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Activity engagement is a modifiable factor that has been widely-cited as being good for the aging brain and cognition and represents a valuable target for reducing dementia risk. However, specific issues about activity engagement (mental, social, and physical) and cognition in older adulthood remain, and Bielak [Gerontology 2010;56: 507-519] reviewed seven major methodological and theoretical questions about this relationship. We present an updated reflection on these key questions, focusing on research published in the last 10 years. For some questions, a significant amount of work has been done and conclusions have become clearer; for others, there have been few additions to the literature and our knowledge remains much the same as it was a decade ago. We review the issues identified in the 2010 paper including the directionality and temporal nature of the relationship; whether specific activity domains offer different benefits to cognition and what domain(s) of cognition are affected; variation in the relation by age, gender, or education; potential mechanisms involved; and how activity engagement is assessed. For each, we present the most up-to-date research, discuss remaining challenges and possible future directions. This formal unifying of the information in the field is intended as a guide to support continued progress by spurring on studies addressing specific questions while reminding researchers of critical issues. We conclude with recommendations that future studies investigating the link between activity engagement and cognitive performance in adulthood should consider., (© 2022 S. Karger AG, Basel.)

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.)

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.

Research has suggested that individuals who play a musical instrument throughout adulthood have better preserved executive function. However, mixed results have been found for associations between musical activity and visuo-spatial abilities, and less is known about associations with fluid intelligence. We explored differences between musicians (N = 30) and non-musicians (N = 30) aged 60-93 years old across a range of neuropsychological measures of cognitive function. Musicians performed significantly better than non-musicians on all domains, which remained after adjusting for age, gender, educational history, languages spoken and physical activity. As a cross-sectional comparison, the results should not be overstated; however, they are consistent with findings suggesting learning a musical instrument throughout the life course may be associated with cognitive benefits. Identifying potential lifestyle factors that have cognitive benefits in later life, such as musical experience, is an important step in developing intervention strategies for cognitive aging.

From 19th to 22nd November 2018, 26 researchers representing nine countries and a variety of academic disciplines met in Snekkersten, Denmark, to reach evidence-based consensus about physical activity and older adults. It was recognised that the term 'older adults' represents a highly heterogeneous population. It encompasses those that remain highly active and healthy throughout the life-course with a high intrinsic capacity to the very old and frail with low intrinsic capacity. The consensus is drawn from a wide range of research methodologies within epidemiology, medicine, physiology, neuroscience, psychology and sociology, recognising the strength and limitations of each of the methods. Much of the evidence presented in the statements is based on longitudinal associations from observational and randomised controlled intervention studies, as well as quantitative and qualitative social studies in relatively healthy community-dwelling older adults. Nevertheless, we also considered research with frail older adults and those with age-associated neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, and in a few cases molecular and cellular outcome measures from animal studies. The consensus statements distinguish between physical activity and exercise. Physical activity is used as an umbrella term that includes both structured and unstructured forms of leisure, transport, domestic and work-related activities. Physical activity entails body movement that increases energy expenditure relative to rest, and is often characterised in terms of intensity from light, to moderate to vigorous. Exercise is defined as a subset of structured physical activities that are more specifically designed to improve cardiorespiratory fitness, cognitive function, flexibility balance, strength and/or power. This statement presents the consensus on the effects of physical activity on older adults' fitness, health, cognitive functioning, functional capacity, engagement, motivation, psychological well-being and social inclusion. It also covers the consensus on physical activity implementation strategies. While it is recognised that adverse events can occur during exercise, the risk can be minimised by carefully choosing the type of activity undertaken and by consultation with the individual's physician when warranted, for example, when the individual is frail, has a number of co-morbidities, or has exercise-related symptoms, such as chest pain, heart arrhythmia or dizziness. The consensus was obtained through an iterative process that began with the presentation of the state-of-the-science in each domain, followed by group and plenary discussions. Ultimately, the participants reached agreement on the 30-item consensus statements., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: We conducted a U.K.-wide survey to collect information on people's beliefs, fears, perceptions, and attitudes to cognitive aging., Methods: This community-based aging survey included 3,146 adults aged 40 years and over., Results: Respondents believed memory might be the earliest cognitive skill to decline (mean: 59.4 years), followed by speed of thinking (mean: 64.9). Those in their 40s were more pessimistic, because they estimated cognitive changes would start up to 15 years earlier than respondents aged over 70. Having a purpose in life, healthy eating, challenging the mind, sleep, and physical activity ranked higher in terms of perceived importance for maintaining or improving cognitive skills. However, less than 50% engaged in any of these activities. Although 91% believed there are things people can do to maintain or improve their cognitive skills, more than 40% were unsure or did not know how to do so. Respondents who strongly agreed that changes in cognitive skills might be a sign of something more serious were significantly more likely to do various activities to benefit their cognitive skills., Conclusion: Results suggest that people are less aware of the potential cognitive benefits of certain activities, such as exercise and diet. It is important to build awareness about the benefits of lifestyles and activities for cognitive health., (Copyright © 2018 The Authors. Published by Elsevier Inc. 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.)

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.)

