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Examining underlying neurostructural correlates of specific cognitive abilities is practically and theoretically complicated by the existence of the positive manifold (all cognitive tests positively correlate): if a brain structure is associated with a cognitive task, how much of this is uniquely related to the cognitive domain, and how much is due to covariance with all other tests across domains (captured by general cognitive functioning, also known as general intelligence, or 'g')? We quantitatively address this question by examining associations between brain structural and diffusion MRI measures (global tissue volumes, white matter hyperintensities, global white matter diffusion fractional anisotropy and mean diffusivity, and FreeSurfer processed vertex-wise cortical volumes, smoothed at 20mm fwhm) with g and cognitive domains (processing speed, crystallised ability, memory, visuospatial ability). The cognitive domains were modelled using confirmatory factor analysis to derive both hierarchical and bifactor solutions using 13 cognitive tests in 697 participants from the Lothian Birth Cohort 1936 study (mean age 72.5 years; SD = .7). Associations between the extracted cognitive factor scores for each domain and g were computed for each brain measure covarying for age, sex and intracranial volume, and corrected for false discovery rate. There were a range of significant associations between cognitive domains and global MRI brain structural measures (r range .008 to .269, p < .05). Regions implicated by vertex-wise regional cortical volume included a widespread number of medial and lateral areas of the frontal, temporal and parietal lobes. However, at both global and regional level, much of the domain-MRI associations were shared (statistically accounted for by g). Removing g-related variance from cognitive domains attenuated association magnitudes with global brain MRI measures by 27.9-59.7% (M = 46.2%), with only processing speed retaining all significant associations. At the regional cortical level, g appeared to account for the majority (range 22.1-88.4%; M = 52.8% across cognitive domains) of regional domain-specific associations. Crystallised and memory domains had almost no unique cortical correlates, whereas processing speed and visuospatial ability retained limited cortical volumetric associations. The greatest spatial overlaps across cognitive domains (as denoted by g) were present in the medial and lateral temporal, lateral parietal and lateral frontal areas., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Identifying predictors of cognitive decline in old age helps us understand its mechanisms and identify those at greater risk. Here, we examined how cognitive change from ages 11 to 70 is associated with cognitive change at older ages (70 to 82 years) in the Lothian Birth Cohort 1936 longitudinal study ( N = 1,091 at recruitment). Using latent-growth-curve models, we estimated rates of change from ages 70 to 82 in general cognitive ability ( g ) and in three cognitive domains: visuospatial, memory, and processing speed. We found that g accounted for 71.3% of interindividual change variance. Greater cognitive gain from ages 11 to 70 predicted slower decline in g over 12 subsequent years (β = 0.163, p = .001), independently of cognitive level in childhood and at age 70, and domain-specific change beyond g . These results contribute to the goal of identifying people at higher risk of age-related cognitive decline.

Background: Studies evaluating the relationship between chronic inflammation and cognitive functioning have produced heterogeneous results. A potential reason for this is the variability of inflammatory mediators which could lead to misclassifications of individuals' persisting levels of inflammation. DNA methylation (DNAm) has shown utility in indexing environmental exposures and could be leveraged to provide proxy signatures of chronic inflammation., Method: We conducted an elastic net regression of interleukin-6 (IL-6) in a cohort of 875 older adults (Lothian Birth Cohort 1936; mean age: 70 years) to develop a DNAm-based predictor. The predictor was tested in an independent cohort (Generation Scotland; N = 7028 [417 with measured IL-6], mean age: 51 years)., Results: A weighted score from 35 CpG sites optimally predicted IL-6 in the independent test set (Generation Scotland; R2 = 4.4%, p = 2.1 × 10-5). In the independent test cohort, both measured IL-6 and the DNAm proxy increased with age (serum IL-6: n = 417, β = 0.02, SE = 0.004, p = 1.3 × 10-7; DNAm IL-6 score: N = 7028, β = 0.02, SE = 0.0009, p < 2 × 10-16). Serum IL-6 did not associate with cognitive ability (n = 417, β = -0.06, SE = 0.05, p = .19); however, an inverse association was identified between the DNAm score and cognitive functioning (N = 7028, β = -0.16, SE = 0.02, pFDR < 2 × 10-16)., Conclusions: These results suggest methylation-based predictors can be used as proxies for inflammatory markers, potentially allowing for further insight into the relationship between inflammation and pertinent health outcomes., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cerebral small vessel disease (SVD) is a leading cause of vascular cognitive impairment, however the precise nature of SVD-related cognitive deficits, and their associations with structural brain changes, remain unclear. We combined computational volumes and visually-rated MRI markers of SVD to quantify total SVD burden, using data from the Lothian Birth Cohort 1936 (n = 540; age: 72.6 ± 0.7 years). We found negative associations between total SVD burden and general cognitive ability (standardized β: -0.363; 95%CI: [-0.49, -0.23]; p (FDR) < 0.001), processing speed (-0.371 [-0.50, -0.24]; p (FDR) < 0.001), verbal memory (-0.265; [-0.42, -0.11]; p (FDR)  = 0.002), and visuospatial ability (-0.170; [-0.32, -0.02]; p (FDR)  = 0.029). Only the association between SVD burden and processing speed remained after accounting for covariance with general cognitive ability (-0.325; [-0.61, -0.04]; p (FDR)  = 0.029). This suggests that SVD's association with poorer processing speed is not driven by, but is independent of its association with poorer general cognitive ability. Tests of processing speed may be particularly sensitive to the cognitive impact of SVD, but all major cognitive domains should be tested to determine the full range of SVD-related cognitive characteristics., (Copyright © 2021. Published by Elsevier Inc.)

Poorer performance on standard tests of pre-morbid cognitive function is related to an elevated risk of death from lower respiratory tract infections but the link with coronavirus (COVID‑19) mortality is untested. Participants in UK Biobank, aged 40 to 69 years at study induction (2006-10), were administered a reaction time test, an indicator of information processing speed, and also had their verbal-numeric reasoning assessed. Between April 1st and September 23rd 2020 there were 388 registry-confirmed deaths (138 women) ascribed to COVID-19 in 494,932 individuals (269,602 women) with a reaction time test result, and 125 such deaths (38 women) in the subgroup of 180,198 people (97,794 women) with data on verbal-numeric reasoning. In analyses adjusted for age, sex, and ethnicity, a one standard deviation slower reaction time was related to a higher rate of death from COVID-19 (hazard ratio; 95% confidence interval: 1.18; 1.09, 1.28), as was a one standard deviation disadvantage on the verbal-numeric reasoning test (1.32; 1.09, 1.59). While there was some attenuation in these relationships after adjustment for additional covariates which included socio-economic status and lifestyle factors, the two pre-pandemic indicators of cognitive function continued to be related to COVID-19 mortality.

