Search

Impaired cognitive function associated with use of anticholinergic drugs may be partly attributed to underlying physical illness and exposure to factors that increase the risk of some physical disorders such as low socioeconomic status (SES) and less education. To estimate the extent of cognitive impairment and risk of progress to dementia associated with anticholinergic drug use and to estimate confounding by gender, APOE, family history of dementia, lower SES, less education, and lower childhood mental ability, we recruited 281 volunteers at age 77-78 without overt dementia who had taken part in the Scottish Mental Survey of 1932. Clinical histories, use of medications, self reported frequency of emotional symptoms and standardized tests of cognitive function were obtained. With and without adjustment for age and childhood IQ, there were significant between-group differences in tests of non-verbal reasoning and spatial ability. During 10 year follow-up, progress to overt dementia was not associated with anticholinergic drugs use on recruitment but female gender and a history of dementia in parent or sibling were associated with dementia. We concluded that anticholinergic drug use in this narrow age range sample was linked to cognitive impairment but not to subsequent dementia. [ABSTRACT FROM AUTHOR]

BACKGROUND: Evidence for an inverse relation between dietary intake of n-3 polyunsaturated fatty acids (PUFAs) and age-related cognitive decline is inconsistent. This inconsistency may arise because the relation is present only in the absence of the apolipoprotein E epsilon4 (APOE epsilon4) allele. OBJECTIVE: We aimed to determine the contribution of erythrocyte n-3 PUFA content to cognitive aging in the presence or absence of the APOE epsilon4 allele. DESIGN: We followed up 120 volunteers, born in 1936, at approximate ages of 64, 66, and 68 y. Their intelligence quotient at 11 y old was available. At first follow-up, we determined APOE genotype and measured the PUFA composition of erythrocyte membranes. Six cognitive tests were administered at all follow-ups. We related cognitive performance at approximately 64 y old and cognitive changes from approximately 64 to approximately 68 y old to erythrocyte n-3 PUFA composition on recruitment and to APOE epsilon4 allele status. RESULTS: Total n-3 PUFA and docosohexaenoic acid concentrations were associated with benefits for cognition at approximately 64 y old and from approximately 64 to approximately 68 y old. After adjustment for sex, APOE epsilon4 status, and intelligence quotient at 11 y old, the effects associated with total n-3 PUFA remained significant. Cognitive benefits were associated with higher erythrocyte n-3 PUFA content but were significant only in the absence of the APOE epsilon4 allele. CONCLUSIONS: These data are evidence of a gene x environment interaction for cognitive aging. They are relevant to the analysis of trials of n-3 PUFA supplements in cognitive aging and dementia prevention, and they support heterogeneity in cognitive aging and, possibly, in Alzheimer disease. Copyright © 2008 American Society for Nutrition [ABSTRACT FROM AUTHOR]

BACKGROUND: Old age is associated with reduced cognitive performance. Nutritional factors may contribute to this association. OBJECTIVE: We tested associations between cognitive performance and plasma vitamin B-12, folate, and homocysteine concentrations in the elderly. DESIGN: We studied survivors of the Scottish Mental Surveys of 1932 (Aberdeen 1921 Birth Cohort, or ABC21) and 1947 (Aberdeen 1936 Birth Cohort, or ABC36), which surveyed childhood intelligence quotient. We measured folate, vitamin B-12, and homocysteine concentrations in fasting blood samples and cognitive performance by the Mini Mental State Examination (MMSE), National Adult Reading Test (NART), Raven's Progressive Matrices (RPM), Auditory Verbal Learning Test (AVLT), digit symbol (DS) subtest, and block design (BD) subtest. RESULTS: Homocysteine was higher in the ABC21 than in the ABC36 (P < 0.0001). There were positive correlations between folate and vitamin B-12 and negative correlations between homocysteine and both folate and vitamin B-12. MMSE, RPM, AVLT, DS, and BD scores were higher in the ABC36. In the ABC21, folate, vitamin B-12, and MMSE score were positively correlated and homocysteine was negatively correlated with RPM, DS, and BD scores. Folic acid was positively correlated with AVLT and DS scores. In the ABC36, folate was positively correlated with BD score. After adjustment for childhood intelligence quotient, partial correlations were strengthened between vitamin B-12 and NART score and between homocysteine and RPM score but weakened between red blood cell folate and DS score. CONCLUSIONS: B vitamins and homocysteine are associated with cognitive variation in old age. In the ABC21 but not the ABC36, homocysteine accounted for approximately 7-8% of the variance in cognitive performance. This may prove relevant to the design of neuroprotective studies in late life. [ABSTRACT FROM AUTHOR]

