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1.  The Attitudes to Ageing Questionnaire: Mokken Scaling Analysis 
PLoS ONE  2014;9(6):e99100.
Background
Hierarchical scales are useful in understanding the structure of underlying latent traits in many questionnaires. The Attitudes to Ageing Questionnaire (AAQ) explored the attitudes to ageing of older people themselves, and originally described three distinct subscales: (1) Psychosocial Loss (2) Physical Change and (3) Psychological Growth. This study aimed to use Mokken analysis, a method of Item Response Theory, to test for hierarchies within the AAQ and to explore how these relate to underlying latent traits.
Methods
Participants in a longitudinal cohort study, the Lothian Birth Cohort 1936, completed a cross-sectional postal survey. Data from 802 participants were analysed using Mokken Scaling analysis. These results were compared with factor analysis using exploratory structural equation modelling.
Results
Participants were 51.6% male, mean age 74.0 years (SD 0.28). Three scales were identified from 18 of the 24 items: two weak Mokken scales and one moderate Mokken scale. (1) ‘Vitality’ contained a combination of items from all three previously determined factors of the AAQ, with a hierarchy from physical to psychosocial; (2) ‘Legacy’ contained items exclusively from the Psychological Growth scale, with a hierarchy from individual contributions to passing things on; (3) ‘Exclusion’ contained items from the Psychosocial Loss scale, with a hierarchy from general to specific instances. All of the scales were reliable and statistically significant with ‘Legacy’ showing invariant item ordering. The scales correlate as expected with personality, anxiety and depression. Exploratory SEM mostly confirmed the original factor structure.
Conclusions
The concurrent use of factor analysis and Mokken scaling provides additional information about the AAQ. The previously-described factor structure is mostly confirmed. Mokken scaling identifies a new factor relating to vitality, and a hierarchy of responses within three separate scales, referring to vitality, legacy and exclusion. This shows what older people themselves consider important regarding their own ageing.
doi:10.1371/journal.pone.0099100
PMCID: PMC4043998  PMID: 24892302
2.  Alzheimer's disease susceptibility genes APOE and TOMM40, and brain white matter integrity in the Lothian Birth Cohort 1936☆ 
Neurobiology of Aging  2014;35(6):1513.e25-1513.e33.
Apolipoprotein E (APOE) ε genotype has previously been significantly associated with cognitive, brain imaging, and Alzheimer's disease-related phenotypes (e.g., age of onset). In the TOMM40 gene, the rs10524523 (“523”) variable length poly-T repeat polymorphism has more recently been associated with similar ph/enotypes, although the allelic directions of these associations have varied between initial reports. Using diffusion magnetic resonance imaging tractography, the present study aimed to investigate whether there are independent effects of apolipoprotein E (APOE) and TOMM40 genotypes on human brain white matter integrity in a community-dwelling sample of older adults, the Lothian Birth Cohort 1936 (mean age = 72.70 years, standard deviation = 0.74, N approximately = 640–650; for most analyses). Some nominally significant effects were observed (i.e., covariate-adjusted differences between genotype groups at p < 0.05). For APOE, deleterious effects of ε4 “risk” allele presence (vs. absence) were found in the right ventral cingulum and left inferior longitudinal fasciculus. To test for biologically independent effects of the TOMM40 523 repeat, participants were stratified into APOE genotype subgroups, so that any significant effects could not be attributed to APOE variation. In participants with the APOE ε3/ε4 genotype, effects of TOMM40 523 status were found in the left uncinate fasciculus, left rostral cingulum, left ventral cingulum, and a general factor of white matter integrity. In all 4 of these tractography measures, carriers of the TOMM40 523 “short” allele showed lower white matter integrity when compared with carriers of the “long” and “very-long” alleles. Most of these effects survived correction for childhood intelligence test scores and vascular disease history, though only the effect of TOMM40 523 on the left ventral cingulum integrity survived correction for false discovery rate. The effects of APOE in this older population are more specific and restricted compared with those reported in previous studies, and the effects of TOMM40 on white matter integrity appear to be novel, although replication is required in large independent samples.
doi:10.1016/j.neurobiolaging.2014.01.006
PMCID: PMC3969262  PMID: 24508314
White matter; Cognitive ageing; Diffusion MRI; Tractography; APOE; TOMM40; Alzheimer's disease
3.  Modifiable cardiovascular disease risk factors as predictors of dementia death: pooling of ten general population-based cohort studies 
Background
With drug treatment for dementia being of limited effectiveness, the role of primary prevention, in particular the predictive value of modifiable cardiovascular disease risk factors, may warrant exploration. The evidence base is, however, characterised by discordant findings and is modest in size. Accordingly, we examined the association of modifiable cardiovascular disease risk factors with dementia death.