This paper is a proposal for an update on the characterization of cognitive impairments associated with sporadic cerebral small vessel disease (SVD). We pose a series of questions about the nature of SVD-related cognitive impairments and provide answers based on a comprehensive review and meta-analysis of published data from 69 studies. Although SVD is thought primarily to affect executive function and processing speed, we hypothesize that SVD affects all major domains of cognitive ability. We also identify low levels of education as a potentially modifiable risk factor for SVD-related cognitive impairment. Therefore, we propose the use of comprehensive cognitive assessments and the measurement of educational level both in clinics and research settings, and suggest several recommendations for future research., (© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Previous cross-sectional findings indicate that hearing and cognitive abilities are positively correlated in childhood, adulthood, and older age. We used an unusually valuable longitudinal dataset from a single-year birth cohort study, the National Child Development Study 1958, to test how hearing and cognitive abilities relate to one another across the life course from childhood to middle age. Cognitive ability was assessed with a single test of general cognitive ability at age 11 years and again with multiple tests at age 50. Hearing ability was assessed, using a pure tone audiogram, in childhood at ages 11 and 16 and again at age 44. Associations between childhood and middle-age hearing and cognitive abilities were investigated using structural equation modelling. We found that higher cognitive ability was associated with better hearing (indicated by a lower score on the hearing ability variables); this association was apparent in childhood ( r   =  -0.120, p <0.001) and middle age ( r   =  -0.208, p <0.001). There was a reciprocal relationship between hearing and cognitive abilities over time: better hearing in childhood was weakly associated with a higher cognitive ability in middle age ( β   =  -0.076, p   =  0.001), and a higher cognitive ability in childhood was associated with better hearing in middle age ( β   =  -0.163, p <0.001). This latter, stronger effect was mediated by occupational and health variables in adulthood. Our results point to the discovery of a potentially life-long relationship between hearing and cognitive abilities and demonstrate how these variables may influence one another over time.

It has been known since 1904 that, in humans, diverse cognitive traits are positively intercorrelated. This forms the basis for the general factor of intelligence (g). Here, we directly test whether there is a partial genetic basis for individual differences in g using data from seven different cognitive tests (n = 11,263-331,679) and genome-wide autosomal single-nucleotide polymorphisms. A genetic g factor accounts for an average of 58.4% (s.e. = 4.8%) of the genetic variance in the cognitive traits considered, with the proportion varying widely across traits (range, 9-95%). We distil genetic loci that are broadly relevant for many cognitive traits (g) from loci associated specifically with individual cognitive traits. These results contribute to elucidating the aetiology of a long-known yet poorly understood phenomenon, revealing a fundamental dimension of genetic sharing across diverse cognitive traits.

Objective: To examine the cross-sectional associations between dietary patterns and cognitive and neuroimaging indices of brain health concurrently in the same sample of healthy older adults., Methods: Dietary patterns were derived from a 130-item food frequency questionnaire for 511 individuals in the Lothian Birth Cohort 1936 (mean age 79.3 ± 0.6 years). Composite scores for global cognitive function, visuospatial ability, processing speed, memory, and verbal ability were assessed. Brain volumes and white matter microstructure were assessed in participants (n = 358) who also underwent structural magnetic resonance imaging., Results: A Mediterranean-style dietary pattern and a processed dietary pattern were identified using principal component analysis of food frequency questionnaire items. In fully-adjusted linear regression models, adherence to the Mediterranean-style pattern was associated with better verbal ability (β = 0.121, P = 0.002). Associations with global cognitive function (β = 0.094, P = 0.043), visuospatial ability (β = 0.113, P = 0.019), and memory (β = 0.105, P = 0.029) did not survive correction for multiple comparisons. Associations between the processed pattern and lower cognitive scores were attenuated by around 50% following adjustment for prior (childhood) cognitive ability; only an association with verbal ability remained (β = -0.130, P = 0.001). Neither dietary pattern was associated with brain volumes or white matter microstructure. Specific Mediterranean diet features-green leafy vegetables and a low intake of red meat-were associated with better cognitive functioning., Conclusions: These observational findings suggest that adherence to a Mediterranean-style diet is associated with better cognitive functioning, but not better brain structural integrity, in older adults., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: While certain infectious diseases have been linked to socioeconomic disadvantage, mental health problems, and lower cognitive function, relationships with COVID-19 are either uncertain or untested. Our objective was to examine the association of a range of psychosocial factors with hospitalisation for COVID-19., Methods: UK Biobank, a prospective cohort study, comprises around half a million people who were aged 40-69 years at study induction between 2006 and 2010 when information on psychosocial factors and covariates were captured. Hospitalisations for COVID-19 were ascertained between 16th March and 26th April 2020., Results: There were 908 hospitalisations for COVID-19 in an analytical sample of 431,051 England-based study members. In age- and sex-adjusted analyses, an elevated risk of COVID-19 was related to disadvantaged levels of education (odds ratio; 95% confidence interval: 2.05; 1.70, 2.47), income (2.00; 1.63, 2,47), area deprivation (2.20; 1.86, 2.59), occupation (1.39; 1.14, 1.69), psychological distress (1.58; 1.32, 1.89), mental health (1.50; 1.25, 1.79), neuroticism (1.19; 1.00, 1.42), and performance on two tests of cognitive function - verbal and numerical reasoning (2.66; 2.06, 3.34) and reaction speed (1.27; 1.08, 1.51). These associations were graded (p-value for trend ≤ 0.038) such that effects were apparent across the full psychosocial continua. After mutual adjustment for these characteristics plus ethnicity, comorbidity, and lifestyle factors, only the relationship between lower cognitive function as measured using the reasoning test and risk of the infection remained (1.98; 1.38, 2.85)., Conclusions: A range of psychosocial factors revealed associations with hospitalisation for COVID-19 of which the relation with cognitive function, a marker of health literacy, was most robust., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Brain iron deposits (IDs) are indicative of microvessel dysfunction which may predispose to small vessel disease (SVD) brain damage and worsen cognition later in life. Visible perivascular spaces in the centrum semiovale (CSO-PVS) are SVD features linked with microvessel dysfunction. We examined possible associations of CSO-PVS volume and count with brain IDs and cognitive abilities in 700 community-dwelling individuals from the Lothian Birth Cohort 1936 who underwent detailed cognitive testing and multimodal brain MRI at mean age 72.7 years. Brain IDs were assessed automatically followed by manual editing. PVS were automatically assessed in the centrum semiovale and deep corona radiata supraventricular. General factors of overall cognitive function (g), processing speed (g-speed) and memory (g-memory) were used in the analyses. Median (IQR) volumes of IDs and CSO-PVS expressed as a percentage of intracranial volume were 0.0021 (0.011) and 0.22 (0.13)% respectively. Median count of CSO-PVS was 410 (IQR = 201). Total volumes of CSO-PVS and ID, adjusted for head size, were correlated (Spearman ρ = 0.13, p < 0.001). CSO-PVS volume, despite being correlated with all three cognitive measures, was only associated with g-memory (B = -114.5, SE = 48.35, p = 0.018) in general linear models, adjusting for age, sex, vascular risk factors, childhood intelligence and white matter hyperintensity volume. The interaction of CSO-PVS count with diabetes (B = -0.0019, SE = 0.00093, p = 0.041) and volume with age (B = 1.57, SE = 0.67, p = 0.019) were also associated with g-memory. Linear regression models did not replicate these associations. Therefore, it does not seem that CSO-PVS burden is directly associated with general cognitive ability in older age.

Polygenic scores can be used to distil the knowledge gained in genome-wide association studies for prediction of health, lifestyle, and psychological factors in independent samples. In this preregistered study, we used fourteen polygenic scores to predict variation in cognitive ability level at age 70, and cognitive change from age 70 to age 79, in the longitudinal Lothian Birth Cohort 1936 study. The polygenic scores were created for phenotypes that have been suggested as risk or protective factors for cognitive ageing. Cognitive abilities within older age were indexed using a latent general factor estimated from thirteen varied cognitive tests taken at four waves, each three years apart (initial n = 1091 age 70; final n = 550 age 79). The general factor indexed over two-thirds of the variance in longitudinal cognitive change. We ran additional analyses using an age-11 intelligence test to index cognitive change from age 11 to age 70. Several polygenic scores were associated with the level of cognitive ability at age-70 baseline (range of standardized β-values = -0.178 to 0.302), and the polygenic score for education was associated with cognitive change from childhood to age 70 (standardized β = 0.100). No polygenic scores were statistically significantly associated with variation in cognitive change between ages 70 and 79, and effect sizes were small. However, APOE e4 status made a significant prediction of the rate of cognitive decline from age 70 to 79 (standardized β = -0.319 for carriers vs. non-carriers). The results suggest that the predictive validity for cognitive ageing of polygenic scores derived from genome-wide association study summary statistics is not yet on a par with APOE e4, a better-established predictor.