INTRODUCTION: although death certification data are commonly used in dementia epidemiology, their reliability has been questioned. METHODS: death certificates were available from the Registrar General for Scotland for all patients with Alzheimer's disease/presenile dementia (AD PSD) or vascular dementia (VaD) who had died in Scotland up until 31 December 1994. Primary (immediate and underlying) and contributory causes of death were noted as well as place of death. Occupations of male patients were obtained from death certificates or from case notes and classified according to the Standard Occupational Classification. Bronchopneumonia was considered a non-specific cause of death and specific causes of death were classified as: cardiac disease, dementia, cerebrovascular disease, neoplasms, other vascular diseases and other diseases. Place of death was recorded as psychiatric hospital, district general hospital, nursing home or private residence. RESULTS: death certificates of 398 people who had been treated for AD PSD and 348 who had been treated for VaD were identified. Bronchopneumonia was the most common immediate cause of death in the AD PSD group (70.9%) but less so for the VaD group (51.7%). For both groups place of death was associated with significant differences in pneumonia being reported as the immediate cause of death as well as specific underlying and contributory causes of death. Dementia was recorded for 90.5% of AD PSD patients but for only 49.7% of the VaD group. CONCLUSIONS: Scottish death certificate data significantly underestimate the prevalence of presenile VaD. Changes in patterns of institutional care may affect dementia rates estimated from death certificate data. [ABSTRACT FROM AUTHOR]

The Aberdeen birth cohorts of 1921 and 1936 (ABC21 and ABC36) were subjected to IQ tests in 1932 or 1947 when they were aged about 11y. They were recruited between 1997-2001 among cognitively healthy community residents and comprehensively phenotyped in a long-term study of brain aging and health up to 2017. Here, we report associations between baseline cognitive test scores and long-term cognitive outcomes. On recruitment, significant sex differences within and between the ABC21 and ABC36 cohorts supported advantages in verbal ability and learning among the ABC36 women that were not significant in ABC21. Comorbid physical disorders were self-reported in both ABC21 and ABC36 but did not contribute to differences in terms of performance in cognitive tests. When used alone without other criteria, cognitive tests scores which fell below the -1.5 SD criterion for tests of progressive matrices, namely verbal learning, digit symbol and block design, did not support the concept that Mild Cognitive Impairment (MCI) is a stable class of acquired loss of function with significant links to the later emergence of a clinical dementia syndrome. This is consistent with many previous reports. Furthermore, because childhood IQ-type data were available, we showed that a lower cognitive performance at about 64 or 78 y than that predicted by IQ at 11 ± 0.5 y did not improve the prediction of progress to MCI or greater cognitive loss. We used binary logistic regression to explore how MCI might contribute to the prediction of later progress to a clinical dementia syndrome. In a fully adjusted model using ABC21 data, we found that non-amnestic MCI, along with factors such as female sex and depressive symptoms, contributed to the prediction of later dementia. A comparable model using ABC36 data did not do so. We propose that (1) MCI criteria restricted to cognitive test scores do not improve the temporal stability of MCI classifications; (2) pathways towards dementia may differ according to age at dementia onset and (3) the concept of MCI may require measures (not captured here) that underly self-reported subjective age-related cognitive decline.

Objectives: Cardiovascular risk is associated with cognitive decline and this effect is attributed to brain pathology, including white matter hyperintensity (WMH) burden. Low-dose aspirin is frequently recommended for reducing vascular events. We investigated the effect of taking aspirin on the association between cardiovascular risk, WMH burden and cognitive function., Study Design: The study sample was drawn from 318 dementia-free adults aged 67-71 years. Brain magnetic resonance imaging (MRI) scans were acquired from 239 participants., Main Outcome Measures: WMH total lesion volumes (TLV) were extracted using the automated lesion segmentation algorithm. We measured cardiovascular risk by calculating ASSIGN score. Cognitive ability was measured using a test of processing speed. We developed structural equation models to test our hypothesis., Results: Sixty-eight participants (47.1 % male, mean age = 68.8 years) reported that they took aspirin. The demographic measures did not differ significantly by aspirin use. Among aspirin users, there was a strong negative association between WMH TLV and cognition (β = -0.43, p-value < 0.001), while in non-users of aspirin the only significant predictor of poorer cognition was cardiovascular risk (β = -0.17, p-value = 0.001)., Conclusions: Aspirin use moderates the negative effect of WMH burden on cognition. Considering WMH burden in addition to cardiovascular risk could improve the prediction of cognitive decline in older adults with aspirin use., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Epidemiological studies of air pollution have shown associations between exposure to particles and dementia. The mechanism of this is unclear. As these seem unlikely in terms of the very small dose likely to reach the brain in usual Western urban circumstances, we extend our 1995 hypothetical explanation of the association of air pollution with cardiac deaths as a plausible alternative explanation of its associations with dementia. Since our original proposal, it has become apparent that inflammation may be carried by blood from organ to organ by biologic microparticles derived from cell membranes. These transmit inflammatory messages to endothelial cells throughout the body as part of a general defensive response to assumed bacterial infection; particulate air pollution has recently been shown to be associated with their release into the blood. We propose that episodic release of biologic microparticles from pollution-induced lung inflammation causes secondary inflammation in the blood-brain barrier and cerebral microbleeds, culminating over time in cognitive impairment. Ultimately, by incomplete repair and accumulation of amyloid, this increases the risk of Alzheimer's disease. Importantly, this mechanism may also explain the relationships of other inflammatory conditions and environmental factors with cognitive decline, and point to new opportunities to understand and prevent dementia.