Background: Iodine deficiency is one of the three key micronutrient deficiencies highlighted as major public health issues by the World Health Organisation. Iodine deficiency is known to cause brain structural alterations likely to affect cognition. However, it is not known whether or how different (lifelong) levels of exposure to dietary iodine influences brain health and cognitive functions., Methods: From 1091 participants initially enrolled in The Lothian Birth Cohort Study 1936, we obtained whole diet data from 882. Three years later, from 866 participants (mean age 72 yrs, SD±0.8), we obtained cognitive information and ventricular, hippocampal and normal and abnormal tissue volumes from brain structural magnetic resonance imaging scans (n=700). We studied the brain structure and cognitive abilities of iodine-rich food avoiders/low consumers versus those with a high intake in iodine-rich foods (namely dairy and fish)., Results: We identified individuals (n=189) with contrasting diets, i) belonging to the lowest quintiles for dairy and fish consumption, ii) milk avoiders, iii) belonging to the middle quintiles for dairy and fish consumption, and iv) belonging to the middle quintiles for dairy and fish consumption. Iodine intake was secured mostly though the diet (n=10 supplement users) and was sufficient for most (75.1%, median 193 µg/day). In individuals from these groups, brain lateral ventricular volume was positively associated with fat, energy and protein intake. The associations between iodine intake and brain ventricular volume and between consumption of fish products (including fish cakes and fish-containing pasties) and white matter hyperintensities (p=0.03) the latest being compounded by sodium, proteins and saturated fats, disappeared after type 1 error correction., Conclusion: In this large Scottish older cohort, the proportion of individuals reporting extreme (low vs. high)/medium iodine consumption is small. In these individuals, low iodine-rich food intake was associated with increased brain volume shrinkage, raising an important hypothesis worth being explored for designing appropriate guidelines., Competing Interests: Dr. Valdés Hernández reports grants from Age UK, grants from Scottish Funding Council (Project for Scotland), grants from Medical Research Council UK, grants from Engineering and Physical Sciences Research Council UK, grants from Row Fogo Charitable Trust, during the conduct of the study; Dr. Kyle has nothing to disclose. Dr. Allan reports grants from Scottish Crucible / Royal Society of Edinburgh, during the conduct of the study; Dr. Allerhand has nothing to disclose. Dr. Clark has nothing to disclose. Dr. Muñoz Maniega has nothing to disclose. Dr. Royle has nothing to disclose. Dr. Pattie has nothing to disclose. Dr. Corley has nothing to disclose. Dr. Bastin has nothing to disclose. Dr. Starr has nothing to disclose. Dr. Wardlaw reports grants from MRC, grants from AgeUK, grants from Scottish Funding Council, grants from Row Fogo Charitable Trust, during the conduct of the study; Dr. Deary reports grants from Age UK, grants from Medical Research Council, grants from Engineering and Physical Sciences Research Council, during the conduct of the study; Dr. Combet reports grants from Scottish Funding Council (Project for Scotland), during the conduct of the study;

It is unknown whether relations between early-life factors and overall health in later life apply to burden of cerebral small vessel disease (cSVD), a major cause of stroke and dementia. We explored relations between early-life factors and cSVD in the Lothian Birth Cohort, a healthy aging cohort. Participants were recruited at age 70 (N = 1091); most had completed a test of cognitive ability at age 11 as part of the Scottish Mental Survey of 1947. Of those, 700 participants had brain MRI that could be rated for cSVD conducted at age 73. Presence of lacunes, white matter hyperintensities, microbleeds, and perivascular spaces were summed in a score of 0-4 representing all MRI cSVD features. We tested associations with early-life factors using multivariate logistic regression. Greater SVD score was significantly associated with lower age-11 IQ (OR higher SVD score per SD age-11 IQ = .78, 95%CI 0.65-.95, p=.01). The associations between SVD score and own job class (OR higher job class, .64 95%CI .43-.95, p=.03), age-11 deprivation index (OR per point deprivation score, 1.08, 95%CI 1.00-1.17, p=.04), and education (OR some qualifying education, .60 95%CI .37-.98, p=.04) trended towards significance (p<.05 for all) but did not meet thresholds for multiple testing. No early-life factor was significantly associated with any one individual score component. Early-life factors may contribute to age-73 burden of cSVD. These relations, and the potential for early social interventions to improve brain health, deserve further study., Competing Interests: The authors declare ni conflicts of interest.

Background: to examine associations between social resources and cognitive ageing over 30 years., Methods: participants in the Glostrup 1914 Cohort, a year of birth sample, completed a standardarised battery of cognitive ability tests every 10 years from age 50 to 80, summarised as general cognitive ability. Participants also provided information concerning a range of social resources, including marital status and living arrangements from age 50, and from age 70, details regarding social support, social contact and loneliness., Results: across the follow-up, participants were less likely to be married, falling from 85.0 to 40.4% between ages 50 and 80, while the proportion of those living alone increased from 13.1 to 54.2%. In separate growth curve models, being married, living with others and not feeling lonely were all associated with higher cognitive ability level, while more telephone contact had a negative association. Marital status (at ages 50 and 60) and loneliness at age 70 were the only social resources associated with cognitive change; married individuals and those not feeling lonely experienced less cognitive decline. When the social resources showing significant associations were considered together (and accounting for sex, education and social class), loneliness was associated with lower cognitive ability level and greater cognitive decline, while married individuals experienced less decline., Conclusions: in a relatively large cohort followed for up to 30 years, marital status and loneliness were associated with cognitive ability or change. Interventions designed to reduce loneliness in older adults might be supported as one avenue to reduce cognitive ageing., (© The Author 2016. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Telomere length is hypothesised to be a biological marker of both cognitive and physical ageing. Here we measure telomere length, and cognitive and physical abilities at mean ages 70, 73 and 76 years in the Lothian Birth Cohort 1936 (LBC1936), and at mean ages 79, 87, 90 and 92 years in the Lothian Birth Cohort 1921 (LBC1921). We investigate whether telomere length change predicts change in cognitive and physical abilities. In LBC1936 telomere length decreased by an average of 65 base pairs per year and in LBC1921 by 69 base pairs per year. However, change in telomere length did not predict change in cognitive or physical abilities. This study shows that, although cognitive ability, walking speed, lung function and grip strength all decline with age, they do so independently of telomere length shortening., (Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Later-life changes in brain tissue volumes--decreases in the volume of healthy grey and white matter and increases in the volume of white matter hyperintensities (WMH)--are strong candidates to explain some of the variation in ageing-related cognitive decline. We assessed fluid intelligence, memory, processing speed, and brain volumes (from structural MRI) at mean age 73 years, and at mean age 76 in a narrow-age sample of older individuals (n = 657 with brain volumetric data at the initial wave, n = 465 at follow-up). We used latent variable modeling to extract error-free cognitive levels and slopes. Initial levels of cognitive ability were predictive of subsequent brain tissue volume changes. Initial brain volumes were not predictive of subsequent cognitive changes. Brain volume changes, especially increases in WMH, were associated with declines in each of the cognitive abilities. All statistically significant results were modest in size (absolute r-values ranged from 0.114 to 0.334). These results build a comprehensive picture of macrostructural brain volume changes and declines in important cognitive faculties during the eighth decade of life., (© 2015 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc.)