The current study investigates the heterogeneity of cognitive trajectories at the end of life by assigning individuals into groups according to their cognitive trajectories prior to death. It also examines the role of childhood intelligence and education on these trajectories and group membership. Participants were drawn from the Lothian Birth Cohort of 1921 (LBC1921), a longitudinal study of individuals with a mean age of 79 years at study entry, and observed up to a maximum of five times to their early 90s. Growth mixture modeling was employed to identify groups of individuals with similar trajectories of global cognitive function measured with the Mini-Mental State Examination (MMSE) in relation to time to death, accounting for childhood intelligence, education, the time to death from study entry, and health conditions (hypertension, diabetes, and cardiovascular disease). Two distinct groups of individuals (classes) were identified: a smaller class (18% of the sample) of individuals whose MMSE scores dropped linearly with about 0.5 MMSE points per year closer to death and a larger group (82% of the sample) with stable MMSE across the study period. Only childhood intelligence was found to be associated with an increased probability of belonging to the stable class of cognitive functioning prior to death (odds ratio = 1.08, standard error = 0.02, p ≤ .001). These findings support a protective role of childhood intelligence, a marker of cognitive reserve, against the loss of cognitive function prior to death. Our results also suggest that terminal decline is not necessarily a normative process. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Background: The ageing process is characterized by declines in physical and cognitive function. However, the relationship between these trajectories remains a topic of investigation., Methods: Using four data waves collected triennially between ages 70 and 79, we tested for associations between multiple cognitive ability domains (verbal memory, processing speed, and visuospatial ability) and physical functions (walking speed, grip strength, and lung function). We first tested for associations between linear declines in physical and cognitive functions over the entire 9-year study period, and then, for lead-lag coupling effects between 3-year changes in cognitive and physical functions., Results: Steeper linear decline in walking speed was moderately correlated with steeper linear declines in each cognitive domain. Steeper linear decline in grip strength was moderately correlated with steeper linear declines in verbal memory and processing speed. Lead-lag coupling models showed that decline in verbal memory was preceded by declines in walking speed and grip strength. By contrast, decline in grip strength was preceded by declines in processing speed and visuospatial ability, and decline in walking speed was preceded by decline in visuospatial ability. Following additional adjustment for covariates, only coupling effects from earlier decline in processing speed to later decline in grip strength remained significant (β = 0.545, p = .006)., Conclusion: Our findings provide further evidence of an association between cognitive and physical declines and point to the potential order in which these changes occur. Decline in processing speed in particular may serve as a unique early marker of declining upper body strength., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Objective: Schizophrenia has recently been associated with widespread white matter microstructural abnormalities, but the functional effects of these abnormalities remain unclear. Widespread heterogeneity of results from studies published to date preclude any definitive characterization of the relationship between white matter and cognitive performance in schizophrenia. Given the relevance of deficits in cognitive function to predicting social and functional outcomes in schizophrenia, the authors carried out a meta-analysis of available data through the ENIGMA Consortium, using a common analysis pipeline, to elucidate the relationship between white matter microstructure and a measure of general cognitive performance, IQ, in patients with schizophrenia and healthy participants., Methods: The meta-analysis included 760 patients with schizophrenia and 957 healthy participants from 11 participating ENIGMA Consortium sites. For each site, principal component analysis was used to calculate both a global fractional anisotropy component (gFA) and a fractional anisotropy component for six long association tracts (LA-gFA) previously associated with cognition., Results: Meta-analyses of regression results indicated that gFA accounted for a significant amount of variation in cognition in the full sample (effect size [Hedges' g]=0.27, CI=0.17-0.36), with similar effects sizes observed for both the patient (effect size=0.20, CI=0.05-0.35) and healthy participant groups (effect size=0.32, CI=0.18-0.45). Comparable patterns of association were also observed between LA-gFA and cognition for the full sample (effect size=0.28, CI=0.18-0.37), the patient group (effect size=0.23, CI=0.09-0.38), and the healthy participant group (effect size=0.31, CI=0.18-0.44)., Conclusions: This study provides robust evidence that cognitive ability is associated with global structural connectivity, with higher fractional anisotropy associated with higher IQ. This association was independent of diagnosis; while schizophrenia patients tended to have lower fractional anisotropy and lower IQ than healthy participants, the comparable size of effect in each group suggested a more general, rather than disease-specific, pattern of association.

UK Biobank is a health resource with data from over 500,000 adults. The cognitive assessment in UK Biobank is brief and bespoke, and is administered without supervision on a touchscreen computer. Psychometric information on the UK Biobank cognitive tests are limited. Despite the non-standard nature of these tests and the limited psychometric information, the UK Biobank cognitive data have been used in numerous scientific publications. The present study examined the validity and short-term test-retest reliability of the UK Biobank cognitive tests. A sample of 160 participants (mean age = 62.59, SD = 10.24) was recruited who completed the UK Biobank cognitive assessment and a range of well-validated cognitive tests ('reference tests'). Fifty-two participants returned 4 weeks later to repeat the UK Biobank tests. Correlations were calculated between UK Biobank tests and reference tests. Two measures of general cognitive ability were created by entering scores on the UK Biobank cognitive tests, and scores on the reference tests, respectively, into separate principal component analyses and saving scores on the first principal component. Four-week test-retest correlations were calculated for UK Biobank tests. UK Biobank cognitive tests showed a range of correlations with their respective reference tests, i.e. those tests that are thought to assess the same underlying cognitive ability (mean Pearson r = 0.53, range = 0.22 to 0.83, p≤.005). The measure of general cognitive ability based on the UK Biobank cognitive tests correlated at r = 0.83 (p < .001) with a measure of general cognitive ability created using the reference tests. Four-week test-retest reliability of the UK Biobank tests were moderate-to-high (mean Pearson r = 0.55, range = 0.40 to 0.89, p≤.003). Despite the brief, non-standard nature of the UK Biobank cognitive tests, some tests showed substantial concurrent validity and test-retest reliability. These psychometric results provide currently-lacking information on the validity of the UK Biobank cognitive tests., Competing Interests: The authors have declared that no competing interests exist.

Methylation levels measured at defined sites across the genome have recently been shown to be correlated with an individual's chronological age. Age acceleration, or the difference between age estimated from DNA methylation status and chronological age, has been proposed as a novel biomarker of aging. In this study, the cross-sectional association between two different measures of age acceleration and cognitive function was investigated using whole blood samples from 2,157 African American participants 47-70 years of age in the population-based Atherosclerosis Risk in Communities (ARIC) Study. Cognition was evaluated using three domain-specific tests. A significant inverse association between a 1-year increase in age acceleration calculated using a blood-based age predictor and scores on the Word Fluency Test was found using a general linear model adjusted for chronological age, gender, and years of education (β = -0.140 words; p = .001) and after adding other potential confounding variables (β = -0.104 words, p = .023). The results were replicated in 1,670 European participants in the Generation Scotland: Scottish Family Health Study (fully adjusted model: β = -0.199 words; p = .034). A significant association was also identified in a trans-ethnic meta-analysis across cohorts that included an additional 708 European American ARIC study participants (fully adjusted model: β = -0.110 words, p = .003). There were no associations found using an estimate of age acceleration derived from multiple tissues. These findings provide evidence that age acceleration is a correlate of performance on a test of verbal fluency in middle-aged adults., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Identifying biological correlates of late life cognitive function is important if we are to ascertain biomarkers for, and develop treatments to help reduce, age-related cognitive decline. Here, we investigated the associations between plasma levels of 90 neurology-related proteins (Olink® Proteomics) and general fluid cognitive ability in the Lothian Birth Cohort 1936 (LBC1936, N = 798), Lothian Birth Cohort 1921 (LBC1921, N = 165), and the INTERVAL BioResource (N = 4451). In the LBC1936, 22 of the proteins were significantly associated with general fluid cognitive ability (β between -0.11 and -0.17). MRI-assessed total brain volume partially mediated the association between 10 of these proteins and general fluid cognitive ability. In an age-matched subsample of INTERVAL, effect sizes for the 22 proteins, although smaller, were all in the same direction as in LBC1936. Plasma levels of a number of neurology-related proteins are associated with general fluid cognitive ability in later life, mediated by brain volume in some cases.