In an observational longitudinal study of a sub-sample of the Aberdeen 1936 birth cohort, from age 62 to 77 years, we investigated childhood intelligence, social class, education, life-course social mobility, memory test performance and memory decline in late life. We examined 388 local residents who had attended school in Aberdeen in 1947 and measured Auditory-Verbal Learning Test (AVLT) at recruitment age about 64 years and up to five times until age about 77 years. Better performance at age about 64 on AVLT was predicted by early socioeconomic status (SES), social mobility and childhood intelligence. The trajectory of AVLT decline was steeper in those who had received less education. This relationship was independent of childhood ability, sex, SES in childhood and social mobility. The protection of memory by education suggests that education supports resilience to age-related cognitive impairment. Upward social mobility does not enhance this effect, suggesting that resilience to age-related decline may be established in early life.

Background: hypertension is a risk for brain ageing, but the mechanisms underlying this effect remain unclear. Magnetic resonance imaging (MRI) detected biomarkers of brain ageing include white matter hyperintensities (WMHs), a marker of cerebrovascular disease, and hippocampal volume, a marker of Alzheimer's disease pathology., Objective: to examine relationships between blood pressure (BP) components and brain pathology in older adults., Subjects: two hundred and twenty-seven members of the Aberdeen 1936 Birth Cohort between ages 64 and 68 years., Methods: BP was assessed biennially between 64 and 68 years and brain MRI performed at 68 years. The risk factors of interest were diastolic and systolic BP and their visit-to-visit variability. Outcomes were WMH abundance and hippocampal volume. Regression models, controlling for confounding factors, examined their relationships., Results: higher diastolic BP predicted increased WMH (β = 0.13, P = 0.044) and smaller hippocampi (β = -0.25, P = 0.006). In contrast, increased systolic BP predicted larger hippocampi (β = 0.22, P = 0.013). Variability of diastolic BP predicted lower hippocampal volume (β = -0.15, P = 0.033). These relationships were independent of confounding life-course risk factors. Anti-hypertensive medication did not modify these relationships, but was independently associated with increased WMH (β = 0.17, P = 0.011)., Conclusion: increased diastolic BP is associated with biomarkers of both cerebrovascular and Alzheimer's diseases, whereas the role of systolic BP is less clear, with evidence for a protective effect on hippocampal volume. These differing relationships emphasise the importance of considering individual BP components with regard to brain ageing and pathology. Interventions targeting diastolic hypertension and its chronic variability may provide new strategies able to slow the accumulation of these harmful pathologies., (© The Author 2017. Published by Oxford University Press on behalf of the British Geriatrics Society.All rights reserved. For permissions, please email: journals.permissions@oup.com)

A single copy of klotho allele KL-VS is associated with longevity, better health, increased cognition, and bigger regional brain volume. However, its longitudinal effects on cognition and brain volumes, both global and regional, in late life are unclear. In this study we show that, relative to noncarriers, KL-VS heterozygotes had (1) shorter survival; (2) smaller white matter volumes; (3) slower cognitive decline; and (4) greater right frontal lobe volumes. The KL-VS heterozygote survival and white matter volume disadvantages were unexpected. A possible explanation for these results in the context of the literature is a potential interaction between the environment and/or age of the participants, leading to a heterozygote disadvantage. The longitudinal cognitive trajectories indicate that heterozygotes would have an advantage in very late life. Collectively these results suggest that the genotype-survival advantage of the KL-VS allele is age-dependent and possibly mediated through differential cognition and brain volume., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Various methods are available to measure hippocampal atrophy rate. We compared methods to predict Alzheimer's dementia., Methods: Participants with brain imaging at ages 69 and 73 years were identified from a previous study. Simple manual measures and computationally automated volumetry were performed. Receiver operating characteristics assessed the predictive ability of each method at baseline and on logit regression analysis of two serial scans., Results: Ten of 149 participants developed Alzheimer's dementia and had lower baseline volumes (3647 vs. 4194 mm 3 P  = .002), rates of volume loss (-126 vs. -36 mm 3 /y; P  = .001), and rates of loss in hippocampal fraction (-8.55 vs. -2.35 x 10 -5 /y; P  = .001). Baseline volume with a rate of change gave the highest area under the curve value of 0.96., Discussion: Automated volumetry measuring hippocampal size at age 69 years and subsequent rate of change predicts Alzheimer's dementia development.