Cerebral small vessel disease (SVD) may cause cognitive dysfunction. We tested the association between the combined presence of magnetic resonance imaging (MRI) features of SVD and cognitive ability in older age. Cognitive testing and brain MRI were performed in 680 older participants. MRI presence of lacunes, white matter hyperintensities, microbleeds, and perivascular spaces were summed in a score of 0-4 representing all SVD features combined. We also applied latent variable modeling to test whether the 4 MRI features form a unitary SVD construct. The SVD score showed significant associations with general cognitive ability. Latent variable modeling indicated that the 4 MRI markers formed a unitary construct, which showed consistent associations with cognitive ability compared with the SVD score. Total MRI load of SVD is associated with lower general cognitive ability in older age. The total SVD score performed consistently with the more complex latent variable model, suggesting validity and potential utility in future research for determining total SVD load., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Several studies have reported associations between brain iron deposits and cognitive status, and cardiovascular and neurodegenerative diseases in older individuals, but the mechanisms underlying these associations remain unclear. We explored the associations between regional brain iron deposits and different factors of cognitive ability (fluid intelligence, speed and memory) in a large sample (n = 662) of individuals with a mean age of 73 years. Brain iron deposits in the corpus striatum were extracted automatically. Iron deposits in other parts of the brain (i.e., white matter, thalamus, brainstem and cortex), brain tissue volume and white matter hyperintensities (WMH) were assessed separately and semi-automatically. Overall, 72.8 % of the sample had iron deposits. The total volume of iron deposits had a small but significant negative association with all three cognitive ability factors in later life (mean r = -0.165), but no relation to intelligence in childhood (r = 0.043, p = 0.282). Regression models showed that these iron deposit associations were still present after control for a variety of vascular health factors, and were separable from the association of WMH with cognitive ability. Iron deposits were also associated with cognition across the lifespan, indicating that they are relevant for cognitive ability only at older ages. Iron deposits might be an indicator of small vessel disease that affects the neuronal networks underlying higher cognitive functioning.

Understanding aging-related cognitive decline is of growing importance in aging societies, but relatively little is known about its neural substrates. Measures of white matter microstructure are known to correlate cross-sectionally with cognitive ability measures, but only a few small studies have tested for longitudinal relations among these variables. We tested whether there were coupled changes in brain white matter microstructure indexed by fractional anisotropy (FA) and three broad cognitive domains (fluid intelligence, processing speed, and memory) in a large cohort of human participants with longitudinal diffusion tensor MRI and detailed cognitive data taken at ages 73 years (n = 731) and 76 years (n = 488). Longitudinal changes in white matter microstructure were coupled with changes in fluid intelligence, but not with processing speed or memory. Individuals with higher baseline white matter FA showed less subsequent decline in processing speed. Our results provide evidence for a longitudinal link between changes in white matter microstructure and aging-related cognitive decline during the eighth decade of life. They are consistent with theoretical perspectives positing that a corticocortical "disconnection" partly explains cognitive aging., (Copyright © 2015 Ritchie et al.)

Allostatic load (AL) has been proposed as a general framework for understanding the cumulative effects of life stress on individuals. Despite growing interest in AL, limited research has been conducted on aging samples. We consider the association of AL (operationalized by a range of inflammatory, cardiovascular, and metabolic measures) with a range of brain volume measurements and cognitive ability in a large cohort sample of older adults (n = 658, mean age = 72.5 years, standard deviation = 0.7) using structural equation modeling. AL was significantly inversely associated with total brain volume (range of standardized β = -0.16 to -0.20) and white-matter volume (-0.35 to -0.36) and positively with hippocampal volume (0.10-0.15) but not gray-matter volume (0.04). AL was also significantly inversely associated with general cognitive ability (range β = -0.13 to -0.20), processing speed (-0.20 to -0.22), and knowledge (-0.18 to -0.20) but not memory or nonverbal reasoning. The associations of AL with cognitive abilities were not mediated by these brain volume measures. AL did not predict cognitive change from age 11 to approximately age 73. The findings suggest a link between AL and later life brain health and cognitive functioning., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To examine associations between complexity of main lifetime occupation and cognitive performance in later life., Methods: Occupational complexity ratings for data, people, and things were collected from the Dictionary of Occupational Titles for 1,066 individuals (men = 534, women = 532) in the Lothian Birth Cohort 1936. IQ data were available from mean age 11 years. Cognitive ability data across the domains of general ability, processing speed, and memory were available at mean age 70 years., Results: General linear model analyses indicated that complexity of work with people and data were associated with better cognitive performance at age 70, after including age 11 IQ, years of education, and social deprivation., Conclusions: The current findings are supportive of the differential preservation hypotheses that more stimulating environments preserve cognitive ability in later life, although the continued effects into old age are still debated. Studies that have early-life cognitive ability measures are rare, and the current study offers interesting prospects for future research that may further the understanding of successful aging., (© 2014 American Academy of Neurology.)

Cognitive decline is a feared aspect of growing old. It is a major contributor to lower quality of life and loss of independence in old age. We investigated the genetic contribution to individual differences in nonpathological cognitive ageing in five cohorts of older adults. We undertook a genome-wide association analysis using 549 692 single-nucleotide polymorphisms (SNPs) in 3511 unrelated adults in the Cognitive Ageing Genetics in England and Scotland (CAGES) project. These individuals have detailed longitudinal cognitive data from which phenotypes measuring each individual's cognitive changes were constructed. One SNP--rs2075650, located in TOMM40 (translocase of the outer mitochondrial membrane 40 homolog)--had a genome-wide significant association with cognitive ageing (P=2.5 × 10(-8)). This result was replicated in a meta-analysis of three independent Swedish cohorts (P=2.41 × 10(-6)). An Apolipoprotein E (APOE) haplotype (adjacent to TOMM40), previously associated with cognitive ageing, had a significant effect on cognitive ageing in the CAGES sample (P=2.18 × 10(-8); females, P=1.66 × 10(-11); males, P=0.01). Fine SNP mapping of the TOMM40/APOE region identified both APOE (rs429358; P=3.66 × 10(-11)) and TOMM40 (rs11556505; P=2.45 × 10(-8)) as loci that were associated with cognitive ageing. Imputation and conditional analyses in the discovery and replication cohorts strongly suggest that this effect is due to APOE (rs429358). Functional genomic analysis indicated that SNPs in the TOMM40/APOE region have a functional, regulatory non-protein-coding effect. The APOE region is significantly associated with nonpathological cognitive ageing. The identity and mechanism of one or multiple causal variants remain unclear.