Background: Physical frailty is associated with many adverse outcomes including disability, chronic disease, hospitalisation, institutionalisation and death. It is unclear what impact it might have on the rate of normal cognitive ageing. We investigated whether physical frailty was related to initial level of, and change in, cognitive abilities from age 70 to 79 years., Method: Participants were 950 members of the Lothian Birth Cohort 1936. Physical frailty was assessed at age 70 years using the Fried criteria. Cognitive function was assessed at ages 70, 73, 76 and 79 years. We used linear regression to examine cross-sectional and prospective associations between physical frailty status at age 70 years and factor score estimates for baseline level of and change in four cognitive domains (visuospatial ability, memory, processing speed and crystallised ability) and in general cognitive ability., Results: Physical frailty, but not prefrailty, was associated with lower baseline levels of visuospatial ability, memory, processing speed and general cognitive ability after control for age, sex, education, depressive symptoms, smoking and number of chronic illnesses. Physical frailty was associated with greater decline in each cognitive domain: age-adjusted and sex-adjusted standardised regression coefficients (95% CIs) were: -0.45 (-0.70 to -0.20) for visuospatial ability, -0.32 (-0.56 to -0.07) for memory, -0.47 (-0.72 to -0.22) for processing speed, -0.43 (-0.68 to -0.18) for crystallised ability and -0.45 (-0.70 to -0.21) for general cognitive ability. These associations were only slightly attenuated after additional control for other covariates., Conclusion: Physical frailty may be an important indicator of age-related decline across multiple cognitive domains., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Objectives: We investigated how youth cognitive and sociodemographic factors are associated with the aetiology of overweight and obesity. We examined both onset (who is at early risk for overweight and obesity) and development (who gains weight and when)., Design: Prospective cohort study., Setting: We used data from the US National Longitudinal Study of Youth 1979 (NLSY) and the UK National Child Development Study (NCDS); most of both studies completed a cognitive function test in youth., Participants: 12 686 and 18 558 members of the NLSY and NCDS, respectively, with data on validated measures of youth cognitive function, youth socioeconomic disadvantage (eg, parental occupational class and time spent in school) and educational attainment. Height, weight and income data were available from across adulthood, from individuals' 20s into their 50s., Primary and Secondary Outcome Measures: Body mass index (BMI) for four time points in adulthood. We modelled gain in BMI using latent growth curve models to capture linear and quadratic components of change in BMI over time., Results: Across cohorts, higher cognitive function was associated with lower overall BMI. In the UK, 1 SD higher score in cognitive function was associated with lower BMI (β=-0.20, 95% CI -0.33 to -0.06 kg/m²). In America, this was true only for women (β=-0.53, 95% CI -0.90 to -0.15 kg/m²), for whom higher cognitive function was associated with lower BMI. In British participants only, we found limited evidence for negative and positive associations, respectively, between education (β=-0.15, 95% CI -0.26 to -0.04 kg/m²) and socioeconomic disadvantage (β=0.33, 95% CI 0.23 to 0.43 kg/m²) and higher BMI. Overall, no cognitive or socioeconomic factors in youth were associated with longitudinal changes in BMI., Conclusions: While sociodemographic and particularly cognitive factors can explain some patterns in individuals' overall weight levels, differences in who gains weight in adulthood could not be explained by any of these factors., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F ROH ) for >1.4 million individuals, we show that F ROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F ROH are confirmed within full-sibling pairs, where the variation in F ROH is independent of all environmental confounding.

Recent advances in genome-wide DNA methylation (DNAm) profiling for smoking behaviour have given rise to a new, molecular biomarker of smoking exposure. It is unclear whether a smoking-associated DNAm (epigenetic) score has predictive value for ageing-related health outcomes which is independent of contributions from self-reported (phenotypic) smoking measures. Blood DNA methylation levels were measured in 895 adults aged 70 years in the Lothian Birth Cohort 1936 (LBC1936) study using the Illumina 450K assay. A DNA methylation score based on 230 CpGs was used as a proxy for smoking exposure. Associations between smoking variables and health outcomes at age 70 were modelled using general linear modelling (ANCOVA) and logistic regression. Additional analyses of smoking with brain MRI measures at age 73 (n = 532) were performed. Smoking-DNAm scores were positively associated with self-reported smoking status (P < 0.001, eta-squared ɳ 2  = 0.63) and smoking pack years (r = 0.69, P < 0.001). Higher smoking DNAm scores were associated with variables related to poorer cognitive function, structural brain integrity, physical health, and psychosocial health. Compared with phenotypic smoking, the methylation marker provided stronger associations with all of the cognitive function scores, especially visuospatial ability (P < 0.001, partial eta-squared ɳp 2  = 0.022) and processing speed (P < 0.001, ɳp 2  = 0.030); inflammatory markers (all P < 0.001, ranges from ɳp 2  = 0.021 to 0.030); dietary patterns (healthy diet (P < 0.001, ɳp 2  = 0.052) and traditional diet (P < 0.001, ɳp 2  = 0.032); stroke (P = 0.006, OR 1.48, 95% CI 1.12, 1.96); mortality (P < 0.001, OR 1.59, 95% CI 1.42, 1.79), and at age 73; with MRI volumetric measures (all P < 0.001, ranges from ɳp 2  = 0.030 to 0.052). Additionally, education was the most important life-course predictor of lifetime smoking tested. Our results suggest that a smoking-associated methylation biomarker typically explains a greater proportion of the variance in some smoking-related morbidities in older adults, than phenotypic measures of smoking exposure, with some of the accounted-for variance being independent of phenotypic smoking status.

Objectives: Loneliness is associated with poorer cognitive function in old age; however, the direction of this association is unknown. We tested for reciprocal associations between loneliness and the cognitive ability domains of processing speed, visuospatial ability, verbal memory, and crystallized ability., Method: We used three triennial waves of longitudinal data from the Lothian Birth Cohort Study 1936, and tested for cross-lagged associations between loneliness and cognitive abilities using cross-lagged panel models., Results: Better processing speed, visuospatial ability, or crystallized ability at age 73, was associated with less positive changes in loneliness between ages 73 and 76; however, these associations were not replicated between ages 76 and 79. Loneliness at ages 73 and 76 did not predict subsequent changes in cognitive abilities., Discussion: Our findings indicate an association between cognitive ability and loneliness, such that individuals with lower cognitive abilities at age 73 may be at a slightly higher risk of becoming lonely. However, we did not find support for the hypothesis that loneliness causes a decline in cognitive health., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Hearing impairment is associated with poorer cognitive function in later life. We tested for the potential contribution of childhood cognitive ability to this relationship. Childhood cognitive ability is strongly related to cognitive function in older age, and may be related to auditory function through its association with hearing impairment risk factors. Using data from the Lothian Birth Cohort, 1936, we tested whether childhood cognitive ability predicted later-life hearing ability then whether this association was mediated by demographic or health differences. We found that childhood cognitive ability was negatively associated with hearing impairment risk at age 76 (odds ratio = .834, p = .042). However, this association was nonsignificant after subsequent adjustment for potentially mediating demographic and health factors. Next, we tested whether associations observed in older age between hearing impairment and general cognitive ability level or change were accounted for by childhood cognitive ability. At age 76, in the minimally adjusted model, hearing impairment was associated with poorer general cognitive ability level (β = -.119, p = .030) but was not related to decline in general cognitive ability. The former association became nonsignificant after additional adjustment for childhood cognitive ability (β = -.068, p = .426) suggesting that childhood cognitive ability contributes (potentially via demographic and health differences) to the association between levels of hearing and cognitive function in older age. Further work is needed to test whether early life cognitive ability also contributes to the association (documented in previous studies) between older-age hearing impairment and cognitive decline. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected ("concordant") direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive ("discordant") relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 × 10 -8 . Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms-early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways-that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the broader biological dimensions implicated in both general health outcomes and psychiatric illness., (Copyright © 2019. Published by Elsevier Inc.)