Objectives: the 'triad of impairment' phenomenon describes the co-occurrence of age-related cognitive, emotional and physical functioning deficits. We investigated how occupational profile and childhood intelligence contribute to the triad of impairment in late life., Methods: we analysed data of a subsample of the Aberdeen Birth Cohort of 1936 (n = 346). Data were collected on participants' childhood intelligence, late-life cognitive ability, physical functioning, depressive symptoms and main lifetime occupation. We summarised the various occupational and impairment measures into two latent variables, 'occupational profile' and the 'triad of impairment'. We used a series of data reduction approaches and structural equation models (SEMs) of increasing complexity to test both the validity of the models and to understand causal relationships between the life-course risks for the triad of impairment., Results: occupational profile had a significant effect on the triad of impairment independent of childhood intelligence. Childhood intelligence was the predominant influence on the triad of impairment and exerted its effect directly and indirectly via its influence on occupation. The direct effect of childhood intelligence exceeded the independent influence of the occupational profile on impairment by a factor of 1.7-1.8 and was greater by a factor of ∼4 from the indirect pathway (via occupation)., Conclusions: childhood intelligence was the predominant influence on the triad of impairment in late life, independently of the occupational profile. Efforts to reduce impairment in older adults should be informed by a life-course approach with special attention to the early-life environment., (© 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.)

Low socio-economic status is a recognised composite measure made up of income, education and occupational social class, which is a risk factor for poor physical and mental health and late life dementia. Here, we distinguish between components of childhood socioeconomic status to explore their separate influences of childhood and adult occupational social class (OSC), childhood mental ability and education on late life cognitive ability and change trajectories. Cognitive data were collected longitudinally from a sub-sample (N = 478) of the Aberdeen 1936 birth cohort tested on up to 5 occasions between ages 63 and 78 years. Age 11 mental ability scores were available for all participants. We used longitudinal multi-level linear modelling to explore models of cognitive change that distinguished between the possible influences of parental occupation, participants' own occupation as adults, duration of formal education, childhood mental ability and the participants' own occupation. We showed that parental occupation and the participants' own occupation are independently associated with cognition in late life, but do not influence the trajectory of cognitive change. However, when models include childhood mental ability and education the influence of parental and participant occupation is no longer significant. The association in these data between parental occupation and late life cognitive variation is accounted for by childhood mental ability and duration of formal education. However, we cannot exclude the possibility that parental occupation in early life influences early life mental ability and duration of education. The trajectory of change with age is similar across all models, with none of the life course factors (education, parental and participant occupational social class and childhood ability) significantly co-varying with the trajectory of cognitive variation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Cognitive reserve is a hypothetical concept introduced to explain discrepancies between severity of clinical dementia syndromes and the extent of dementia pathology. We examined cognitive reserve in a research programme that followed up a non-clinical sample born in 1921 or 1936 and IQ-tested age 11 years in 1932 or 1947. Structural MRI exams were acquired in about 50% of the sample from whom a subsample were recruited into an additional fMRI study. Here, we summarise findings from seven inter-related studies. These support an understanding of cognitive reserve as a balance between positive life course activity-driven experiences and the negative effects of brain pathologies including cerebrovascular disease and total and regional brain volume loss. Hypothesised structural equation models illustrate the relative causal effects of these positive and negative contributions. Cognitive reserve is considered in the context of choice of interventions to prevent dementia and the opposing effects of cerebrovascular disease and Alzheimer like brain appearances., (Crown Copyright © 2015. Published by Elsevier Ireland Ltd. All rights reserved.)

Two themes are emerging regarding the molecular genetic aetiology of intelligence. The first is that intelligence is influenced by many variants and those that are tagged by common single nucleotide polymorphisms account for around 30% of the phenotypic variation. The second, in line with other polygenic traits such as height and schizophrenia, is that these variants are not randomly distributed across the genome but cluster in genes that work together. Less clear is whether the very low range of cognitive ability (intellectual disability) is simply one end of the normal distribution describing individual differences in cognitive ability across a population. Here, we examined 40 genes with a known association with non-syndromic autosomal recessive intellectual disability (NS-ARID) to determine if they are enriched for common variants associated with the normal range of intelligence differences. The current study used the 3511 individuals of the Cognitive Ageing Genetics in England and Scotland (CAGES) consortium. In addition, a text mining analysis was used to identify gene sets biologically related to the NS-ARID set. Gene-based tests indicated that genes implicated in NS-ARID were not significantly enriched for quantitative trait loci (QTL) associated with intelligence. These findings suggest that genes in which mutations can have a large and deleterious effect on intelligence are not associated with variation across the range of intelligence differences.