Cerebral white matter hyperintensities (WMH) reflect accumulating white matter damage with aging and impair cognition. The role of childhood intelligence is rarely considered in associations between cognitive impairment and WMH. We studied community-dwelling older people all born in 1936, in whom IQ had been assessed at age 11 years. We assessed medical histories, current cognitive ability and quantified WMH on MR imaging. Among 634 participants, mean age 72.7 (SD 0.7), age 11 IQ was the strongest predictor of late life cognitive ability. After accounting for age 11 IQ, greater WMH load was significantly associated with lower late life general cognitive ability (β = -0.14, p < 0.01) and processing speed (β = -0.19, p < 0.001). WMH were also associated independently with lower age 11 IQ (β = -0.08, p < 0.05) and hypertension. In conclusion, having more WMH is significantly associated with lower cognitive ability, after accounting for prior ability, age 11IQ. Early-life IQ also influenced WMH in later life. Determining how lower IQ in youth leads to increasing brain damage with aging is important for future successful cognitive aging., (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)

Brain tissue deterioration is a significant contributor to lower cognitive ability in later life; however, few studies have appropriate data to establish how much influence prior brain volume and prior cognitive performance have on this association. We investigated the associations between structural brain imaging biomarkers, including an estimate of maximal brain volume, and detailed measures of cognitive ability at age 73 years in a large (N = 620), generally healthy, community-dwelling population. Cognitive ability data were available from age 11 years. We found positive associations (r) between general cognitive ability and estimated brain volume in youth (male, 0.28; females, 0.12), and in measured brain volume in later life (males, 0.27; females, 0.26). Our findings show that cognitive ability in youth is a strong predictor of estimated prior and measured current brain volume in old age but that these effects were the same for both white and gray matter. As 1 of the largest studies of associations between brain volume and cognitive ability with normal aging, this work contributes to the wider understanding of how some early-life factors influence cognitive aging., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: The present study investigates associations between brain white matter tract integrity and cognitive abilities in community-dwelling older people (N = 655). We explored two potential confounds of white matter tract-cognition associations in later life: (a) whether the associations between tracts and specific cognitive abilities are accounted for by general cognitive ability (g); and (b) how the presence of atrophy and white matter lesions affect these associations., Method: Tract integrity was determined using quantitative diffusion magnetic resonance imaging tractography (tract-averaged fractional anisotropy [FA]). Using confirmatory factor analysis, we compared first-order and bifactor models to investigate whether specific tract-ability associations were accounted for by g., Results: Significant associations were found between g and FA in bilateral anterior thalamic radiations (r range: .16-.18, p < .01), uncinate (r range: .19-.26, p < .001), arcuate fasciculi (r range: .11-.12, p < .05), and the splenium of corpus callosum (r = .14, p < .01). After controlling for g within the bifactor model, some significant specific cognitive domain associations remained. Results also suggest that the primary effects of controlling for whole brain integrity were on g associations, not specific abilities., Conclusion: Results suggest that g accounts for most of, but not all, the tract-cognition associations in the current data. When controlling for age-related overall brain structural changes, only minor attenuations of the tract-cognition associations were found, and these were primarily with g. In totality, the results highlight the importance of controlling for g when investigating associations between specific cognitive abilities and neuropsychology variables.

Background: Social networks and support have been proposed as cognitively protective in old age. As studies often consider these social factors in isolation the question of which characteristics of the social environment are beneficial remains., Objective: The current study examined associations between measures of social networks (including contact with friends/family, marital status and living arrangement), feelings of loneliness and social support, and a range of cognitive outcomes., Methods: Social network, loneliness and support data were available in the Lothian Birth Cohort 1936 (LBC1936, n = 1,091) at age 70. Participants completed a battery of cognitive tests, and factor scores were available for general cognitive ability, and the cognitive domains of processing speed and memory. Childhood cognitive ability data from age 11 were also available., Results: When examined in separate ANCOVAs, lower loneliness and more social support were significantly associated with better cognitive abilities at age 70, though not memory (independently of age, sex, childhood cognitive ability and social class), accounting for about 0.5-1.5% of the variance. When the social factors were considered simultaneously, higher loneliness remained associated with lower general cognitive ability (ηp(2) = 0.005, p = 0.046), and those living alone (ηp(2) = 0.007, p = 0.014) or with less social support (ηp(2) = 0.007, p = 0.016) had slower processing speed. When these final models were repeated including a depression symptoms score as a covariate, the associations between loneliness and general cognitive ability, and social support and processing speed, were no longer significant. However, the association between living alone and processing speed remained (ηp(2) = 0.006, p = 0.031)., Conclusions: Of the social factors considered, loneliness, social support and living arrangement were most consistently associated with aspects of cognitive ability in older people, and these associations appeared to be partly, though not wholly, accounted for by symptoms of depression. Although longitudinal follow-up is required to examine the causal direction of the effects more definitively, it may be beneficial to promote the development of interventions to reduce loneliness and social isolation, and to increase social support., (Copyright © 2013 S. Karger AG, Basel.)

This cohort profile describes the origins, tracing, recruitment, testing and follow-up of the University of Edinburgh-based Lothian Birth Cohorts of 1921 (LBC1921; N = 550) and 1936 (LBC1936; N = 1091). The participants undertook a general intelligence test at age 11 years and were recruited for these cohorts at mean ages of 79 (LBC1921) and 70 (LBC1936). The LBC1921 have been examined at mean ages of 79, 83, 87 and 90 years. The LBC1936 have been examined at mean ages of 70 and 73 years, and are being seen at 76 years. Both samples have an emphasis on the ageing of cognitive functions as outcomes. As they have childhood intelligence test scores, the cohorts' data have been used to search for determinants of lifetime cognitive changes, and also cognitive change within old age. The cohorts' outcomes also include a range of physical and psycho-social aspects of well-being in old age. Both cohorts have a wide range of variables: genome-wide genotyping, demographics, psycho-social and lifestyle factors, cognitive functions, medical history and examination, and biomarkers (from blood and urine). The LBC1936 participants also have a detailed structural magnetic resonance imaging (MRI) brain scan. A range of scientific findings is described, to illustrate the possible uses of the cohorts.