Background: Studies with single baseline measurements of cognitive function consistently reveal inverse relationships with mortality risk. The relation of change in functioning, particularly from early in the life course, which may offer additional insights into causality, has not, to the best of our knowledge, been tested., Aims: To examine the association of change in cognition between late adolescence and middle age with cause-specific mortality using data from a prospective cohort study., Methods: The analytical sample consisted of 4289 former US male military personnel who were administered the Army General Technical Test in early adulthood (mean age 20.4 years) and again in middle age (mean age 38.3 years)., Results: A 15-year period of mortality surveillance subsequent to the second phase of cognitive testing gave rise to 237 deaths. Following adjustment for age, a 10-unit increase in cognitive function was related to a reduced risk of death from all causes (HR 0.84; 95% CI 0.75 to 0.93) and cardiovascular disease (HR 0.78; 95% CI 0.64 to 0.95) but not from all cancers (HR 1.14; 95% CI 0.88 to 1.47) nor injury (HR 1.02; 95% CI 0.81 to 1.29). Adjustment for markers of socioeconomic status in middle age resulted in marked attenuation in the magnitude of these associations and statistical significance at conventional levels was lost in all analyses., Conclusions: In the present study, the apparent link between increased cognition and mortality was mediated by socioeconomic status., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Insulin resistance, broadly defined as the reduced ability of insulin to exert its biological action, has been associated with depression and cognitive dysfunction in observational studies. However, it is unclear whether these associations are causal and whether they might be underpinned by other shared factors. To address this knowledge gap, we capitalized on the stability of genetic biomarkers through the lifetime, and on their unidirectional relationship with depression and cognition. Specifically, we determined the association between quantitative measures of cognitive function and depression and genetic instruments of insulin resistance traits in two large-scale population samples, the Generation Scotland: Scottish Family Health Study (GS: SFHS; N = 19,994) and in the UK Biobank (N = 331,374). In the GS:SFHS, the polygenic risk score (PRS) for fasting insulin was associated with verbal intelligence and depression while the PRS for the homeostasis model assessment of insulin resistance was associated with verbal intelligence. Despite this overlap in genetic architecture, Mendelian randomization analyses in the GS:SFHS and in the UK Biobank samples did not yield evidence for causal associations from insulin resistance traits to either depression or cognition. These findings may be due to weak genetic instruments, limited cognitive measures and insufficient power but they may also indicate the need to identify other biological mechanisms that may mediate the relationship from insulin resistance to depression and cognition., (Copyright © 2019. Published by Elsevier Inc.)

We examined associations between self-reported sleep measures and cognitive level and change (age 70-76 years) in a longitudinal, same-year-of-birth cohort study (baseline N = 1091; longitudinal N = 664). We also leveraged GWAS summary data to ascertain whether polygenic scores (PGS) of chronotype and sleep duration related to self-reported sleep, and to cognitive level and change. Shorter sleep latency was associated with significantly higher levels of visuospatial ability, processing speed, and verbal memory (β ≥ |0.184|, SE ≤ 0.075, p ≤ 0.003). Longer daytime sleep duration was significantly associated slower processing speed (β = -0.085, SE = 0.027, p = 0.001), and with steeper 6-year decline in visuospatial reasoning (β = -0.009, SE = 0.003, p = 0.008), and processing speed (β = -0.009, SE = 0.002, p < 0.001). Only longitudinal associations between longer daytime sleeping and steeper cognitive declines survived correction for important health covariates and false discovery rate (FDR). PGS of chronotype and sleep duration were nominally associated with specific self-reported sleep characteristics for most SNP thresholds (standardized β range = |0.123 to 0.082|, p range = 0.003 to 0.046), but neither PGS predicted cognitive level or change following FDR. Daytime sleep duration is a potentially important correlate of cognitive decline in visuospatial reasoning and processing speed in older age, whereas cross-sectional associations are partially confounded by important health factors. A genetic propensity toward morningness and sleep duration were weakly, but consistently, related to self-reported sleep characteristics, and did not relate to cognitive level or change., (© Sleep Research Society 2019. Published by Oxford University Press [on behalf of the Sleep Research Society].)

Higher early-life cognitive function is associated with better later-life health outcomes, including hypertension. Associations between higher prior cognitive function and less hypertension persist even when accounting for socioeconomic status, but socioeconomic status-hypertension gradients are more pronounced in women. We predicted that differences in hypertension development between sexes might be associated with cognitive function and its interaction with sex, such that higher early-life cognitive function would be associated with lower hypertension risk more in women than in men. We used accelerated failure time modeling with the National Longitudinal Study of Youth 1979. Cognitive function was assessed in youth, when participants were aged between 14 and 21 years. Of 2572 men and 2679 women who completed all assessments, 977 men and 940 women reported hypertension diagnoses by 2015. Socioeconomic status in youth and adulthood were investigated as covariates, as were components of adult socioeconomic status: education, occupational status, and family income. An SD of higher cognitive function in youth was associated with reduced hypertension risk (acceleration factor: ĉ=0.97; 95% CI, 0.96-0.99; P=0.001). The overall effect was stronger in women (sex×cognitive function: ĉ=0.97; 95% CI, 0.94-0.99; P=0.010); especially, higher functioning women were less at risk than their male counterparts. This interaction was itself attenuated by a sex by family income interaction. People with better cognitive function in youth, especially women, are less likely to develop hypertension later in life. Income differences accounted for these associations. Possible causal explanations are discussed.

Cognitive functions are important correlates of health outcomes across the life-course. Individual differences in cognitive functions are partly heritable. Epigenetic modifications, such as DNA methylation, are susceptible to both genetic and environmental factors and may provide insights into individual differences in cognitive functions. Epigenome-wide meta-analyses for blood-based DNA methylation levels at ~420,000 CpG sites were performed for seven measures of cognitive functioning using data from 11 cohorts. CpGs that passed a Bonferroni correction, adjusting for the number of CpGs and cognitive tests, were assessed for: longitudinal change; being under genetic control (methylation QTLs); and associations with brain health (structural MRI), brain methylation and Alzheimer's disease pathology. Across the seven measures of cognitive functioning (meta-analysis n range: 2557-6809), there were epigenome-wide significant (P < 1.7 × 10 -8 ) associations for global cognitive function (cg21450381, P = 1.6 × 10 -8 ), and phonemic verbal fluency (cg12507869, P = 2.5 × 10 -9 ). The CpGs are located in an intergenic region on chromosome 12 and the INPP5A gene on chromosome 10, respectively. Both probes have moderate correlations (~0.4) with brain methylation in Brodmann area 20 (ventral temporal cortex). Neither probe showed evidence of longitudinal change in late-life or associations with white matter brain MRI measures in one cohort with these data. A methylation QTL analysis suggested that rs113565688 was a cis methylation QTL for cg12507869 (P = 5 × 10 -5 and 4 × 10 -13 in two lookup cohorts). We demonstrate a link between blood-based DNA methylation and measures of phonemic verbal fluency and global cognitive ability. Further research is warranted to understand the mechanisms linking genomic regulatory changes with cognitive function to health and disease.