Public health and therapeutic measures to reduce cardiac and stroke risk may already be reducing risks of dementia in populations. In routine clinical care, dementia risk could be further reduced by optimized management of delirium, depressive disorders, traumatic brain injury and stroke. These are opportunities to minimize risk of progression to dementia during acute care and subsequent rehabilitation. Although interventions to protect against progress to dementia may be of small effect in each clinical situation, awareness of dementia risk and appropriate steps to reduce that risk should contribute to an overall reduction in the incidence of dementia., (© The Author 2014. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Brain morphology and cognitive ability change with age. Gray and white matter volumes decrease markedly by the 7th decade of life when cognitive decreases first become readily detectable. As a consequence, the shape complexity of the cortical mantle may also change. The purposes of this study are to examine changes over a five year period in brain structural complexity in late life, and to investigate cognitive correlates of any changes. Brain magnetic resonance images at 1.5 Tesla were acquired from the Aberdeen 1936 Birth Cohort at about ages 68 years (243 participants) and 73 years (148 participants returned). Measures of brain complexity were extracted using Fractal Dimension (FD) and calculated using the box-counting method. White matter complexity, brain volumes and cognitive performance were measured at both 68 and 73 years. Childhood ability was measured at age 11 using the Moray House Test. FD and brain volume decrease significantly from age 68 to 73 years. Using a multilevel linear modeling approach, we conclude that individual decreases in late life white matter complexity are not associated with differences in executive function but are linked to information processing speed, auditory-verbal learning, and reasoning in specific models-with adjustment for childhood mental ability. A significant association was found after adjustment for age, brain volume and childhood mental ability. Complexity of white matter is associated with higher fluid cognitive ability and, in a longitudinal study, predicts retention of cognitive ability within late life., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Previous functional gene group analyses implicated common single nucleotide polymorphisms (SNPs) in heterotrimeric G protein coding genes as being associated with differences in human intelligence. Here, we sought to replicate this finding using five independent cohorts of older adults including current IQ and childhood IQ, and using both gene- and SNP-based analytic strategies. No significant associations were found between variation in heterotrimeric G protein genes and intelligence in any cohort at either of the two time points. These results indicate that, whereas G protein systems are important in cognition, common genetic variation in these genes is unlikely to be a substantial influence on human intelligence differences.

Context: There have been many reports confirming the association between lower childhood socioeconomic circumstance and cardiovascular disease but evidence for links with cerebrovascular disease is contradictory. Hyperintensities on brain magnetic resonance imaging are associated with vascular risk factors, cognitive decline, dementia and death. However, the relationship between childhood socioeconomic circumstance and these lesions is unclear., Objective: To test the hypothesis that childhood socioeconomic circumstance is associated with late life hyperintensity burden and that neither adult socioeconomic circumstance nor change in socioeconomic circumstance during life influence this effect., Design: Cohort study., Setting: Community., Participants: 227 community dwelling members of the 1936 Aberdeen Birth Cohort aged 68 years, who were free from dementia., Main Outcome Measures: Relationship between early life socioeconomic circumstance (paternal occupation) and abundance of late life brain hyperintensities., Results: We find significant negative correlations between childhood socioeconomic circumstance and white matter hyperintensities (ρ = -0.18, P<0.01), and periventricular hyperintensities (ρ = -0.15, P<0.05), between educational attainment and white matter hyperintensities (ρ = -0.15, P<0.05) and periventricular hyperintensities (ρ = -0.17, P<0.05), and between childhood intelligence and periventricular hyperintensities (ρ = -0.14, P<0.05). The relationship is strongest for childhood socioeconomic circumstance and regional white matter hyperintensities, where there is a step change in increased burden from paternal occupation grades equivalent to a shift from "white collar" to "blue collar" paternal occupation. Significant correlations were also found between hypertension and hyperintensity burden in all brain regions (ρ = 0.15-0.24, P<0.05). In models that include hypertension, the magnitude of the effect of childhood socioeconomic circumstance is similar to and independent from that of hypertension., Conclusions: Childhood socioeconomic circumstance predicts the burden of brain white matter hyperintensities aged 68 years. The mechanism underlying this effect is unknown, but may act through fetal and/or early life programming of cerebrovascular disease. Future work to understand this vulnerability will inform strategies to reduce dementia and stroke.