Design and methods
We pooled raw data from 10 UK general population-based prospective cohort studies within the context of an individual participant meta-analysis.
Results
A total of 103,764 men and women were followed up for a mean of 8 years giving rise to 443 dementia-related deaths and 2612 cardiovascular disease deaths. Cardiovascular disease mortality was, as anticipated, associated with the full range of risk factors under study, including raised blood pressure, smoking, diabetes, physical inactivity. By contrast, dementia death was related to very few of the cardiovascular disease risk factors: of those classified as modifiable, only smoking was associated with a raised risk and higher levels of non-HDL with a lower risk.
Conclusions
In the present individual participant meta-analysis, there was limited evidence that cardiovascular disease risk factors were related to dementia death.
doi:10.1186/1477-5751-13-8
PMCID: PMC4036694  PMID: 24886432
4.  Coordinated Analysis of Age, Sex, and Education Effects on Change in MMSE Scores 
Objectives.
We describe and compare the expected performance trajectories of older adults on the Mini-Mental Status Examination (MMSE) across six independent studies from four countries in the context of a collaborative network of longitudinal studies of aging. A coordinated analysis approach is used to compare patterns of change conditional on sample composition differences related to age, sex, and education. Such coordination accelerates evaluation of particular hypotheses. In particular, we focus on the effect of educational attainment on cognitive decline.
Method.
Regular and Tobit mixed models were fit to MMSE scores from each study separately. The effects of age, sex, and education were examined based on more than one centering point.
Results.
Findings were relatively consistent across studies. On average, MMSE scores were lower for older individuals and declined over time. Education predicted MMSE score, but, with two exceptions, was not associated with decline in MMSE over time.
Conclusion.
A straightforward association between educational attainment and rate of cognitive decline was not supported. Thoughtful consideration is needed when synthesizing evidence across studies, as methodologies adopted and sample characteristics, such as educational attainment, invariably differ.
doi:10.1093/geronb/gbs077
PMCID: PMC3693608  PMID: 23033357
Cognitive; Coordinated Analysis; Education; Longitudinal; Mental Status Exam; Meta-analysis; Mixed Model
5.  Patterns and associates of cognitive function, psychosocial wellbeing and health in the Lothian Birth Cohort 1936 
BMC Geriatrics  2014;14:53.
Background
Cognitive function, psychosocial wellbeing and health are important domains of function. Consistencies and inconsistencies in patterns of wellbeing across these domains may be informative about wellbeing in old age and the ways it is manifested amongst individuals. In this study we investigated whether there were groups of individuals with different profiles of scores across these domains. We also aimed to identify characteristics of any evident groups by comparing them on variables that were not used in identifying the groups.
Methods
The sample was the Lothian Birth Cohort 1936, which included 1091 participants born in 1936. They are a community-dwelling, narrow-age-range sample of 70-year-olds. Most had taken part in the Scottish Mental Survey 1947 at an average age of 11, making available a measure of childhood intelligence. We used latent class analysis (LCA) to explore possible profiles using 9 variables indicating cognitive functioning, psychosocial wellbeing and health status. Demographic, personality, and lifestyle variables – none of which were used in the LCA – were used to characterize the resulting profile groups.
Results
We accepted a 3-group solution, which we labeled High Wellbeing (65.3%), Low Cognition (20.3%), and Low Bio-Psychosocial (14.5%). Notably, the High Wellbeing group had significantly higher childhood IQ, lower Neuroticism scores, and a lower percentage of current smokers than the other 2 groups.
Conclusion
The majority of individuals were functioning generally well; however, there was evidence of the presence of groups with different profiles, which may be explained in part in terms of cognitive ability differences. Results suggested that higher life-long intelligence, personality traits associated with less mental distress, and basic health practices such as avoiding smoking are important associates of wellbeing in old age.
doi:10.1186/1471-2318-14-53
PMCID: PMC3999738  PMID: 24754844
6.  11ß-Hydroxysteroid dehydrogenase type 1, brain atrophy and cognitive decline 
Neurobiology of aging  2010;33(1):207.e1-207.e8.