Objectives: We used logistic regression to investigate whether health literacy and cognitive ability independently predicted whether participants have ever smoked and, in ever smokers, whether participants still smoked nowadays., Design: Cross-sectional study., Setting: This study used data from Wave 2 (2004-05) of the English Longitudinal Study of Ageing, which is a cohort study of adults who live in England and who, at baseline, were aged 50 years and older., Participants: 8734 (mean age=65.31 years, SD=10.18) English Longitudinal Study of Ageing participants who answered questions about their current and past smoking status, and completed cognitive ability and health literacy tests at Wave 2., Primary and Secondary Outcome Measures: The primary outcome measures were whether participants reported ever smoking at Wave 2 and whether ever smokers reported still smoking at Wave 2., Results: In models adjusting for age, sex, age left full-time education and occupational social class, limited health literacy (OR=1.096, 95% CI 0.988 to 1.216) and higher general cognitive ability (OR=1.000, 95% CI 0.945 to 1.057) were not associated with reporting ever smoking. In ever smokers, limited compared with adequate health literacy was associated with greater odds of being a current smoker (OR=1.194, 95% CI 1.034 to 1.378) and a 1 SD higher general cognitive ability score was associated with reduced odds of being a current smoker (OR=0.878, 95% CI 0.810 to 0.951), when adjusting for age, sex, age left full-time education and occupational social class., Conclusions: When adjusting for education and occupation variables, this study found that health literacy and cognitive ability were independently associated with whether ever smokers continued to smoke nowadays, but not with whether participants had ever smoked., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY. Published by BMJ.)

Background: Cognitive ability is an important predictor of lifelong physical and mental well-being, and impairments are associated with many psychiatric disorders. Higher cognitive ability is also associated with greater educational attainment and increased household income. Understanding neural mechanisms underlying cognitive ability is of crucial importance for determining the nature of these associations. In the current study, we examined the spontaneous activity of the brain at rest to investigate its relationships with not only cognitive ability but also educational attainment and household income., Methods: We used a large sample of resting-state neuroimaging data from the UK Biobank (n = 3950)., Results: First, analysis at the whole-brain level showed that connections involving the default mode network (DMN), frontoparietal network (FPN), and cingulo-opercular network (CON) were significantly positively associated with levels of cognitive performance assessed by a verbal-numerical reasoning test (standardized β cingulo-opercular values ranged from 0.054 to 0.097, p corrected < .038). Connections associated with higher levels of cognitive performance were also significantly positively associated with educational attainment (r = .48, n = 4160) and household income (r = .38, n = 3793). Furthermore, analysis on the coupling of functional networks showed that better cognitive performance was associated with more positive DMN-CON connections, decreased cross-hemisphere connections between the homotopic network in the CON and FPN, and stronger CON-FPN connections (absolute βs ranged from 0.034 to 0.063, p corrected < .045)., Conclusions: The current study found that variation in brain resting-state functional connectivity was associated with individual differences in cognitive ability, largely involving the DMN and lateral prefrontal network. In addition, we provide evidence of shared neural associations of cognitive ability, educational attainment, and household income., (Copyright © 2018 Society of Biological Psychiatry. All rights reserved.)

Objectives: We investigated the role that childhood and old age cognitive ability play in the association between functional health literacy and mortality., Design: Prospective cohort study., Setting: This study used data from the Lothian Birth Cohort 1936 (LBC1936) study, which recruited participants living in the Lothian region of Scotland when aged 70 years, most of whom had completed an intelligence test at age 11 years., Participants: 795 members of the LBC1936 with scores on tests of functional health literacy and cognitive ability in childhood and older adulthood., Primary and Secondary Outcome Measures: Participants were followed up for 8 years to determine mortality. Time to death in days was used as the primary outcome measure., Results: Using Cox regression, higher functional health literacy was associated with lower risk of mortality adjusting for age and sex, using the Shortened Test of Functional Health Literacy in Adults (HR 0.95, 95% CI 0.92 to 0.98), the Newest Vital Sign (HR 0.88, 95% CI 0.80 to 0.97) and a functional health literacy composite measure (HR 0.77, 95% CI 0.65 to 0.92), but not the Rapid Estimate of Adult Literacy in Medicine (HR 0.95, 95% CI 0.90 to 1.01). Adjusting for childhood intelligence did not change these associations. When additionally adjusting for fluid-type cognitive ability in older age, associations between functional health literacy and mortality were attenuated and non-significant., Conclusions: Current fluid ability, but not childhood intelligence, attenuated the association between functional health literacy and mortality. Functional health literacy measures may, in part, assess fluid-type cognitive abilities, and this may account for the association between functional health literacy and mortality., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY. Published by BMJ.)

Background: Maintaining cognitive function is an important aspect of healthy ageing. In this study, we examined age trajectories of cognitive decline in a large nationally representative sample of older people in England. We explored the factors that influence such decline and whether these differed by gender., Methods: Latent growth curve modelling was used to explore age-specific changes, and influences on them, in an 8-year period in memory, executive function, processing speed and global cognitive function among 10 626 participants in the English Longitudinal Study of Ageing. We run gender-specific models with the following exposures: age, education, wealth, childhood socioeconomic status, cardiovascular disease, diabetes, physical function, body mass index, physical activity, alcohol, smoking, depression and dementia., Results: After adjustment, women had significantly less decline than men in memory (0.011, SE 0.006), executive function (0.012, SE 0.006) and global cognitive function (0.016, SE 0.004). Increasing age and dementia predicted faster rates of decline in all cognitive function domains. Depression and alcohol consumption predicted decline in some cognitive function domains in men only. Poor physical function, physical inactivity and smoking were associated with faster rates of decline in specific cognitive domains in both men and women. For example, relative to study members who were physically active, the sedentary experienced greater declines in memory (women -0.018, SE 0.009) and global cognitive function (men -0.015, SE 0.007 and women -0.016, SE 0.007)., Conclusions: The potential determinants of cognitive decline identified in this study, in particular modifiable risk factors, should be tested in the context of randomised controlled trials., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Anxiety and depression are both important correlates of cognitive function. However, longitudinal studies investigating how they covary with cognition within the same individual are scarce. We aimed to simultaneously estimate associations of between-person differences and within-person variability in anxiety and depression with cognitive performance in a sample of non-demented older people., Methods: Participants in the Lothian Birth Cohort 1921 study, a population-based narrow-age sample (mean age at wave 1 = 79 years, n = 535), were examined on five occasions across 13 years. Anxiety and depression were measured with the Hospital Anxiety and Depression Scale (HADS) and cognitive performance was assessed with tests of reasoning, logical memory, and letter fluency. Data were analyzed using two-level linear mixed-effects models with within-person centering., Results: Divergent patterns were observed for anxiety and depression. For anxiety, between-person differences were more influential; people who scored higher on HADS anxiety relative to other same-aged individuals demonstrated poorer cognitive performance on average. For depression, on the other hand, time-varying within-person differences were more important; scoring higher than usual on HADS depression was associated with poorer cognitive performance relative to the average level for that participant. Adjusting for gender, childhood mental ability, emotional stability, and disease burden attenuated these associations., Conclusions: The results from this study highlight the importance of addressing both between- and within-person effects of negative mood and suggest that anxiety and depression affect cognitive function in different ways. The current findings have implications for assessment and treatment of older age cognitive deficits.