Purpose: To distinguish between contributions to dementia made by homocysteine, folate, B12 and antioxidant micronutrients., Methods: This is a follow-up study of a sample reported in 2002. Homocysteine was measured at baseline in 201 individuals born in 1921 and without dementia at age 77 years and followed up to age 88 years. Baseline macro- and micronutrient status was estimated from BMI, the MONICA food frequency questionnaire, plasma folate, B12 and, in a subgroup (N = 173), plasma antioxidant micronutrients. Time to dementia onset during follow-up was compared between participants grouped by homocysteine concentration using Cox regression. Model 1 adjusted for age, sex, childhood IQ, education, socioeconomic deprivation, presence of heart disease, hypertension, plasma folate and B12. In model 2 plasma, antioxidants were added to these covariables., Results: During a mean follow-up of about 5 years, there were 39 incident dementia cases among 201 participants. In model 1, being in the highest homocysteine group (>14 μmol/L) was associated with a 234 % increased risk (HR 3.34, 95 % CI 1.16-9.57) of any dementia. After inclusion of plasma antioxidants in model 2, there were 32 incident dementia cases from a subsample (N = 173). Homocysteine >14 μmol was associated with a 272 % increased dementia risk (HR = 3.72, 95 % CI 1.06-13.08)., Conclusions: High homocysteine increases the risk of dementia. The association between tHcy and dementia is independent of plasma folate, B12 and antioxidant micronutrient status.

Differences in general cognitive ability (intelligence) account for approximately half of the variation in any large battery of cognitive tests and are predictive of important life events including health. Genome-wide analyses of common single-nucleotide polymorphisms indicate that they jointly tag between a quarter and a half of the variance in intelligence. However, no single polymorphism has been reliably associated with variation in intelligence. It remains possible that these many small effects might be aggregated in networks of functionally linked genes. Here, we tested a network of 1461 genes in the postsynaptic density and associated complexes for an enriched association with intelligence. These were ascertained in 3511 individuals (the Cognitive Ageing Genetics in England and Scotland (CAGES) consortium) phenotyped for general cognitive ability, fluid cognitive ability, crystallised cognitive ability, memory and speed of processing. By analysing the results of a genome wide association study (GWAS) using Gene Set Enrichment Analysis, a significant enrichment was found for fluid cognitive ability for the proteins found in the complexes of N-methyl-D-aspartate receptor complex; P=0.002. Replication was sought in two additional cohorts (N=670 and 2062). A meta-analytic P-value of 0.003 was found when these were combined with the CAGES consortium. The results suggest that genetic variation in the macromolecular machines formed by membrane-associated guanylate kinase (MAGUK) scaffold proteins and their interaction partners contributes to variation in intelligence.

Alzheimer's disease (AD) and non-pathological cognitive aging have phenotypic similarities which may be influenced by an overlapping set of genetic variants. Genome-wide complex trait analysis estimates that common genetic variants account for about 24% of the variation contributing to liability for AD. It is also estimated that 24% of the variance of non-pathological cognitive aging is accounted for by common single nucleotide polymorphisms. However, although the APOE locus is associated with both AD and cognitive aging, it is not known to what extent other common genetic variants, with smaller effect sizes that influence both, overlap. We test the hypothesis that polygenic risk for AD is associated with cognitive ability and cognitive change in about 3,000 non-demented older people (Cognitive Ageing Genetics England and Scotland-CAGES-consortium). We found no significant association of polygenic risk for AD with cognitive ability or cognitive change in CAGES, indicating that the genetic etiologies of AD and non-pathological cognitive decline differ.

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.

Background: The influence of white matter lesions on depressive symptoms in healthy ageing populations remains unclear. In this study, we examined the relationship between depressive symptoms and magnetic resonance imaging (MRI) detected cerebrovascular disease in a normal population living independently in the community, and measured the influence of location of brain abnormalities, fluid intelligence, living alone, and sex., Methods: Prospective cohort: 497 community dwelling individuals all born in 1936, who took part in the Scottish Mental Survey of 1947, were followed up in 2000 and at biannual intervals in a longitudinal study of health and cognitive aging. Two hundred forty-four volunteered for brain MRI in 2004-2006. Suitable data were available in 219/244, of whom 115 were men. Brain hyperintensities in lobar white matter, basal ganglia , periventricular, and infratentorial regions were measured using Scheltens' scale. Depressed mood was assessed using the Hospital Anxiety and Depression Scale (HADS) on three biannual intervals. Relationships between Scheltens' scores, HADS-D scores, fluid intelligence, living alone, and sex were assessed using general linear modeling., Results: The main predictor of depressive symptom scores was poorer fluid intelligence (partial η(2) =0.023-0.028, P < .05). Ischemic change in the brainstem (partial η(2) = 0.026, P ≤.05) and basal ganglia (partial η(2) =0.018, P ≤ .05) also predicted HADS-D scores. There was no relationship with sex or living alone., Conclusions: Hyperintensities in the brainstem and basal ganglia are associated with depressive symptoms. Higher fluid intelligence is associated with lower depressive symptoms in this normal, ageing population., (© 2012 Wiley Periodicals, Inc.)

Objective: We aimed to investigate three reports of a possible role of early parental death in late onset dementia. We tested a multivariate model of risk factors for late onset dementia that included established (female sex, a family history of dementia, APOE ε4) and putative influences (vascular risk factors, years of full-time education, parental ages at death, and childhood IQ) on dementia risk., Methods: We examined contributions of early life and late life risk factors for dementia by using childhood social and family data and blood samples obtained at interview at age about 78 years. In 1997-1999, we recruited 281 subjects without dementia from a 1932 Scottish IQ survey of children born in 1921 and followed them up to 2010 (at age 88). Binary logistic regression and Bayesian structural equation modelling were used to model dementia risk., Results: Risk of dementia was associated with increasing age from 77 to 88 years, female sex, death of either parent before age 11 and APOE ε4 genotype. Family history of dementia, childhood IQ, years of education and vascular risk factors did not contribute to the model., Conclusions: Our multivariate models of the possible causes of late onset dementia confirm previous associations of dementia with female sex and APOE ε4 genotype and supports earlier reports of a role for early parental death., (Copyright © 2012 John Wiley & Sons, Ltd.)

The current study used data from the Aberdeen Birth Cohort, 1936, to investigate the hypothesis that the positive effects of the personality trait Openness on cognitive ability are mediated by activity levels. Results of latent growth modeling analysis revealed that higher Openness predicted better reading ability, inductive reasoning, and memory performance across three testing occasions when participants were aged 64-68 years. Higher Openness predicted higher activity levels, and higher activity levels in turn predicted higher reading ability, but not higher performance on measures of inductive reasoning, memory, and speed of processing. Overall, Openness and activity engagement appear related to preserved higher cognitive ability in older adults, with Openness having a direct effect on marker tests of fluid ability and with the combined influence of Openness and activity being particularly important for marker tests of crystallized intelligence., (2013 APA, all rights reserved)

Fractal measures such as fractal dimension (FD) can quantify the structural complexity of the brain. These have been used in clinical neuroscience to investigate brain development, ageing and in studies of psychiatric and neurological disorders. Here, we examined associations between the FD of white matter and cognitive changes across the life course in the absence of detectable brain disease. The FD was calculated from segmented cerebral white matter MR images in 217 subjects aged about 68years, in whom archived intelligence scores from age 11years were available. Cognitive test scores of fluid and crystallised intelligence were obtained at the time of MR imaging. Significant differences were found (intracranial volume, brain volume, white matter volume and Raven's Progressive Matrices score) between men and women at age 68years and novel associations were found between FD and measures of cognitive change over the life course from age 11 to 68years. Those with greater FD were found to have greater than expected fluid abilities at age 68years than predicted by their childhood intelligence and less cognitive decline from age 11 to 68years. These results are consistent with other reports that FD measures of cortical structural complexity increase across the early life course during maturation of the cerebral cortex and add new data to support an association between FD and cognitive ageing., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: To investigate in older adults without dementia the relationships between socioeconomic status (SES) in childhood and magnetic resonance imaging (MRI)-derived brain volume measures typical of brain aging and Alzheimer's disease (AD)., Methods: Using a cross-sectional and longitudinal observation approach, we invited volunteers without dementia, all born in 1936, and who were participants in the 1947 Scottish Mental Survey, for MR brain imaging; 249 of 320 (77%) agreed. We measured whole brain and hippocampal volumes and recorded childhood SES history, the number of years of education undertaken, and adult SES history. Mental ability at age 11 years was recorded in 1947 and was also available., Results: Analysis shows a significant association between childhood SES and hippocampal volume after adjusting for mental ability at age 11 years, adult SES, gender, and education., Interpretation: A significant association between childhood SES and hippocampal volumes in late life is consistent with the established neurodevelopmental findings that early life conditions have an effect on structural brain development. This remains detectable more than 50 years later., (Copyright © 2012 American Neurological Association.)

The objectives of this study are to model the relative effects of positive (childhood intelligence) and negative (magnetic resonance imaging (MRI)-derived white matter hyperintensities (WMH)) predictors of late-life intelligence in two well-characterised normal cohorts aged 68 and 78 and to measure the influence of hypertension on WMH and lifelong cognitive change. The Scottish Mental Surveys of 1932 and 1947 tested the intelligence of almost all school children at age 11. One hundred and one participants born in 1921 and 233 participants born in 1936 had brain MRI, with measurement of WMH using Scheltens' scale, and tests of late-life fluid intelligence. Structural equation models of the effect of childhood intelligence and brain WMH on the general intelligence factor 'g' in late life in the two samples were constructed using AMOS 18. Similar models were constructed to test the effect of hypertension on WMH and lifelong cognitive change. Fluid intelligence scores were lower and WMH scores were higher in the older samples. Hypertensive participants in both samples had more WMH than normotensive participants. The positive influence of childhood intelligence on 'g' was greater in the younger sample. The negative effect of WMH on 'g' was linear and greater in the older sample due to greater WMH burden. The negative effect of hypertension on lifelong cognitive ageing was all mediated via MRI-derived brain WMH. The positive relationship between childhood and late-life intelligence decreases with age. The negative relationship between WMH and late-life intelligence is linear and increases with age.

