Identification of circulating proteins associated with general cognitive function among middle-aged and older adults

Identifying circulating proteins associated with cognitive function may point to biomarkers and molecular process of cognitive impairment. Few studies have investigated the association between circulating proteins and cognitive function. We identify 246 protein measures quantified by the SomaScan assay as associated with cognitive function (p < 4.9E-5, n up to 7289). Of these, 45 were replicated using SomaScan data, and three were replicated using Olink data at Bonferroni-corrected significance. Enrichment analysis linked the proteins associated with general cognitive function to cell signaling pathways and synapse architecture. Mendelian randomization analysis implicated higher levels of NECTIN2, a protein mediating viral entry into neuronal cells, with higher Alzheimer’s disease (AD) risk (p = 2.5E-26). Levels of 14 other protein measures were implicated as consequences of AD susceptibility (p < 2.0E-4). Proteins implicated as causes or consequences of AD susceptibility may provide new insight into the potential relationship between immunity and AD susceptibility as well as potential therapeutic targets

Similarities and differences between sexes in regional loss of cortical and trabecular bone in the mid-femoral neck: the AGES-Reykjavik longitudinal study.

The risk of hip fracture rises rapidly with age, and is notably higher in women. After falls and prior fragility fractures, the main clinically recognized risk factor for hip fracture is reduced bone density. To better understand the extent to which femoral neck density and structure change with age in each sex, we carried out a longitudinal study in subjects not treated with agents known to influence bone mineral density (BMD), to investigate changes in regional cortical thickness, as well as cortical and trabecular BMD at the mid-femoral neck. Segmental quantitative computed tomography (QCT) analysis was used to assess bone measurements in two anatomic subregions, the superolateral (superior) and inferomedial (inferior). A total of 400 older individuals (100 men and 300 women, aged 66-90 years) who were participants in the Age Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik), were studied. Participants had two QCT scans of the hip over a median follow-up of 5.1 years (mean baseline age 74 years). Changes in bone values during follow-up were estimated from mixed effects regression models. At baseline women had lower bone values in the superior region than men. At follow-up all bone values were lower in women, except cortical volumetric bone mineral density (vBMD) inferiorly. The relative losses in all bone values estimated in the superior region were substantially (about threefold) and significantly greater compared to those estimated in the inferior region in both sexes. Women lost cortical thickness and cortical vBMD more rapidly than men in both regions; and this was only weakly reflected in total femoral neck dual-energy X-ray absorptiometry (DXA)-like results. The higher rate of bone loss in women at critical locations may contribute materially to the greater femoral neck fracture incidence among women than men

Similarities and differences between sexes in regional loss of cortical and trabecular bone in the mid-femoral neck: the AGES-Reykjavik longitudinal study.

The risk of hip fracture rises rapidly with age, and is notably higher in women. After falls and prior fragility fractures, the main clinically recognized risk factor for hip fracture is reduced bone density. To better understand the extent to which femoral neck density and structure change with age in each sex, we carried out a longitudinal study in subjects not treated with agents known to influence bone mineral density (BMD), to investigate changes in regional cortical thickness, as well as cortical and trabecular BMD at the mid-femoral neck. Segmental quantitative computed tomography (QCT) analysis was used to assess bone measurements in two anatomic subregions, the superolateral (superior) and inferomedial (inferior). A total of 400 older individuals (100 men and 300 women, aged 66-90 years) who were participants in the Age Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik), were studied. Participants had two QCT scans of the hip over a median follow-up of 5.1 years (mean baseline age 74 years). Changes in bone values during follow-up were estimated from mixed effects regression models. At baseline women had lower bone values in the superior region than men. At follow-up all bone values were lower in women, except cortical volumetric bone mineral density (vBMD) inferiorly. The relative losses in all bone values estimated in the superior region were substantially (about threefold) and significantly greater compared to those estimated in the inferior region in both sexes. Women lost cortical thickness and cortical vBMD more rapidly than men in both regions; and this was only weakly reflected in total femoral neck dual-energy X-ray absorptiometry (DXA)-like results. The higher rate of bone loss in women at critical locations may contribute materially to the greater femoral neck fracture incidence among women than men

Carta de Joan M. Malapeira, Vice-rector d'Ordenació Acadèmica i Professorat de la UB, a Pere Pascual convocant-lo pel Tribunal que jutgi la provisió de la plaça de Catedràtic d'Universitat de Física Teòrica

In this prospective nested case-control study we analyzed the circumferential differences in estimated cortical thickness (Est CTh) of the mid femoral neck as a risk factor for osteoporotic hip fractures in elderly women and men. Segmental QCT analysis of the mid femoral neck was applied to assess cortical thickness in anatomical quadrants. The superior region of the femoral neck was a stronger predictor for hip fracture than the inferior region, particularly in men. There were significant gender differences in Est CTh measurements in the control group but not in the case group. In multivariable analysis for risk of femoral neck (FN) fracture, Est CTh in the supero-anterior (SA) quadrant was significant in both women and men, and remained a significant predictor after adjustment for FN areal BMD (aBMD, dimensions g/cm², DXA-like), (p=0.05 and p<0.0001, respectively). In conclusion, Est CTh in the SA quadrant best discriminated cases (n=143) from controls (n=298), especially in men. Cortical thinning superiorly in the hip might be of importance in determining resistance to fracture

Genome-wide Studies of Verbal Declarative Memory in Nondemented Older People: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium

BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting. METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia-and stroke-free individuals of European descent, aged >= 45 years. Replication of suggestive associations (p < 5 x 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults. RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 55.7 x 10(-10)) and replication cohorts (p = 5.65 x 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 x 10(-8), and rs6813517 [SPOCK3], p = 2.58 x 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism. CONCLUSIONS: This largest study to date exploring the genetics of memory function in similar to 40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways

Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium

Erythrocyte measures are heritable and have important health implications, yet their genetic determinants are largely unknown. We performed genome-wide association analyses in 24,167 European-ancestry individuals for six erythrocyte traits and identified associations at 23 loci (P values 5×10(-8) to 1×10(-57)). Replication testing in an independent set of 9,456 European-ancestry individuals showed strong evidence of association in all 23 loci in meta-analysis of the discovery and replication cohorts. Our findings include previously identified loci (HBS1L/MYB, HFE, TMPRSS6, TFR2, SPTA1) and novel associations (EPO, TFRC, SH2B3, and 15 other loci). This study has identified novel determinants of erythrocyte traits, offering insight into common variants underlying variation in erythrocyte measures

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes