Learning deficit in cognitively normal apoe ε4 carriers with low β-amyloid

Introduction: In cognitively normal (CN) adults, increased rates of amyloid beta (Aβ) accumulation can be detected in low Aβ (Aβ–) apolipoprotein E (APOE) ε4 carriers. We aimed to determine the effect of ε4 on the ability to benefit from experience (ie, learn) in Aβ–CNs. Methods: Aβ– CNs(n= 333) underwent episodic memory assessments every 18 months for 108 months. A subset (n = 48) completed the Online Repeatable Cognitive Assessment-Language Learning Test (ORCA-LLT) over 6 days. Results: Aβ– ε4 carriers showed significantly lower rates of improvement on episodic memory over 108 months compared to non-carriers (d = 0.3). Rates of learning on the ORCA-LLT were significantly slower in Aβ– ε4 carriers compared to non-carriers (d = 1.2). Discussion: In Aβ– CNs,ε4 is associated with a reduced ability to benefit from experience. This manifested as reduced practice effects (small to moderate in magnitude) over 108 months on the episodic memory composite, and a learning deficit (large in magnitude) over 6 days on the ORCA-LLT. Alzheimer’s disease (AD)–related cognitive abnormalities can manifest before preclinical AD thresholds

Amyloid-related memory decline in preclinical Alzheimer\u27s disease in dependent on APOE ε4 and is detectable over 18-months

High levels of β-amyloid (Aβ) in the brain and carriage of the APOE ε4 allele have each been linked to cognitive impairment in cognitively normal (CN) older adults. The aim of this study was to investigate the relationship between cerebral Aβ level, APOE ε4 carrier status, and cognitive decline over 18 monthes, in 317 cognitively healthy (CN) older adults (47% males, 52.4% females) aged between 60 and 89 years (Mean = 69.9, SC = 6.8). Cognition was assessed using the Cogstate Brief Battery (CBB) and the California Verbal Learning Test, Second Edition (CVLT-II). Planned comparisons indicated that CN older adults with high Aβ who were also APOE ε4 carriers demonstrated the most pronounced decline in learning and working memory. In CN older adults who were APOE ε4 non-carriers, high Aβwas unrelated to cognitive decline in learning and working memory. Carriage of APOE ε4 in CN older adults with low Aβ was associated with a significantly increased rate of decline in learning and unexpectedly, improved cognitive performance on measures of verbal episodic memory over 18 months. These results suggest that Aβ and APOE ε4 interact to increase the rate of cognitive decline in CN older adults and provide further support for the use of Aβ and APOE ε4 as biomarkers of early Alzheimer’s disease

Association of β-amyloid level, clinical progression and longitudinal cognitive change in normal older individuals

Objective To determine the effect of β-amyloid (Aβ) level on progression risk to mild cognitive impairment (MCI) or dementia and longitudinal cognitive change in cognitively normal (CN) older individuals. Methods All CN from the Australian Imaging Biomarkers and Lifestyle study with Aβ PET and ≥ 3 years follow-up were included (n = 534; age 72 ± 6 years; 27% Aβ positive; follow-up 5.3 ± 1.7 years). Aβ level was divided using the standardized 0–100 Centiloid scale: \u3c 15 CL negative, 15–25 CL uncertain, 26–50 CL moderate, 51–100 CL high, \u3e 100 CL very high, noting \u3e 25 CL approximates a positive scan. Cox proportional hazards analysis and linear mixed effect models were used to assess risk of progression and cognitive decline. Results Aβ levels in 63% were negative, 10% uncertain, 10% moderate, 14% high, and 3% very high. Fifty-seven (11%) progressed to MCI or dementia. Compared to negative Aβ, the hazard ratio for progression for moderate Aβ was 3.2 (95% confidence interval [CI] 1.3–7.6; p \u3c 0.05), for high was 7.0 (95% CI 3.7–13.3; p \u3c 0.001), and for very high was 11.4 (95% CI 5.1–25.8; p \u3c 0.001). Decline in cognitive composite score was minimal in the moderate group (−0.02 SD/year, p = 0.05), while the high and very high declined substantially (high −0.08 SD/year, p \u3c 0.001; very high −0.35 SD/year, p \u3c 0.001). Conclusion The risk of MCI or dementia over 5 years in older CN is related to Aβ level on PET, 5% if negative vs 25% if positive but ranging from 12% if 26–50 CL to 28% if 51–100 CL and 50% if \u3e 100 CL. This information may be useful for dementia risk counseling and aid design of preclinical AD trials

COMT val158met is not associated with Aβ-amyloid and APOE ε4 related cognitive decline in cognitively normal older adults

The non-synonymous single nucleotide polymorphism (SNP), Val158Met within the Catechol-O-methyltransferase (COMT) gene has been associated with altered levels of cognition and memory performance in cognitively normal adults. This study aimed to investigate the independent and interactional effects of COMT Val158Met on cognitive performance. In particular, it was hypothesised that COMT Val158Met would modify the effect of neocortical Aβ-amyloid (Aβ) accumulation and carriage of the apolipoprotein E (APOE) ε4 allele on cognition in preclinical Alzheimer’s disease (AD). In 598 cognitively normal older adults with known neocortical Aβ levels, linear mixed modelling revealed no significant independent or interactional associations between COMT Val158Met and cognitive decline. These findings do not support previous associations between COMT Val158Met and cognitive performance and suggest this variant does not influence Aβ-amyloid or APOE ε4 driven cognitive decline in a well characterised cohort of cognitively normal older adults

Rates of age- and amyloid β-associated cortical atrophy in older adults with superior memory performance

Introduction: Superior cognitive performance in older adults may reflect underlying resistance to age-associated neurodegeneration. While elevated amyloid b (Ab) deposition (Ab1) has been associated with increased cortical atrophy, it remains unknown whether “SuperAgers” may be protected from Ab-associated neurodegeneration. Methods: Neuropsychologically defined SuperAgers (n 5 172) and cognitively normal for age (n 5 172) older adults from the Australian Imaging, Biomarkers and Lifestyle study were case matched. Rates of cortical atrophy over 8 years were examined by SuperAger classification and Ab status. Results: Of the case-matched SuperAgers and cognitively normal for age older adults, 40.7% and 40.1%, respectively, were Ab1. Rates of age- and Ab-associated atrophy did not differ between the groups on any measure. Ab2 individuals displayed the slowest rates of atrophy. Discussion: Maintenance of superior memory in late life does not reflect resistance to age- or Abassociated atrophy. However, those individuals who reached old age without cognitive impairment nor elevated Ab deposition (i.e. Ab2) displayed reduced rates of cortical atrophy

SPON1 is associated with amyloid-β and APOE ϵ4-related cognitive decline in cognitively normal adults

Background: Genetic variation in Spondin-1, specifically rs11023139, has been associated with reduced rates of cognitive decline in individuals with Alzheimer\u27s disease. Objective: The aim of this study was to assess whether the association was present in cognitively normal older adults. Methods: Longitudinal cognitive decline was investigated using linear mixed modelling in a cohort of 590 cognitively normal older adults enrolled in the Australian Imaging, Biomarkers and Lifestyle Study. Results: No independent effect of Spondin-1 rs11023139 on cognitive decline was observed. However, significant associations were observed for the interaction between Apolipoprotein E (APOE) ϵ4 and rs11023139 in individuals with high amyloid-β burden. APOE ϵ4/rs11023139-A carriers declined significantly faster than APOE ϵ4/rs11023139-G-G carriers in measures of global cognition (p=0.011) and verbal episodic memory (p=0.020). Conclusion: These results suggest that carriage of the Spondin-1 rs11023139-A allele significantly contributes to a worsening of cognitive performance in APOE ϵ4 cognitively normal older adults with a high neocortical amyloid-β burden

Galaxies in X-ray Groups I: Robust Membership Assignment and the Impact of Group Environments on Quenching