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.

There are well-established differences in dementia incidence between communities and within communities over time. In part, these differences may be attributable to local improvements in dementia diagnosis and classification. Nevertheless, there are grounds for cautious optimism that there have been slight, but significant, recent reductions in dementia incidence. Possible causes include public health measures to reduce mortality attributable to stroke and heart disease, improved nutrition, and greater personal wealth. A life-course approach to dementia pathophysiology may help to elucidate the nature and timing of interventions that might delay dementia onset., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Understanding the determinants of healthy mental ageing is a priority for society today. So far, we know that intelligence differences show high stability from childhood to old age and there are estimates of the genetic contribution to intelligence at different ages. However, attempts to discover whether genetic causes contribute to differences in cognitive ageing have been relatively uninformative. Here we provide an estimate of the genetic and environmental contributions to stability and change in intelligence across most of the human lifetime. We used genome-wide single nucleotide polymorphism (SNP) data from 1,940 unrelated individuals whose intelligence was measured in childhood (age 11 years) and again in old age (age 65, 70 or 79 years). We use a statistical method that allows genetic (co)variance to be estimated from SNP data on unrelated individuals. We estimate that causal genetic variants in linkage disequilibrium with common SNPs account for 0.24 of the variation in cognitive ability change from childhood to old age. Using bivariate analysis, we estimate a genetic correlation between intelligence at age 11 years and in old age of 0.62. These estimates, derived from rarely available data on lifetime cognitive measures, warrant the search for genetic causes of cognitive stability and change.

Background: Poorer cognitive ability in youth is a risk factor for later mental health problems but it is largely unknown whether cognitive ability, in youth or in later life, is predictive of mental wellbeing. The purpose of this study was to investigate whether cognitive ability at age 11 years, cognitive ability in later life, or lifetime cognitive change are associated with mental wellbeing in older people., Methods: We used data on 8191 men and women aged 50 to 87 years from four cohorts in the HALCyon collaborative research programme into healthy ageing: the Aberdeen Birth Cohort 1936, the Lothian Birth Cohort 1921, the National Child Development Survey, and the MRC National Survey for Health and Development. We used linear regression to examine associations between cognitive ability at age 11, cognitive ability in later life, and lifetime change in cognitive ability and mean score on the Warwick Edinburgh Mental Wellbeing Scale and meta-analysis to obtain an overall estimate of the effect of each., Results: People whose cognitive ability at age 11 was a standard deviation above the mean scored 0.53 points higher on the mental wellbeing scale (95% confidence interval 0.36, 0.71). The equivalent value for cognitive ability in later life was 0.89 points (0.72, 1.07). A standard deviation improvement in cognitive ability in later life relative to childhood ability was associated with 0.66 points (0.39, 0.93) advantage in wellbeing score. These effect sizes equate to around 0.1 of a standard deviation in mental wellbeing score. Adjustment for potential confounding and mediating variables, primarily the personality trait neuroticism, substantially attenuated these associations., Conclusion: Associations between cognitive ability in childhood or lifetime cognitive change and mental wellbeing in older people are slight and may be confounded by personality trait differences.

The cognitive reserve hypothesis explains the disparity between clinical and pathological phenotypes and why, in two individuals with the same extent of neuropathology, one may be demented while the other remains cognitively intact. We examined the balance between brain magnetic resonance imaging measures of the two most common pathologies associated with brain ageing, cerebrovascular disease and Alzheimer's disease, and parameters of cerebral reserve in well-characterized participants born in 1936, for whom childhood intelligence is known. Brain magnetic resonance imaging was carried out at 1.5T using fluid attenuation inversion recovery and T(1)-weighted volumetric sequences in 249 participants. Cerebrovascular disease was quantified by measuring brain white matter hyperintensities on fluid attenuation inversion recovery images using Scheltens' scale and Alzheimer's disease was measured from volumetric data using FreeSurfer to extract whole brain volume and hippocampal volumes in turn. The effect of these measures of brain burden on life-long cognitive ageing from the age of 11 to 68 years was compared with the effect of educational attainment and occupational grade using structural equation modelling. Complete brain burden and reserve data were available in 224 participants. We found that educational attainment, but not occupation, has a measurable and positive effect, with a standardized regression weight of +0.23, on late life cognitive ability in people without cognitive impairment aged 68 years, allowing for the influence of childhood intelligence and the two most common subclinical brain pathological burdens in the ageing brain. In addition, we demonstrate that the magnitude of the contribution of education is greater than the negative impact of either neuropathological burden alone, with standardized regression weights of -0.14 for white matter hyperintensities and -0.20 for hippocampal atrophy. This study illustrates how education counteracts the deleterious effects of cerebrovascular disease and Alzheimer's disease and highlights the importance of quantifying cognitive reserve in dementia research.