Ultra-high resolution snapshots of three multi-decadal periods in an Antarctic ice core

We offer the first sub-seasonal view of glacial age archives from the Siple Dome-A (SDMA) ice core using the ultra-high resolution capabilities of a newly developed laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS; 121 μm sampling resolution) system capable of conducting multi-element glaciochemical analysis. Our ultra-high resolution data demonstrates that: (1) the SDMA ice core record can be annually dated based on seasonality in chemical inputs at a depth not previously possible using previous glaciochemical sampling methods, (2) winter accumulation at the SD site was greater than summer accumulation during the three late glacial periods selected (∼15.3, 17.3, 21.4 Ka ago) in this study and (3) resulting annual layer thicknesses results show greater variability than the current SD ice core depth/age model (Brook and others, 2005), possibly due to depositional effects such as wind scouring and/or decadal variability in snow accumulation that is not captured by the resolution of the current depth/age model

Associations of Sex, Race, and Apolipoprotein E Alleles With Multiple Domains of Cognition Among Older Adults

This genetic association study analyzes data from 4 Alzheimer disease and cognitive aging cohorts to investigate whether sex and race modify associations of APOE ε4 and ε2 with cognition

Sex‐specific genetic architecture of multiple domains of cognition among older adults

Abstract Background Genetic analyses of cognitive endophenotypes have led to discoveries of novel loci contributing to Alzheimer’s disease (AD) risk. Sex differences are present in cognitive trajectories in aging and AD, and these may vary across cognitive domain. However, genetic drivers that may contribute to sex differences in cognitive trajectories have yet to be explored. Thus, we sought to investigate the sex‐specific genetic architecture of cognition. Method We leveraged 10 cohorts of cognitive aging and AD to complete this sex‐aware genetic study (N = 31,800; mean age = 73 yrs.; 55% female). Harmonized cognitive scores for memory, executive functioning, and language were derived using confirmatory factor analysis models. We calculated change in cognitive scores over time using a mixed effects model, to facilitate analysis on cognitive decline. We performed GWAS of baseline score and of estimated rate of decline in each domain and in each cohort separately among non‐Hispanic white (NHW) individuals, adjusting for baseline age and genetic principal components. Then we meta‐analyzed the results. Result In addition to the well‐characterized APOE locus, we identified a genome‐wide significant chromosome 2 locus that was associated with language decline among NHW women (rs13387871: MAF = 0.20; β women = 2.97×10 −3 ; P women = 2.65×10 −9 ), but not among male counterparts (β men = ‐3.14×10 −4 , P men = 0.60). This locus contains multiple eQTLs for VRK2 , a serine/threonine kinase that has been previously linked to neuropsychiatric disorders, including schizophrenia. Furthermore, the top variant in this locus (rs13387871) was nominally significant for memory decline (β women = 1.74×10 −3 , P women = 0.01) and for executive functioning decline (β women = 7.58×10 −4 , P women = 0.02) in meta‐analyses among NHW women. Conclusion Our genetic analysis suggests that there may be some genetic drivers of language performance that differ by sex, and that these drivers may be shared to an extent across domains. Our future sex‐aware meta‐analyses will also include 1) non‐Hispanic black (NHB) within ancestry (N = 4,200), 2) cross‐ancestry (NHW + NHB), 3) diagnosis‐stratified, and 4) analysis of X‐chromosome. Planned follow‐up analyses will include gene‐set analyses, heritability tests, and genetic correlation tests. Through our preliminary analysis, we identified a promising locus for further exploration, and this is the first of many steps in elucidating the sex‐specific genetic architecture of cognition across ancestry groups

Genetic predictors of multiple cognitive domains within ancestry groups in older adults