Objectives: To examine the cognitively protective effect of leisure and physical activities while accounting for prior cognitive ability, a rarely considered confounder of the previously reported associations between activity and cognitive aging., Design: Longitudinal cohort study., Setting: Glostrup, Denmark., Participants: Community-dwelling sample of adults recruited into the Glostrup 1914 Cohort (baseline N = 802). All were born in 1914 and were assessed at ages 50, 60, 70, and 80. New participants were recruited during the study to counter attrition., Measurements: On each occasion, cognitive ability was assessed using four tests, which defined a general cognitive ability score. Self-reported participation in leisure and physical activities was also collected. In general, physical activity was summarized on a 3- or 4-point scale, and leisure activity as none versus some (ages 50 and 60) or according to participation in a list of common activities (age 70). The effect of activity-leisure and physical-on the level of cognitive ability and cognitive change over time from age 60 to 80 was examined in growth curve models., Results: Greater activity (leisure or physical) was consistently associated with a higher level of cognitive ability. Adjusting for baseline cognitive ability (age 50) attenuated these associations, suggesting that associations between activity and cognition reported in old age are largely a consequence of preserved differentiation. A small but significant association remained between greater physical activity at age 60 or 70 and less cognitive decline., Conclusion: The association between more-frequent leisure activity and less cognitive decline mainly reflects the positive cross-sectional association between activity and cognition, although the link that remains between greater physical activity and a more-successful cognitive aging trajectory is of particular relevance to those who are developing interventions., (© 2012, Copyright the Authors Journal compilation © 2012, The American Geriatrics Society.)

Objectives: To examine the association between smoking history and cognitive function in old age, and whether it remains after controlling for childhood cognitive ability (IQ) and adult socioeconomic status (SES)., Methods: In the Lothian Birth Cohort 1936 Study, 1080 men and women, who previously participated in a nationwide IQ-type test in childhood, were followed up at age 70. The associations between smoking history and age 70 IQ, general cognitive ability (g), processing speed, memory, and verbal ability were assessed., Results: Lower childhood IQ was associated with a higher risk of becoming a smoker and continuing to smoke in late life, and with reduced lung function (FEV1) in late life. Current smokers scored significantly lower than ex-smokers and never smokers on tests of age 70 IQ, general cognitive ability, and processing speed, but not memory or verbal ability. After controlling for childhood IQ and SES, current smoking at age 70 (but not pack years of smoking) was associated with impairments in general cognitive ability and processing speed., Conclusion: Smoking in old age makes a small, independent contribution to cognitive performance in old age., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Active lifestyles might protect cognitive abilities; however, studies rarely consider the reverse causal direction. Activity-cognition associations might reflect stable intelligence differences rather than a protective effect of activity. The Lothian Birth Cohort 1936 (n = 1091) completed cognitive tests aged 70, having taken an intelligence test aged 11. Activity (assessed by participation in 15 activities that produced a socio-intellectual activity factor, and by physical activity) was positively associated with cognition (r = .08 to .32, p ≤ .05). When age-11 IQ and adult social class were controlled, only physical activity remained significantly associated with general cognitive ability and processing speed.

Genetic influences have an important role in the ageing process. The genetic factors that influence success in bodily ageing may also contribute to the successful ageing of cognitive abilities. A comparative genomics approach found longevity genes conserved between yeast Saccharomyces cerevisiae and nematode Caenorhabditis elegans. We hypothesised that these longevity genes influence variance in cognitive ability and age-related cognitive decline in humans. Here, we investigated six of these genes that have human orthologs and show expression in the brain. We tested AFG3L2 (MIM: 604581, AFG3 ATPase family gene 3-like 2 (yeast)), FRAP1 (MIM: 601231, a FK506 binding protein 12-rapamycin associated protein), MAT1A, MAT2A (MIM: 610550 and 601468, methionine adenosyltransferases I alpha and II alpha, respectively), SYNJ1 and SYNJ2 (MIM: 604297 and 609410, synaptojanin-1 and synaptojanin-2, respectively) in approximately 1000 healthy older Scots: the Lothian Birth Cohort 1936 (LBC1936). They were tested on general cognitive ability at age 11 years. At a mean age of 70 years, they re-sat the same general cognitive ability test and underwent an additional battery of diverse cognitive tests. In all, 70 tag and functional SNPs in the six longevity genes were genotyped and tested for association with cognition and cognitive ageing in LBC1936. Suggestive associations were detected between SNPs in SYNJ2, MAT1A, AFG3L2 and SYNJ1 and a general memory factor and general cognitive ability at age 11 and 70 years. Replication studies for cognitive ability associations were performed in 2506 samples from the Cognitive Ageing Genetics in England and Scotland consortium. A meta-analysis replicated the SYNJ2 association with cognitive abilities (lowest P=0.00077). SYNJ2 is a novel gene in which variation is potentially associated with cognitive abilities.

A novel analysis of magnetic resonance imaging (MRI) scans based on multispectral image fusion was used to quantify iron deposits in basal ganglia and microbleeds in 143 nondemented subjects of the generally healthy Lothian Birth Cohort, who were tested for general cognitive ability (intelligence) at mean ages of 11, 70, and 72 years. Possessing more iron deposits at age 72 was significantly associated with lower general cognitive ability at age 11, 70, and 72, explaining 4% to 9% of the variance. The relationships with old age general cognitive ability remained significant after controlling for childhood cognition, suggesting that iron deposits are related to lifetime cognitive decline. Most iron deposits were in the basal ganglia, with few microbleeds. While iron deposits in the general population have so far been dismissed in the literature, our results show substantial associations with cognitive functioning. The pattern of results suggests that iron deposits are not only a biomarker of general cognitive ability in old age and age-related cognitive decline, but that they are also related to the lifelong-stable trait of intelligence., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Differences in genomic structure between individuals are ubiquitous features of human genetic variation. Specific copy number variants (CNVs) have been associated with susceptibility to numerous complex psychiatric disorders, including attention-deficit-hyperactivity disorder, autism-spectrum disorders and schizophrenia. These disorders often display co-morbidity with low intelligence. Rare chromosomal deletions and duplications are associated with these disorders, so it has been suggested that these deletions or duplications may be associated with differences in intelligence. Here we investigate associations between large (≥500kb), rare (<1% population frequency) CNVs and both fluid and crystallized intelligence in community-dwelling older people. We observe no significant associations between intelligence and total CNV load. Examining individual CNV regions previously implicated in neuropsychological disorders, we find suggestive evidence that CNV regions around SHANK3 are associated with fluid intelligence as derived from a battery of cognitive tests. This is the first study to examine the effects of rare CNVs as called by multiple algorithms on cognition in a large non-clinical sample, and finds no effects of such variants on general cognitive ability.