Excess cortisol levels are linked with brain atrophy and cognitive decline in older people. 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) potently amplifies intracellular glucocorticoid action by converting inert cortisone to active cortisol, but any causal importance in brain ageing is unexplored. We tested the hypotheses that higher systemic 11ß-HSD1 activity predicts brain atrophy and cognitive decline in older men.
In a longitudinal study of 41 men (65-70y at baseline) we measured baseline systemic 11ß-HSD1 activity, the urinary 5alpha- and 5beta-tetrahydrocortisol to tetrahydrocortisone ratio (THFs/THE), and assessed change in brain atrophy, white matter lesions and cognitive function over six years.
Baseline THFs/THE correlated negatively with baseline hippocampal volumes (left: r=-0.37; right: r=-0.34; p<0.05) and positively with ventricular volumes (r=0.43, p=0.006) and periventricular white matter lesions (rho=0.31, p=0.047). Importantly, baseline THFs/THE but not cortisol predicted increase in ventricular volumes (r=0.33, p=0.037) and decline in processing speed (r=-0.55, p=0.0002) over six years.
The predictive link between systemic 11β-HSD1 activity and progressive brain atrophy and cognitive decline suggests 11β-HSD1 inhibition as a plausible therapy for brain ageing.
doi:10.1016/j.neurobiolaging.2010.09.010
PMCID: PMC3977035  PMID: 20961667
Cognition; glucocorticoids; cortisol; cerebral atrophy; white matter lesions; dementia; aging
7.  The effect of funding sources on donepezil randomised controlled trial outcome: a meta-analysis 
BMJ Open  2014;4(4):e004083.
Objective
To investigate whether there is a difference in the treatment effect of donepezil on cognition in Alzheimer disease between industry-funded and independent randomised controlled trials.
Design
Fixed effects meta-analysis of standardised effects of donepezil on cognition as measured by the Mini Mental State Examination and the Alzheimer’s Disease Assessment Scale-cognitive subscale.
Data sources
Studies included in the meta-analyses reported in the National Institute for Health and Care Excellence (NICE) technical appraisal 217 updated with new studies through a PubMed search.
Eligibility criteria
Inclusion criteria were double-blind, placebo-controlled trials of any length comparing patients diagnosed with probable Alzheimer disease (according to the NINCDS-ADRDA/DSM-III/IV criteria) taking any dosage of donepezil. Studies of combination therapies (eg, donepezil and memantine) were excluded, as were studies that enrolled patients with a diagnosis of Alzheimer disease associated with other disorders (eg, Parkinson's disease and Down's syndrome).
Results
Our search strategy identified 14 relevant trials (4 independent) with suitable data. Trials sponsored by pharmaceutical companies reported a larger effect of donepezil on standardised cognitive tests than trials published by independent research groups (standardised mean difference (SMD)=0.46, 95% CI 0.37 to 0.55 vs SMD=0.33, 95% CI 0.18 to 0.48, respectively). This difference remained when only data representing change up to 12 weeks from baseline were analysed (industry SMD=0.44, 95% CI 0.34 to 0.53 vs independent SMD=0.35, 95% CI 0.18 to 0.52). Analysis revealed that the effect of funding as a moderator variable of study heterogeneity was not statistically significant at either time point.
Conclusions
The effect size of donepezil on cognition is larger in industry-funded than independent trials and this is not explained by the longer duration of industry-funded trials. The lack of a statistically significant moderator effect may indicate that the differences are due to chance, but may also result from lack of power.
doi:10.1136/bmjopen-2013-004083
PMCID: PMC3987717  PMID: 24710130
CLINICAL PHARMACOLOGY; STATISTICS & RESEARCH METHODS
8.  Quantitative multi-modal MRI of the Hippocampus and cognitive ability in community-dwelling older subjects 
Hippocampal structural integrity is commonly quantified using volumetric measurements derived from brain magnetic resonance imaging (MRI). Previously reported associations with cognitive decline have not been consistent. We investigate hippocampal integrity using quantitative MRI techniques and its association with cognitive abilities in older age.