Neurodegenerative disorders are associated with impaired cognitive function and worse physical health outcomes. This study aims to test whether polygenic risk for Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), or frontotemporal dementia (FTD) is associated with cognitive function and physical health in the UK Biobank, a cohort of healthy individuals. Group-based analyses were then performed to compare the top and bottom 10% for the three neurodegenerative polygenic risk scores; these groups were compared on the cognitive and physical health variables. Higher polygenic risk for AD, ALS, and FTD was associated with lower cognitive performance. Higher polygenic risk for FTD was also associated with increased forced expiratory volume in 1s and peak expiratory flow. A significant group difference was observed on the symbol digit substitution task between individuals with high polygenic risk for FTD and high polygenic risk for ALS. The results suggest some overlap between polygenic risk for neurodegenerative disorders, cognitive function and physical health., Competing Interests: The authors have declared that no competing interests exist.

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10 -8 ) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

Introduction: This study examines the role of educational attainment, an indicator of cognitive reserve, on transitions in later life between cognitive states (normal Mini-Mental State Examination (MMSE), mild MMSE impairment, and severe MMSE impairment) and death., Methods: Analysis of six international longitudinal studies was performed using a coordinated approach. Multistate survival models were used to estimate the transition patterns via different cognitive states. Life expectancies were estimated., Results: Across most studies, a higher level of education was associated with a lower risk of transitioning from normal MMSE to mild MMSE impairment but was not associated with other transitions. Those with higher levels of education and socioeconomic status had longer nonimpaired life expectancies., Discussion: This study highlights the importance of education in later life and that early life experiences can delay later compromised cognitive health. This study also demonstrates the feasibility and benefit in conducting coordinated analysis across multiple studies to validate findings., (Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Higher cognitive ability is associated with being more physically active. Much less is known about the associations between cognitive ability and sedentary behavior. Ours is the first study to examine whether historic and contemporaneous cognitive ability predicts objectively measured sedentary behavior in older age. Participants were drawn from 3 cohorts (Lothian Birth Cohort, 1936 [LBC1936] [n = 271]; and 2 West of Scotland Twenty-07 cohorts: 1950s [n = 310] and 1930s [n = 119]). Regression models were used to assess the associations between a range of cognitive tests measured at different points in the life course, with sedentary behavior in older age recorded over 7 days. Prior simple reaction time (RT) was significantly related to later sedentary time in the youngest, Twenty-07 1950s cohort (p = .04). The relationship was nonsignificant after controlling for long-standing illness or employment status, or after correcting for multiple comparisons in the initial model. None of the cognitive measures were related to sedentary behavior in either of the 2 older cohorts (LBC1936, Twenty-07 1930s). There was no association between any of the cognitive tests and the number of sit-to-stand transitions in any of the 3 cohorts. The meta-analytic estimates for the measures of simple and choice RT that were identical in all cohorts (n = 700) were also not significant. In conclusion, we found no evidence that objectively measured sedentary time in older adults is associated with measures of cognitive ability at different time points in life, including cognitive change from childhood to older age. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

Fully characterizing age differences in the brain is a key task for combating aging-related cognitive decline. Using propensity score matching on 2 independent, narrow-age cohorts, we used data on childhood cognitive ability, socioeconomic background, and intracranial volume to match participants at mean age of 92 years (n = 42) to very similar participants at mean age of 73 years (n = 126). Examining a variety of global and regional structural neuroimaging variables, there were large differences in gray and white matter volumes, cortical surface area, cortical thickness, and white matter hyperintensity volume and spatial extent. In a mediation analysis, the total volume of white matter hyperintensities and total cortical surface area jointly mediated 24.9% of the relation between age and general cognitive ability (tissue volumes and cortical thickness were not significant mediators in this analysis). These findings provide an unusual and valuable perspective on neurostructural aging, in which brains from the 8th and 10th decades of life differ widely despite the same cognitive, socioeconomic, and brain-volumetric starting points., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

International evidence suggests that green space has beneficial effects on general and mental health but little is known about how lifetime exposure to green space influences cognitive ageing. Employing a novel longitudinal life course approach, we examined the association between lifetime availability of public parks and cognitive ageing. Lifetime residential information was gathered from the participants of the Lothian Birth Cohort 1936 using a "life-grid" questionnaire at age 78 years. Parks information from 1949, 1969 and 2009 was used to determine a percentage of parks within a 1500 m buffer zone surrounding residence for childhood, adulthood, and later adulthood periods. Linear regressions were undertaken to test for association with age-standardised, residualised change in cognitive function (Moray House Test score) from age 11 to 70 years, and from age 70 to 76 (n = 281). The most appropriate model was selected using the results of a partial F-test, and then stratified by demographic, genetic and socioeconomic factors. The local provision of park space in childhood and adulthood were both important in explaining the change in cognitive function in later life. The association between childhood and adulthood park availability and change in the Moray House Test Score from age 70 to 76 was strongest for women, those without an APOE e4 allele (a genetic risk factor), and those in the lowest socioeconomic groups. Greater neighbourhood provision of public parks from childhood through to adulthood may help to slow down the rate of cognitive decline in later life, recognising that such environmental associations are always sensitive to individual characteristics., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Regional cortical brain volume is the product of surface area and thickness. These measures exhibit partially distinct trajectories of change across the brain's cortex in older age, but it is unclear which cortical characteristics at which loci are sensitive to cognitive ageing differences. We examine associations between change in intelligence from age 11 to 73 years and regional cortical volume, surface area, and thickness measured at age 73 years in 568 community-dwelling older adults, all born in 1936. A relative positive change in intelligence from 11 to 73 was associated with larger volume and surface area in selective frontal, temporal, parietal, and occipital regions (r < 0.180, FDR-corrected q < 0.05). There were no significant associations between cognitive ageing and a thinner cortex for any region. Interestingly, thickness and surface area were phenotypically independent across bilateral lateral temporal loci, whose surface area was significantly related to change in intelligence. These findings suggest that associations between regional cortical volume and cognitive ageing differences are predominantly driven by surface area rather than thickness among healthy older adults. Regional brain surface area has been relatively underexplored, and is a potentially informative biomarker for identifying determinants of cognitive ageing differences.

Elevated cortisol levels have been hypothesized to contribute to cognitive aging, but study findings are inconsistent. In the present study, we examined the association between salivary cortisol in older age and cognitive ability across the life course. We used data from 370 members of the 36-Day Sample of the Scottish Mental Survey 1947, who underwent cognitive testing at age 11 years and were then followed up at around age 78 years, completing further cognitive tests and providing diurnal salivary cortisol samples. We hypothesized that higher cortisol levels would be associated with lower cognitive ability in older age and greater cognitive decline from childhood to older age but also lower childhood cognitive ability. Few of the tested associations were significant, and of those that were, most suggested a positive relationship between cortisol and cognitive ability. Only 1 cognitive measure showed any sign of cortisol-related impairment. However, after correcting for multiple comparisons, no results remained significant. These findings suggest that cortisol may not play an important role in cognitive aging across the life course., (Copyright © 2017. Published by Elsevier Inc.)