There is increasing evidence to suggest that elevated plasma levels of fibrinogen are associated with late-life cognitive performance. This study tested the association of single nucleotide polymorphisms in the fibrinogen α (FGA) and β (FGB) genes with cognitive performance. Data were analysed from three community-dwelling populations of older persons (>50 years) in central Scotland: the Aspirin for Asymptomatic Atherosclerosis (AAA) Trial (n = 2,091), the Edinburgh Type 2 Diabetes Study (ET2DS, n = 1,066), and the Lothian Birth Cohort 1936 (LBC1936, n = 1,091). Cognition was assessed using a battery of five, seven, and four psychometric tests, respectively. This information was used to derive a general cognitive factor. Weakly significant associations were found between the rs4220 (FGB), and rs2227412 (FGB) SNPs and a single test of cognitive performance in the AAA Trial (p < 0.05). These findings did not replicate in the LBC1936 or ET2DS cohorts, except for the rs2227412 SNP, which was significantly associated with the general cognitive factor in the ET2DS (p = 3.3 × 10(-4)). A summary term that combined results from all three studies suggested that the rs2227412 genotype associated with reduced cognitive ability also associated with higher plasma fibrinogen levels. These findings suggest a tentative role for fibrinogen as a determinant of late-life cognitive performance and justify further attempts at replication in older persons.

Previous studies have suggested a link between flavonoid intake and better cognitive function in later life but have not been able to control for possible confounding by prior intelligence quotient (IQ). The aim of the present study was to address this issue in a cross-sectional survey of 1091 men and women born in 1936, in whom IQ was measured at age 11 years. At the age of 70 years, participants carried out various neuropsychological tests and completed a FFQ. Associations between test scores and nutrient intake were assessed by linear regression with adjustment for potentially confounding variables. Total fruit, citrus fruits, apple and tea intakes were initially found to be associated with better scores in a variety of cognitive tests, but the associations were no longer statistically significant after adjusting for confounding factors, including childhood IQ. Flavanone intake was initially found to be associated with better scores in verbal fluency (P = 0·003, with standardised regression coefficient 0·10), but, again, the association was no longer statistically significant after adjusting for confounding factors. These findings do not support a role for flavonoids in the prevention of cognitive decline in later life. Studies of diet and cognitive function should include measurement of potential confounding variables, including prior IQ wherever possible.

Background/objectives: Cross-sectional and longitudinal studies provide some evidence for an association between intake of antioxidants and B vitamins, and cognitive function in later life, but intervention studies have not provided clear evidence of beneficial effects. The possibility that those with higher cognitive ability during earlier adult life consume more nutrient-rich diets in later life could provide an alternative explanation for the associations seen in observational studies., Methods: Survey of 1091 men and women born in 1936 living in Edinburgh, Scotland, in whom previous cognitive ability was available from intelligence quotient (IQ) measurements at age 11 years. At age 70 years, participants carried out a range of cognitive tests and completed a semiquantitative food-frequency questionnaire (FFQ)., Results: A total of 882 participants returned completed FFQs from which intake of β-carotene, vitamin C, B12, folate and riboflavin was estimated. IQ at age 11 years was positively associated with dietary intake of vitamin C (P=0.048) and inversely associated with dietary intake of riboflavin (P<0.001) at age 70 years, and was higher in those taking folate supplements at age 70 years (P<0.005). Weak associations between intake of vitamins B12, C, riboflavin and folate and cognitive performance at age 70 years were attenuated by adjustment for confounding variables, including IQ at age 11 years. In the fully adjusted models, the proportion of total variance in cognitive function at age 70 years accounted for by intake of these nutrients was less than 1%., Conclusion: These results provide no evidence for a clinically significant beneficial association between intake of these antioxidants and B vitamins, and cognitive function at age 70 years.

Objective: Moderate alcohol consumption has been associated with better cognitive performance in late adulthood, possibly by improving vascular health. Few studies have examined the potentially confounding roles of prior cognitive ability and social class in this relationship., Method: Participants were 922 healthy adults about 70 years old in the Lothian Birth Cohort 1936 study, for whom there are IQ data from age 11. Alcohol consumption was obtained by self-report questionnaire. Cognitive outcome measures included general cognitive ability, speed of information processing, memory, and verbal ability., Results: Moderate to substantial drinking (>2 units/day) was associated with better performance on cognitive tests than low-level drinking (≤2 units/day) or nondrinking in men and women. After adjusting for childhood IQ and adult social class, most of these associations were removed or substantially attenuated. After full adjustment, a small, positive association remained between overall alcohol intake and memory (women and men) and verbal ability (women only). Women's overall alcohol intake was derived almost exclusively from wine. In men, effects differed according to beverage type: wine and sherry-port consumption was associated with better verbal ability, but beer was associated with a poorer verbal ability and spirits intake was associated with better memory., Conclusions: Prior intelligence and socioeconomic status influence both amount and type of alcohol intake and may partly explain the link between alcohol intake and improved cognitive performance at age 70. Alcohol consumption was found to make a small, independent contribution to memory performance and verbal ability, but these findings' clinical significance is uncertain., ((c) 2011 APA, all rights reserved)

We tested the hypothesis that the previously reported association between a higher body mass index (BMI) and poorer cognition in later adulthood is an artifact of confounding by previous cognitive ability and socioeconomic status. Participants were 1,079 adults aged about 70 years in the Lothian Birth Cohort 1936 Study, on whom there are IQ data from age 11. Cognitive outcome measures included: IQ at age 70 using the same test that was administered at age 11; composite measures of general cognitive ability (g factor), speed of information processing, and memory; and two tests of verbal ability. People classified as overweight or obese in later adulthood had significantly lower scores on tests of childhood IQ, age 70 IQ, g factor, and verbal ability. There was no significant association with processing speed or memory performance. After adjusting for childhood IQ and social class in general linear models, associations with age 70 IQ and g factor were nonsignificant or attenuated. However, throughout the models, there was a persistent (inverse) relationship between BMI and performance on the National Adult Reading Test (NART) and Wechsler Test of Adult Reading (WTAR), which remained significant after full adjustment for all sociodemographic and health covariates (for the NART, p = .025; for the WTAR, p = .011). The findings suggest that the previously reported BMI-cognition associations in later adulthood could be largely accounted for by prior ability and socioeconomic status, and by the possible influence of these factors on the adoption of health behaviors in adulthood., ((c) 2010 APA, all rights reserved).)