Abstract Background Alzheimer’s disease (AD) is clinically characterized by disabling cognitive impairment, though substantial variability in cognitive symptoms and trajectories is observed in AD individuals. However, genetic predictors of domain‐specific cognitive performance remain undiscovered. We investigated cross‐sectional and longitudinal genetic architecture of harmonized memory, executive function, and language scores within and across ancestry groups. Method Using data from 7 cohorts of cognitive aging and AD, individuals >60 years at baseline were included (mean age at baseline = 71.2). Cognitive scores for memory, executive function, and language were harmonized using latent variable models. Slopes for cognitive scores were calculated for each domain with linear mixed‐effects models. GWAS was performed on each cognitive domain for individual cohorts, both at baseline and longitudinally. Models covaried for baseline age, sex, and the first three genetic principal components. Individual models were assessed among non‐Hispanic Whites (NHW) (N = 26,455), non‐Hispanic Blacks (NHB) (N = 3,410), and cross‐ancestry (NHW + NHB) (N = 29,865). Results were meta‐analyzed across cohorts. Result We identified six genetic loci showing a genome‐wide significant effect on cognition, in addition to well‐established associations between cognition and APOE: three loci in NHW, one locus in NHB, and two loci in cross‐ancestry results. In NHW, a chromosome 2 locus (rs6733839) near BIN1, a previously reported AD risk gene, was associated with longitudinal memory performance (MAF = 0.40, p = 3.36E‐08). Additionally, in NHW, two chromosome 2 loci (rs2940785 and rs2972059) were associated with memory decline (MAF = 0.05, = 3.92E‐09; MAF = 0.05, p = 5.06E‐09, respectively). Despite the small sample size, a chromosome 10 locus (rs77595416) was associated with longitudinal executive function in NHB (MAF = 0.01, p = 7.68E‐09). When analyzing cross‐ancestry results, two chromosome 2 loci near BIN1 (rs4663105 and rs6733839) were associated with memory decline (MAF = 0.44, p = 2.65E‐08; MAF = 0.40, p = 9.48E‐10, respectively). Conclusion We elucidate novel and replicate known genetic predictors of domain‐specific cognition in older adults. Furthermore, we show that genetic architecture of multiple cognitive domains in older adults differs by ancestry, highlighting SNPs observed in longitudinal memory (NHW and cross‐ancestry) and executive function (NHB). While replication is warranted, our results underscore the contribution of genetic predictors beyond APOE to cognitive decline and suggest the importance of ancestry‐specific analyses of cognition

APOE4‐stratified GWAS across cognitive domains in non‐Hispanic white and non‐Hispanic black individuals

Abstract Background Apolipoprotein E4 (APOE4) is common in the population yet is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD). Here, we sought to identify genetic effects that differ by APOE4 genotype leveraging stratified and APOE interaction analyses. We hypothesized that we could identify novel genetic associations with longitudinal cognitive decline across three neuropsychological domains (memory, executive function, and language) that differ by APOE4 status. We leveraged a large, multi‐ancestry harmonized cognitive dataset (Nparticipants ∼ 23,000) from the AD Sequencing Project Phenotype Harmonization Consortium including more than 50,000 total longitudinal measures of cognition. Method This study included data from four cohort studies of aging and AD (NNHW = 20,117, NNHB = 2,631, Nobs = 22,748, 39% APOE4 carriers, 16% AD cases). Memory, executive function, and language composite scores were harmonized leveraging latent variable modeling. APOE4‐ stratified GWAS were performed on these phenotypes, controlled for age at baseline, sex, and genetic ancestry. APOE4 interaction models were leveraged to test for statistical differences based on markers identified in stratified discovery analyses. Post‐GWAS included gene tests with MAGMA and genetic correlation analyses with GNOVA. Result Among NHW, we identified an APOE4pos‐specific locus on chromosome 1 (rs7537669, βE4pos = ‐0.12, pE4pos = 2.2E‐08, βE4neg = ‐0.01, pE4neg = 0.17). This variant is with a strong eQTL for CD46, a regulatory element of the complement system. Among APOEneg NHW, we found TXNRD3 was associated with memory and a negative genetic correlation between amyotrophic lateral sclerosis (ALS) and memory performance that was not observed in APOE4pos individuals. Finally, we observed an APOE4neg association between CRELD and executive function among NHB individuals. Conclusion In the largest APOE4‐stratified GWAS of multi‐domain cognitive performance, we identified a number of novel genetic loci and genetic correlations that appear to act in an APOE4‐stratified manner. Given the known heterogeneity in clinical progression, age‐related risk, and response to therapeutics that has been reported, it will be important to disentangle molecular pathways that differ by APOE genotype to move towards precision interventions