Participants from the Lothian Birth Cohort 1936 underwent brain MRI at mean age 73 years. Longitudinal relaxation time (T1), magnetization transfer ratio (MTR), fractional anisotropy (FA) and mean diffusivity (MD) were measured in the hippocampus. General factors of fluid-type intelligence (g), cognitive processing speed (speed) and memory were obtained at age 73 years, as well as childhood IQ test results at age 11 years. Amongst 565 older adults, multivariate linear regression showed that, after correcting for ICV, gender and age 11 IQ, larger left hippocampal volume was significantly associated with better memory ability (β = .11, p = .003), but not with speed or g. Using quantitative MRI and after correcting for multiple testing, higher T1 and MD were significantly associated with lower scores of g (β range = −.11 to −.14, p < .001), speed (β range = −.15 to −.20, p < .001) and memory (β range = −.10 to −.12, p < .001). Higher MTR and FA in the hippocampus were also significantly associated with higher scores of g (β range = .17 to .18, p < .0001) and speed (β range = .10 to .15, p < .0001), but not memory.
Quantitative multi-modal MRI assessments were more sensitive at detecting cognition-hippocampal integrity associations than volumetric measurements, resulting in stronger associations between MRI biomarkers and age-related cognition changes.
doi:10.1016/j.cortex.2013.12.012
PMCID: PMC3979658  PMID: 24561387
Longitudinal relaxation times; Diffusion tensor imaging; Hippocampus; Cognition; Ageing; Magnetic resonance imaging
9.  Alcohol consumption and lifetime change in cognitive ability: a gene × environment interaction study 
Age  2014;36(3):9638.
Studies of the effect of alcohol consumption on cognitive ability are often confounded. One approach to avoid confounding is the Mendelian randomization design. Here, we used such a design to test the hypothesis that a genetic score for alcohol processing capacity moderates the association between alcohol consumption and lifetime change in cognitive ability. Members of the Lothian Birth Cohort 1936 completed the same test of intelligence at age 11 and 70 years. They were assessed for recent alcohol consumption in later life and genotyped for a set of four single-nucleotide polymorphisms in three alcohol dehydrogenase genes. These variants were unrelated to late-life cognition or to socioeconomic status. We found a significant gene × alcohol consumption interaction on lifetime cognitive change (p = 0.007). Individuals with higher genetic ability to process alcohol showed relative improvements in cognitive ability with more consumption, whereas those with low processing capacity showed a negative relationship between cognitive change and alcohol consumption with more consumption. The effect of alcohol consumption on cognitive change may thus depend on genetic differences in the ability to metabolize alcohol.
doi:10.1007/s11357-014-9638-z
PMCID: PMC4082597  PMID: 24652602
Alcohol; Cognitive ageing; Longitudinal modelling; Genetics; Alcohol dehydrogenase; Mendelian randomization
10.  Lower Ankle-Brachial Index Is Related to Worse Cognitive Performance in Old Age 
Neuropsychology  2013;28(2):281-289.
Objective: We aimed to study the associations between peripheral artery disease (PAD) and ankle-brachial index (ABI) and performance in a range of cognitive domains in nondemented elderly persons. Methods: Data were collected within the Lothian Birth Cohort 1921 and 1936 studies. These are two narrow-age cohorts at age 87 (n = 170) and 73 (n = 748) years. ABI was analyzed as a dichotomous (PAD vs. no PAD) and a continuous measure. PAD was defined as having an ABI less than 0.90. Measures of nonverbal reasoning, verbal declarative memory, verbal fluency, working memory, and processing speed were administered. Both samples were screened for dementia. Results: We observed no significant differences in cognitive performance between persons with or without PAD. However, higher ABI was associated with better general cognition (β = .23, p = .02, R2 change = .05) and processing speed (β = .29, p < .01, R2 change = .08) in the older cohort and better processing speed (β = .12, p < .01, R2 change = .01) in the younger cohort. This was after controlling for age, sex, and childhood mental ability and excluding persons with abnormally high ABI (>1.40) and a history of cardiovascular or cerebrovascular disease. Conclusion: Lower ABI is associated with worse cognitive performance in old age, especially in the oldest old (>85 years), possibly because of long-term exposure to atherosclerotic disease. Interventions targeting PAD in persons free of manifest cardiovascular and cerebrovascular disease may reduce the incidence of cognitive impairment and dementia.
doi:10.1037/neu0000028
PMCID: PMC3942013  PMID: 24295206
cognition; ankle-brachial index; peripheral artery disease; atherosclerosis; aging
11.  Item response theory analysis of cognitive tests in people with dementia: a systematic review 
BMC Psychiatry  2014;14:47.