Understanding the mechanisms that lead dense environments to host galaxies with redder colors, more spheroidal morphologies, and lower star formation rates than field populations remains an important problem. As most candidate processes ultimately depend on host halo mass, accurate characterizations of the local environment, ideally tied to halo mass estimates and spanning a range in halo mass and redshift are needed. In this work, we present and test a rigorous, probabalistic method for assigning galaxies to groups based on precise photometric redshifts and X-ray selected groups drawn from the COSMOS field. The groups have masses in the range 10^13 < M_200c/M_sun < 10^14 and span redshifts 0<z<1. We characterize our selection algorithm via tests on spectroscopic subsamples, including new data obtained at the VLT, and by applying our method to detailed mock catalogs. We find that our group member galaxy sample has a purity of 84% and completeness of 92% within 0.5 R200c. We measure the impact of uncertainties in redshifts and group centering on the quality of the member selection with simulations based on current data as well as future imaging and spectroscopic surveys. As a first application of our new group member catalog which will be made publicly available, we show that member galaxies exhibit a higher quenched fraction compared to the field at fixed stellar mass out to z~1, indicating a significant relationship between star formation and environment at group scales. We also address the suggestion that dusty star forming galaxies in such groups may impact the high-l power spectrum of the cosmic microwave background and find that such a population cannot explain the low power seen in recent SZ measurements.Comment: ApJ accepted. Catalogs will be posted at IRSA upon publication, currently available upon reques

A Polygenic Risk Score Derived From Episodic Memory Weighted Genetic Variants Is Associated With Cognitive Decline in Preclinical Alzheimer's Disease

Studies of Alzheimer's disease risk-weighted polygenic risk scores (PRSs) for cognitive performance have reported inconsistent associations. This inconsistency is particularly evident when PRSs are assessed independent of APOE genotype. As such, the development and assessment of phenotype-specific weightings to derive PRSs for cognitive decline in preclinical AD is warranted. To this end a episodic memory-weighted PRS (emPRS) was derived and assessed against decline in cognitive performance in 226 healthy cognitively normal older adults with high brain Aβ-amyloid burden participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. The effect size for decline in a verbal episodic memory was determined individually for 27 genetic variants in a reference sample (n = 151). These were then summed to generate a emPRS either including APOE (emPRSc̅APOE) or excluding APOE (emPRSs̅APOE ). Resultant emPRS were then evaluated, in a test sample (n = 75), against decline in global cognition, verbal episodic memory and a pre-Alzheimer's cognitive composite (AIBL-PACC) over 7.5 years. The mean (SD) age of the 226 participants was 72.2 (6.6) years and 116 (51.3%) were female. Reference and test samples did not differ significantly demographically. Whilst no association of emPRSs were observed with baseline cognition, the emPRSc̅ APOE was associated with longitudinal global cognition (-0.237, P = 0.0002), verbal episodic memory (-0.259, P = 0.00003) and the AIBL-PACC (-0.381, P = 0.02). The emPRSs̅ APOE was also associated with global cognition (-0.169, P = 0.021) and verbal episodic memory (-0.208, P = 0.004). Stratification by APOE ε4 revealed that the association between the emPRS and verbal episodic memory was limited to carriage of no ε4 or one ε4 allele. This was also observed for global cognition. The emPRS and rates of decline in AIBL-PACC were associated in those carrying one ε4 allele. Overall, the described novel emPRS has utility for the prediction of decline in cognition in preclinical AD. This study provides evidence to support the further use and evaluation of phenotype weightings in PRS development

The Eighth Data Release of the Sloan Digital Sky Survey: First Data from SDSS-III

The Sloan Digital Sky Survey (SDSS) started a new phase in August 2008, with new instrumentation and new surveys focused on Galactic structure and chemical evolution, measurements of the baryon oscillation feature in the clustering of galaxies and the quasar Ly alpha forest, and a radial velocity search for planets around ~8000 stars. This paper describes the first data release of SDSS-III (and the eighth counting from the beginning of the SDSS). The release includes five-band imaging of roughly 5200 deg^2 in the Southern Galactic Cap, bringing the total footprint of the SDSS imaging to 14,555 deg^2, or over a third of the Celestial Sphere. All the imaging data have been reprocessed with an improved sky-subtraction algorithm and a final, self-consistent photometric recalibration and flat-field determination. This release also includes all data from the second phase of the Sloan Extension for Galactic Understanding and Evolution (SEGUE-2), consisting of spectroscopy of approximately 118,000 stars at both high and low Galactic latitudes. All the more than half a million stellar spectra obtained with the SDSS spectrograph have been reprocessed through an improved stellar parameters pipeline, which has better determination of metallicity for high metallicity stars.Comment: Astrophysical Journal Supplements, in press (minor updates from submitted version

The clinical and functional significance of c-Met in breast cancer: a review

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.CMH-Y is funded by a Cancer Research UK Clinical Research Fellowship. JLJ is funded by the Breast Cancer Campaign Tissue Bank