Sex differences in APOE effects on cognition are domain‐specific

Background Two‐thirds of Alzheimer’s disease (AD) patients are women and there are well‐established sex differences in the association between APOE and cognitive impairment in AD. However, it is not clear whether sex‐specific cognitive consequences of APOE emerge across all cognitive domains or in a domain‐specific manner. Method Data were obtained from 38,386 participants in four longitudinal studies of aging and AD. The average age of participants at baseline was 75±8 years (10% AD, 42% male, 12% African American [AA], 12% APOE‐ε2 carriers, and 36% APOE‐ε4 carriers). Based on detailed neuropsychological exams, harmonized composite scores for memory, executive function, and language were generated using latent variable modeling. Linear regression assessed APOE*sex interactions on each baseline cognitive domain score. Mixed‐effects regression models assessed sex interactions with APOE on cognitive trajectories, including fixed and random effects for both the intercept and the slope (years from baseline). All models adjusted for age at baseline, sex, and race/ethnicity. Exploratory analyses of the potential effect of race/ethnicity were also performed using an APOE*sex*race interaction term in the model. Result As expected, APOE‐ε4 was associated with worse cognitive performance, and APOE‐ε2 was associated with better performance in all domains, both at baseline and longitudinally (p<0.001). At baseline, we observed a significant sex*APOE‐ε4 interaction on memory (β=‐0.06, p<0.001) and significant sex*APOE‐ε2 interaction on memory (β=0.05, p=0.03). In both cases, the association between APOE and memory was significantly stronger in females compared to males. Notably, despite the large sample size, no interactions were observed in the two other cognitive domains or in the longitudinal analysis. Additionally, we observed a significant interaction between sex*APOE‐ε2*race on baseline memory (β=‐0.19, p=0.02), whereby the APOE‐ε2*sex interaction was significant in non‐Hispanic whites (β=0.06, p<0.01) but not in AA (β=‐0.11, p=0.10). Conclusion We provide new evidence that the sex difference in APOE in cognition is most pronounced in relation to memory performance and is particularly driven by differences in baseline performance rather than trajectories of performance over time. Future work will examine intersections with clinical diagnosis to better differentiate sex differences in APOE associations in the context of normal aging and neurodegenerative disease

Roosevelt Island Climate Evolution (RICE) ice core isotope record

High-resolution, well-dated climate archives provide an opportunity to investigate the dynamic interactions of climate patterns relevant for future projections. Here, we present data from a new, annually-dated ice core record from the eastern Ross Sea. Comparison of the Roosevelt Island Climate Evolution (RICE) ice core records with climate reanalysis data for the 1979-2012 calibration period shows that RICE records reliably capture temperature and snow precipitation variability of the region. RICE is compared with data from West Antarctica (West Antarctic Ice Sheet Divide Ice Core) and the western (Talos Dome) and eastern (Siple Dome) Ross Sea. For most of the past 2,700 years, the eastern Ross Sea was warming with perhaps increased snow accumulation and decreased sea ice extent. However, West Antarctica cooled whereas the western Ross Sea showed no significant temperature trend. From the 17th Century onwards, this relationship changes. All three regions now show signs of warming, with snow accumulation declining in West Antarctica and the eastern Ross Sea, but increasing in the western Ross Sea. Analysis of decadal to centennial-scale climate variability superimposed on the longer term trend reveal that periods characterised by opposing temperature trends between the Eastern and Western Ross Sea have occurred since the 3rd Century but are masked by longer-term trends. This pattern here is referred to as the Ross Sea Dipole, caused by a sensitive response of the region to dynamic interactions of the Southern Annual Mode and tropical forcings

The Ross Sea Dipole – Temperature, Snow Accumulation and Sea Ice Variability in the Ross Sea Region, Antarctica, over the Past 2,700 Years

Abstract. High-resolution, well-dated climate archives provide an opportunity to investigate the dynamic interactions of climate patterns relevant for future projections. Here, we present data from a new, annually-dated ice core record from the eastern Ross Sea. Comparison of the Roosevelt Island Climate Evolution (RICE) ice core records with climate reanalysis data for the 1979–2012 calibration period shows that RICE records reliably capture temperature and snow precipitation variability of the region. RICE is compared with data from West Antarctica (West Antarctic Ice Sheet Divide Ice Core) and the western (Talos Dome) and eastern (Siple Dome) Ross Sea. For most of the past 2,700 years, the eastern Ross Sea was warming with perhaps increased snow accumulation and decreased sea ice extent. However, West Antarctica cooled whereas the western Ross Sea showed no significant temperature trend. From the 17th Century onwards, this relationship changes. All three regions now show signs of warming, with snow accumulation declining in West Antarctica and the eastern Ross Sea, but increasing in the western Ross Sea. Analysis of decadal to centennial-scale climate variability superimposed on the longer term trend reveal that periods characterised by opposing temperature trends between the Eastern and Western Ross Sea have occurred since the 3rd Century but are masked by longer-term trends. This pattern here is referred to as the Ross Sea Dipole, caused by a sensitive response of the region to dynamic interactions of the Southern Annual Mode and tropical forcings