Background
Performance on psychometric tests is key to diagnosis and monitoring treatment of dementia. Results are often reported as a total score, but there is additional information in individual items of tests which vary in their difficulty and discriminatory value. Item difficulty refers to an ability level at which the probability of responding correctly is 50%. Discrimination is an index of how well an item can differentiate between patients of varying levels of severity. Item response theory (IRT) analysis can use this information to examine and refine measures of cognitive functioning. This systematic review aimed to identify all published literature which had applied IRT to instruments assessing global cognitive function in people with dementia.
Methods
A systematic review was carried out across Medline, Embase, PsychInfo and CINHAL articles. Search terms relating to IRT and dementia were combined to find all IRT analyses of global functioning scales of dementia.
Results
Of 384 articles identified four studies met inclusion criteria including a total of 2,920 people with dementia from six centers in two countries. These studies used three cognitive tests (MMSE, ADAS-Cog, BIMCT) and three IRT methods (Item Characteristic Curve analysis, Samejima’s graded response model, the 2-Parameter Model). Memory items were most difficult. Naming the date in the MMSE and memory items, specifically word recall, of the ADAS-cog were most discriminatory.
Conclusions
Four published studies were identified which used IRT on global cognitive tests in people with dementia. This technique increased the interpretative power of the cognitive scales, and could be used to provide clinicians with key items from a larger test battery which would have high predictive value. There is need for further studies using IRT in a wider range of tests involving people with dementia of different etiology and severity.
doi:10.1186/1471-244X-14-47
PMCID: PMC3931670  PMID: 24552237
Item response theory; Dementia; Psychometrics; Cognition; Alzheimer disease; MMSE; Systematic review
12.  Socioeconomic status as a risk factor for dementia death: individual participant meta-analysis of 86 508 men and women from the UK* 
Background
Life-course socioeconomic factors may have a role in dementia aetiology but there is a current paucity of studies. Meta-analyses of individual participant data would considerably strengthen this evidence base.
Aims
To examine the association between socioeconomic status in early life and adulthood with later dementia death.
Method
Individual participant meta-analysis of 11 prospective cohort studies (1994-2004, n = 86 508).
Results
Leaving full-time education at an earlier age was associated with an increased risk of dementia death in women (fully adjusted hazard ratio (HR) for age ⩽14 v. age ⩾16: HR = 1.76, 95% CI 1.23-2.53) but not men. Occupational social class was not statistically significantly associated with dementia death in men or women.
Conclusions
Lower educational attainment in women was associated with an increased risk of dementia-related death independently of common risk behaviours and comorbidities.
doi:10.1192/bjp.bp.112.119479
PMCID: PMC3696876  PMID: 23818534
13.  Complex Variation in Measures of General Intelligence and Cognitive Change 
PLoS ONE  2013;8(12):e81189.
Combining information from multiple SNPs may capture a greater amount of genetic variation than from the sum of individual SNP effects and help identifying missing heritability. Regions may capture variation from multiple common variants of small effect, multiple rare variants or a combination of both. We describe regional heritability mapping of human cognition. Measures of crystallised (gc) and fluid intelligence (gf) in late adulthood (64–79 years) were available for 1806 individuals genotyped for 549,692 autosomal single nucleotide polymorphisms (SNPs). The same individuals were tested at age 11, enabling us the rare opportunity to measure cognitive change across most of their lifespan. 547,750 SNPs ranked by position are divided into 10, 908 overlapping regions of 101 SNPs to estimate the genetic variance each region explains, an approach that resembles classical linkage methods. We also estimate the genetic variation explained by individual autosomes and by SNPs within genes. Empirical significance thresholds are estimated separately for each trait from whole genome scans of 500 permutated data sets. The 5% significance threshold for the likelihood ratio test of a single region ranged from 17–17.5 for the three traits. This is the equivalent to nominal significance under the expectation of a chi-squared distribution (between 1df and 0) of P<1.44×10−5. These thresholds indicate that the distribution of the likelihood ratio test from this type of variance component analysis should be estimated empirically. Furthermore, we show that estimates of variation explained by these regions can be grossly overestimated. After applying permutation thresholds, a region for gf on chromosome 5 spanning the PRRC1 gene is significant at a genome-wide 10% empirical threshold. Analysis of gene methylation on the temporal cortex provides support for the association of PRRC1 and fluid intelligence (P = 0.004), and provides a prime candidate gene for high throughput sequencing of these uniquely informative cohorts.
doi:10.1371/journal.pone.0081189
PMCID: PMC3865348  PMID: 24349040
14.  Brain white matter damage in aging and cognitive ability in youth and older age☆ 
Neurobiology of Aging  2013;34(12):2740-2747.