Understanding human cognitive ageing is important to improve the health of an increasing elderly population. Serum uric acid levels have been linked to many ageing illnesses and are also linked to cognitive functioning, though the direction of the association is equivocal. SLC2A9, a urate transporter, influences uric acid levels. This study first tested four SLC2A9 SNPs, previously associated with uric acid levels, in approximately 1000 Scots: the Lothian Birth Cohort 1936 (LBC1936). These participants were tested on general cognitive ability at ages 11 and 70. At age 70, they took a battery of diverse cognitive tests. Two replication cohorts were investigated. First, the LBC1921, who were tested on general cognitive ability at age 11. At ages 79 (n = 520), 83 (n = 281) and age 87 (n = 177), they completed cognitive ability test batteries. Second, the Edinburgh Type 2 Diabetes Study (ET2DS) were tested for cognitive abilities aged between 60 and 75 years (n = 1066). All analyses were adjusted for age, gender, body mass index and either childhood cognitive ability test score (LBC) or vocabulary-a measure of prior cognitive ability in ET2DS. Significant associations were detected with SLC2A9 and a general memory factor in LBC1936 and other individual cognitive ability tests (lowest P = 0.0002). The association with logical memory replicated in LBC1921 at all ages (all P < 0.05). These associations were not replicated in ET2DS (all P > 0.1). If the positive associations withstand, then this study could suggest that higher uric acid levels may be associated with increased performance on memory-related tasks.

Objective: To investigate the association between caffeine consumption and cognitive outcomes in later life., Methods: Participants were 923 healthy adults from the Lothian Birth Cohort 1936 Study, on whom there were intelligence quotient (IQ) data from age 11 years. Cognitive function at age 70 years was assessed, using tests measuring general cognitive ability, speed of information processing, and memory. Current caffeine consumption (using multiple measures of tea, coffee, and total dietary caffeine) was obtained by self-report questionnaire, and demographic and health information was collected in a standardized interview., Results: In age- and sex-adjusted models, there were significant positive associations between total caffeine intake and general cognitive ability and memory. After adjustment for age 11 IQ and social class, both individually and together, most of these associations became nonsignificant. A robust positive association, however, was found between drinking ground coffee (e.g., filter and espresso) and performance on the National Adult Reading Test (NART, p = .007), and the Wechsler Test of Adult Reading (WTAR, p = .02). No gender effects were observed, contrary to previous studies. Generally, higher cognitive scores were associated with coffee consumption, and lower cognitive scores with tea consumption, but these effects were not significant in the fully adjusted model., Conclusions: The present study is rare in having childhood IQ in a large sample of older people. The results suggest that the significant caffeine intake-cognitive ability associations are bidirectional-because childhood IQ and estimated prior IQ are associated with the type of caffeine intake in old age-and partly confounded by social class.

Objective: To test the hypothesis that increased levels of inflammatory and hemostatic markers are associated with poorer cognitive performance and to assess the influence of childhood intelligence quotient (IQ) and current cardiovascular disease (CVD) risk factors on this relationship. Blood inflammatory markers have been shown to predict late-life cognition, although the mechanism through which this occurs is unknown., Methods: Levels of the biomarkers C-reactive protein and fibrinogen were measured in 1053 Scottish participants (50.2% female) from the Lothian Birth Cohort 1936 ranging in age from 67 to 71 years. Biomarker levels were tested for their association with diverse cognitive abilities., Results: Significant cross-sectional associations were found between the biomarkers and various cognitive abilities: their effect size was around 1% of the variance and was in the direction of higher marker levels conferring poorer cognitive performance. With the exception of the reaction time measures (and fibrinogen), these associations could be explained by childhood IQ, CVD risk factors, or both. Importantly, both the inflammatory markers at age 70 years were associated (p < .001) with childhood IQ., Conclusions: Whereas inflammatory marker levels predict contemporaneous general cognitive ability, the results support a model of reverse causation because childhood IQ predicts late-life inflammation. This might be through its association with later life CVD risk factors or because it is a measure of system integrity. Unlike general cognitive ability, the association between inflammatory markers (particularly fibrinogen) and processing speed was maintained in the presence of childhood IQ and/or CVD risk factor adjustments. This might also reflect variation in physiological integrity.

As the proportion of older people in societies has increased, research into the determinants of cognitive ageing has risen in importance. Genetic influences account for over 50% of the variance in adult cognitive abilities. Previous studies on cognition and illnesses with cognitive impairments have identified single nucleotide polymorphisms (SNPs) within candidate genes that might influence cognition or age-related cognitive change. This study investigated 10 candidate genes in over 1000 Scots: the Lothian Birth Cohort 1936 (LBC1936). These participants were tested on general cognitive ability (Scottish Mental Survey 1947) at age 11. At mean age 70, they completed the same general cognitive ability test and a battery of diverse cognitive tests. Nineteen SNPs in 10 genes previously associated with cognition, Alzheimer's disease or autism were genotyped in 1063 individuals. The genes include BDNF, COMT, DISC1, KL, NCSTN, PPP1R1B, PRNP, SHANK3, SORL1 and WRN. Linear regression analysis investigated the additive effect of each SNP on the cognitive variables, covarying for gender and age. Childhood cognitive ability was also included as a covariate to identify associations specifically with cognitive ageing. Certain SNPs reached the conventional significance threshold for association with cognitive traits or cognitive ageing in LBC1936 (P < 0.05). No SNPs reached the Bonferroni-level of significance (all P > 0.0015). Of the 10 genes, we discuss that COMT, KL, PRNP, PPP1R1B, SORL1 and WRN especially merit further attention for association with cognitive ability and/or age-related cognitive change. All results are also presented so that they are valuable for future meta-analyses of candidate genes for cognition.

