Magnetic polarity zonations for holes 744A and 748B were constructed after inspection of vector component plots at 1-cm stratigraphic intervals from continuous u-channel measurements. The magnetizations are generally stable and a robust polarity stratigraphy has been obtained for both holes. The increased resolution of our study and identification of persistent secondary overprints, which were not recognised in previous studies, suggests that the previously published interpretations need to be revised. Our magnetostratigraphic interpretations for both holes are constrained by foraminiferal and calcareous nannofossil datums, as well as by Sr isotope ages. We have calibrated four diatom datums, which are synchronous at the two studied sites, to the geomagnetic polarity timescale, including the first occurrence (FO) of Lisitzinia ornata (27.8 Ma), the FO of Rocella vigilans var. B (27.8 Ma), the FO of Cavitatus jouseanus (30.9 Ma) and the FO of Rhizosolenia oligocaenica (33.8 Ma). The synchroneity of these datums suggests that diatom biostratigraphy has considerable potential for Palaeogene biostratigraphic correlation in the Southern Ocean. Although the ages of some datums are obscured by an unconformity in Hole 744A, our age model from Hole 748B suggests age estimates for the last common occurrence of Rocella vigilans var. A (~29.0 Ma), the FO of Rocella vigilans var. A (30.0 Ma) and the FO of Rhizosolenia antarctica (33.2 Ma). It should also be noted that the last occurrence of the calcareous nannofossil Chiasmolithus altus occurs in Chron C8r rather than C8n in our revised magnetostratigraphic interpretation, which indicates that this datum is not diachronous between low and mid latitudes as had previously been suggested. Significant unconformities are documented in both holes, in the middle Oligocene and in the middle late Oligocene, respectively, which probably resulted from periods of enhanced circumpolar deep-water circulatio

Evolution of the diatoms: insights from fossil, biological and molecular data

Molecular sequence analyses have yielded many important insights into diatom evolution, but there have been few attempts to relate these to the extensive fossil record of diatoms, probably because of unfamiliarity with the data available, which are scattered widely through the geological literature. We review the main features of molecular phylogenies and concentrate on the correspondence between these and the fossil record; we also review the evolution of major morphological, cytological and life cycle characteristics, and possible diatom origins. The first physical remains of diatoms are from the Jurassic, and well-preserved, diverse floras are available from the Lower Cretaceous. Though these are unequivocally identifiable as centric diatoms, none except a possible Stephanopyxis can be unequivocally linked to lineages of extant diatoms, although it is almost certain that members of the Coscinodiscophyceae (radial centrics) and Mediophyceae (polar centrics) were present; some display curious morphological features that hint at an unorthodox cell division mechanism and life cycle. It seems most likely that the earliest diatoms were marine, but recently discovered fossil deposits hint that episodes of terrestrial colonization may have occurred in the Mesozoic, though the main invasion of freshwaters appears to have been delayed until the Cenozoic. By the Upper Cretaceous, many lineages are present that can be convincingly related to extant diatom taxa. Pennate diatoms appear in the late Cretaceous and raphid diatoms in the Palaeocene, though molecular phylogenies imply that raphid diatoms did in fact evolve considerably earlier. Recent evidence shows that diatoms are substantially underclassified at the species level, with many semicryptic or cryptic species to be recognized; however, there is little prospect of being able to discriminate between such taxa in fossil material