Cognitive decline and carotid artery atheroma are common at older ages. In community-dwelling subjects, we assessed cognition at ages 70, 73 and 76 and carotid Doppler ultrasound at age 73, to determine whether carotid stenosis was related to cognitive decline. We used latent growth curve models to examine associations between four carotid measures (internal carotid artery stenosis, velocity, pulsatility and resistivity indices) and four cognitive ability domains (memory, visuospatial function, crystallised intelligence, processing speed) adjusted for cognitive ability at age 11, current age, gender and vascular risk factors. Amongst 866 participants, carotid stenosis (median 12.96%) was not associated with cognitive abilities at age 70 or cognitive decline from age 70 to 76. Increased ICA pulsatility and resistivity indices were associated with slower processing speed (both P < 0.001) and worse visuospatial function ( P = 0.036, 0.031, respectively) at age 70, and declining crystallised intelligence from ages 70 to 76 ( P = 0.008, 0.006, respectively). The findings suggest that vascular stiffening, rather than carotid luminal narrowing, adversely influences cognitive ageing and provides a potential target for ameliorating age-related cognitive decline.

Aim: To examine the relationship between retinal vascular morphology and cognitive abilities in a narrow-age cohort of community-dwelling older people., Methods: Digital retinal images taken at age ∼73 years from 683 participants of the Lothian Birth Cohort 1936 (LBC1936) were analysed with Singapore I Vessel Assessment (SIVA) software. Multiple regression models were applied to determine cross-sectional associations between retinal vascular parameters and general cognitive ability ( g ), memory, processing speed, visuospatial ability, crystallised cognitive ability and change in IQ from childhood to older age., Results: After adjustment for cognitive ability at age 11 years and cardiovascular risk factors, venular length-to-diameter ratio was nominally significantly associated with processing speed (β=-0.116, p=0.01) and g (β=-0.079, p=0.04). Arteriolar length-to-diameter ratio was associated with visuospatial ability (β=0.092, p=0.04). Decreased arteriolar junctional exponent deviation and increased arteriolar branching coefficient values were associated with less relative decline in IQ between childhood and older age (arteriolar junctional exponent deviation: β=-0.101, p=0.02; arteriolar branching coefficient: β=0.089, p=0.04). Data are presented as standardised β coefficients (β) reflecting change in cognitive domain score associated with an increase of 1 SD unit in retinal parameter. None of these nominally significant associations remained significant after correction for multiple statistical testing., Conclusions: Retinal parameters contributed <1% of the variance in the majority of associations observed. Whereas retinal analysis may have potential for early detection of some types of age-related cognitive decline and dementia, our results present little evidence that retinal vascular features are associated with non-pathological cognitive ageing., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Causes of the association between cognitive ability and health remain unknown, but may reflect a shared genetic aetiology. This study examines the causal genetic associations between cognitive ability and physical health. We carried out two-sample Mendelian randomization analyses using the inverse-variance weighted method to test for causality between later life cognitive ability, educational attainment (as a proxy for cognitive ability in youth), BMI, height, systolic blood pressure, coronary artery disease, and type 2 diabetes using data from six independent GWAS consortia and the UK Biobank sample (N = 112 151). BMI, systolic blood pressure, coronary artery disease and type 2 diabetes showed negative associations with cognitive ability; height was positively associated with cognitive ability. The analyses provided no evidence for casual associations from health to cognitive ability. In the other direction, higher educational attainment predicted lower BMI, systolic blood pressure, coronary artery disease, type 2 diabetes, and taller stature. The analyses indicated no causal association from educational attainment to physical health. The lack of evidence for causal associations between cognitive ability, educational attainment, and physical health could be explained by weak instrumental variables, poorly measured outcomes, or the small number of disease cases.

Objectives: To investigate whether poorer cognitive ability is a risk factor for development of physical frailty and whether this risk varies according to cognitive domain., Design: Prospective longitudinal study with 6-year follow-up., Setting: Edinburgh, Scotland., Participants: Members of the Lothian Birth Cohort 1936 (N = 594)., Measurements: Frailty was assessed at ages 70 and 76 using the Fried criteria. Cognitive function was assessed at age 70, 73, and 76. Factor score estimates were derived for baseline level of and change in four cognitive domains: visuospatial ability, memory, processing speed, and crystallized cognitive ability., Results: Higher baseline levels of processing speed, memory, visuospatial ability and crystallized ability at age 70, and less decline in speed, memory, and crystallized ability were associated with less risk of becoming physically frail by age 76. When all cognitive domains were modelled together, processing speed was the only domain associated with frailty risk, for a standard deviation (SD) increment in initial level of processing speed, the risk of frailty was 47% less (0.53 95% confidence interval (CI) = 0.33-0.85) after adjustment for age, sex, baseline frailty status, social class, depressive symptoms, number of chronic physical diseases, levels of inflammatory biomarkers, and other cognitive factor score estimates; for a SD increment in processing speed change (less decline) risk of frailty was 74% less (RRR = 0.26, 95% CI = 0.16-0.42). When additional analyses were conducted using a single test of processing speed that did not require fast motor responses (inspection time), results were similar., Conclusions: The speed with which older adults process information and the rate at which this declines over time may be an important indicator of the risk of physical frailty., (© 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.)

Background: The prevention of dementia is a global priority but its etiology is poorly understood. Early life cognitive ability has been linked to subsequent dementia risk but studies to date have been small and none has examined sex differences., Methods: In the 1932 Scottish Mental Survey cohort, we related intelligence test scores at age 11 years in 16,370 boys and 16,097 girls (born in 1921) to incident dementia ages ≥65 years as ascertained using probabilistic linkage to electronic health records up to the age of 92 years (1,231 cases in men, 2,163 in women; median follow-up 15 years)., Results: Compared with the highest intelligence group (IQ ≥115), dementia risk was raised in the lowest-scoring category (<85) and these associations were stronger for women (hazard ratio; 95% confidence interval: 1.51; 1.29, 1.76) than men (1.19; 0.98, 1.44; P value for interaction by gender: 0.054). There was evidence of a dose-response association between childhood IQ and dementia in women (IQ 100-114.9 compared with ≥115: 1.18; 1.03, 1.34; IQ 85-99.9: 1.32; 1.15, 1.51; P value for trend <0.001) but not in men (1.05; 0.89, 1.24 and 1.01; 0.85, 1.21; 0.44)., Conclusions: Childhood intelligence is related to subsequent dementia risk but this association is not the same in men and women. See video abstract at, http://links.lww.com/EDE/B184.

Structural measures of the hippocampus have been linked to a variety of memory processes and also to broader cognitive abilities. Gross volumetry has been widely used, yet the hippocampus has a complex formation, comprising distinct subfields which may be differentially sensitive to the deleterious effects of age, and to different aspects of cognitive performance. However, a comprehensive analysis of multidomain cognitive associations with hippocampal deformations among a large group of cognitively normal older adults is currently lacking. In 654 participants of the Lothian Birth Cohort 1936 (mean age = 72.5, SD = 0.71 years), we examined associations between the morphology of the hippocampus and a variety of memory tests (spatial span, letter-number sequencing, verbal recall, and digit backwards), as well as broader cognitive domains (latent measures of speed, fluid intelligence, and memory). Following correction for age, sex, and vascular risk factors, analysis of memory subtests revealed that only right hippocampal associations in relation to spatial memory survived type 1 error correction in subiculum and in CA1 at the head (β = 0.201, p = 5.843 × 10 -4 , outward), and in the ventral tail section of CA1 (β = -0.272, p = 1.347 × 10 -5 , inward). With respect to latent measures of cognitive domains, only deformations associated with processing speed survived type 1 error correction in bilateral subiculum (β absolute ≤ 0.247, p < 1.369 × 10 -4 , outward), bilaterally in the ventral tail section of CA1 (β absolute ≤ 0.242, p < 3.451 × 10 -6 , inward), and a cluster at the left anterior-to-dorsal region of the head (β = 0.199, p = 5.220 × 10 -6 , outward). Overall, our results indicate that a complex pattern of both inward and outward hippocampal deformations are associated with better processing speed and spatial memory in older age, suggesting that complex shape-based hippocampal analyses may provide valuable information beyond gross volumetry., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)