The association between DTNBP1 genotype and cognitive abilities was investigated in three population samples (1054 Scottish, 1806 Australian and 745 English) of varying age. There was evidence in each of the cohorts for association (P < 0.05) to single nucleotide polymorphisms (SNPs) and haplotypes previously shown to relate to cognition. By comparison with previous findings, these associations included measures of memory, and there was at best equivocal evidence of association with general cognitive ability. Of the SNPs typed in all three cohorts, rs2619528 and rs1011313 showed significant association with measures of executive function in two cohorts, rs1018381 showed significant association with verbal ability in one cohort and rs2619522 showed significance/marginal significance with tests of memory, speed and executive function in two cohorts. For all these SNPs, the direction and magnitude of the allelic effects were consistent between cohorts and with previous findings. In the English cohort, a previously untested SNP (rs742105) located in a distinct haplotype block upstream of the other SNPs showed the strongest significance (P < 0.01) for measures of memory but weaker significance for general cognitive ability. Our results therefore support involvement of the dysbindin gene in cognitive function, but further work is needed to clarify the specific functional variants involved and the cognitive abilities with which they are associated.

Introduction: Age-associated cognitive decline-or normal (non-pathological, normative, usual) cognitive ageing-is an important human experience which differs in extent between individuals. The determinants of the differences in age-related cognitive decline are not fully understood. Progress in the field is taking place across many areas of biomedical and psychosocial sciences., Areas of Agreement and Controversy: The phenotype of normal cognitive ageing is well described. Some mental capabilities are well maintained into old age. From early adulthood, there are declines in mental domains such as processing speed, reasoning, memory and executive functions, some of which is underpinned by a decline in a general cognitive factor. There are contributions to understanding individual differences in normal cognitive ageing from genetics, general health and medical disorders such as atherosclerotic disease, biological processes such as inflammation, neurobiological changes, diet and lifestyle. Many of these effect sizes are small; some are poorly replicated; and in some cases, there is the possibility of reverse causation, with prior cognitive ability causing the supposed 'cause' of cognitive ability in old age., Emerging Areas for Developing Research: Genome-wide scans are a likely source to establish genetic contributions. The role of vascular factors in cognitive ageing is increasingly studied and understood. The same applies to diet, biomarkers such as inflammation and lifestyle factors such as exercise. There are marked advances in brain imaging, affording better in vivo studies of brain correlates of cognitive changes. There is growing appreciation that factors affecting general bodily ageing also influence cognitive functions in old age.

Background: Identifying the determinants of cognitive aging is a research priority; however, few studies are able to examine the influence of pre-morbid cognitive ability on later changes in cognitive function., Objective: To examine the association between childhood cognitive ability and cognitive change from age 79 to 83 in the presence of other demographic and lifestyle indicators., Methods: The participants took a test of mental ability when aged 11 as part of the Scottish Mental Survey 1932. Cognitive ability based on Raven's Matrices, Verbal Fluency, and Logical Memory was assessed at ages 79 and 83. We used both linear regression and latent variable growth curve modeling to compare methods and results., Results: Using linear regression, childhood mental ability was a significant predictor of cognitive change from 79 to 83, accounting for about 1.4% of the variance. Sex, education, social class, smoking status and alcohol intake were non-significant. In contrast, using latent variable growth curve modeling, there was no association between childhood mental ability and cognitive change. Sex (male), years of education, drinking status (positive), and childhood IQ were associated with better cognitive ability at age 79. The difference in results was due to the inability of linear regression to account completely for test-specific variance., Conclusion: Within a group of non-demented older people, greater childhood mental ability was associated with level of cognitive ability at age 79, but not with change in cognitive ability to age 83. To obtain accurate results regarding covariates of change, it is important to use methodology that can appropriately allocate all measured sources of variance., ((c) 2008 S. Karger AG, Basel.)

Background: Cognitive ageing is a major burden for society and a major influence in lowering people's independence and quality of life. It is the most feared aspect of ageing. There are large individual differences in age-related cognitive changes. Seeking the determinants of cognitive ageing is a research priority. A limitation of many studies is the lack of a sufficiently long period between cognitive assessments to examine determinants. Here, the aim is to examine influences on cognitive ageing between childhood and old age., Methods/design: The study is designed as a follow-up cohort study. The participants comprise surviving members of the Scottish Mental Survey of 1947 (SMS1947; N = 70,805) who reside in the Edinburgh area (Lothian) of Scotland. The SMS1947 applied a valid test of general intelligence to all children born in 1936 and attending Scottish schools in June 1947. A total of 1091 participants make up the Lothian Birth Cohort 1936. They undertook: a medical interview and examination; physical fitness testing; extensive cognitive testing (reasoning, memory, speed of information processing, and executive function); personality, quality of life and other psycho-social questionnaires; and a food frequency questionnaire. They have taken the same mental ability test (the Moray House Test No. 12) at age 11 and age 70. They provided blood samples for DNA extraction and testing and other biomarker analyses. Here we describe the background and aims of the study, the recruitment procedures and details of numbers tested, and the details of all examinations., Discussion: The principal strength of this cohort is the rarely captured phenotype of lifetime cognitive change. There is additional rich information to examine the determinants of individual differences in this lifetime cognitive change. This protocol report is important in alerting other researchers to the data available in the cohort.

The Paced Auditory Serial Addition Task (PASAT) is a test of attention and concentration in which participants add each number from a taped list to the one preceding it (Gronwall & Wrightson, 1974). As it requires mental addition at an externally determined pace the task often causes anxiety (Roman, Edwall, Buchanan, & Patton 1991). We devised the Paced Auditory Serial Opposites Task (PASOT) as a nonnumerical replacement (Deary, 2001). PASOT AND PASAT were administered to 40 participants, and the correlation between them was .71. The correlations of the PASOT and other cognitive measures did not differ significantly from those of the PASAT (with the exception of the Digit Span Backward). Performing the PASOT was significantly less aversive; teh PASAT induced more negative feelings of Tense Arousal (t38 = -4.52, p < .001).

To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32,070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.