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.
doi:10.1016/j.neurobiolaging.2013.05.032
PMCID: PMC3898072  PMID: 23850341
Cerebrovascular disease/stroke; Cognition; Cognitive aging; MRI; White matter hyperintensities; Dementia
15.  Associations between Level and Change in Physical Function and Brain Volumes 
PLoS ONE  2013;8(11):e80386.
Background
Higher levels of fitness or physical function are positively associated with cognitive outcomes but the potential underlying mechanisms via brain structure are still to be elucidated in detail. We examined associations between brain structure and physical function (contemporaneous and change over the previous three years) in community-dwelling older adults.
Methodology/Principal Findings
Participants from the Lothian Birth Cohort 1936 (N=694) underwent brain MRI at age 73 years to assess intracranial volume, and the volumes of total brain tissue, ventricles, grey matter, normal-appearing white matter, and white matter lesions. At ages 70 and 73, physical function was assessed by 6-meter walk, grip strength, and forced expiratory volume. A summary ‘physical function factor’ was derived from the individual measures using principal components analysis. Performance on each individual physical function measure declined across the three year interval (p<0.001). Higher level of physical function at ages 70 and 73 was associated with larger total brain tissue and white matter volumes, and smaller ventricular and white matter lesion volumes (standardized β ranged in magnitude from 0.07 to 0.17, p<0.001 to 0.034). Decline in physical function from age 70 to 73 was associated with smaller white matter volume (0.08, p<0.01, though not after correction for multiple testing), but not with any other brain volumetric measurements.
Conclusions/Significance
Physical function was related to brain volumes in community-dwelling older adults: declining physical function was associated with less white matter tissue. Further study is required to explore the detailed mechanisms through which physical function might influence brain structure, and vice versa.
doi:10.1371/journal.pone.0080386
PMCID: PMC3827194  PMID: 24265818
16.  Geographical variation in dementia: systematic review with meta-analysis 
Background Geographical variation in dementia prevalence and incidence may indicate important socio-environmental contributions to dementia aetiology. However, previous comparisons have been hampered by combining studies with different methodologies. This review systematically collates and synthesizes studies examining geographical variation in the prevalence and incidence of dementia based on comparisons of studies using identical methodologies.
Methods Papers were identified by a comprehensive electronic search of relevant databases, scrutinising the reference sections of identified publications, contacting experts in the field and re-examining papers already known to us. Identified articles were independently reviewed against inclusion/exclusion criteria and considered according to geographical scale. Rural/urban comparisons were meta-analysed.
Results Twelve thousand five hundred and eighty records were reviewed and 51 articles were included. Dementia prevalence and incidence varies at a number of scales from the national down to small areas, including some evidence of an effect of rural living [prevalence odds ratio (OR) = 1.11, 90% confidence interval (CI) 0.79–1.57; incidence OR = 1.20, 90% CI 0.84–1.71]. However, this association of rurality was stronger for Alzheimer disease, particularly when early life rural living was captured (prevalence OR = 2.22, 90% CI 1.19–4.16; incidence OR = 1.64, 90% CI 1.08–2.50).
Conclusions There is evidence of geographical variation in rates of dementia in affluent countries at a variety of geographical scales. Rural living is associated with an increased risk of Alzheimer disease, and there is a suggestion that early life rural living further increases this risk. However, the fact that few studies have been conducted in resource-poor countries limits conclusions.
doi:10.1093/ije/dys103
PMCID: PMC3429875  PMID: 22798662
Dementia; Alzheimer disease; epidemiology; geography; disease clustering
17.  Retinal nerve fiber layer thickness and cognitive ability in older people: the Lothian Birth Cohort 1936 study 
BMC Ophthalmology  2013;13:28.
Background
This study aims to examine the relationship between the retinal nerve fiber layer (RNFL) thickness as measured by optical coherence tomography (OCT) and lifetime cognitive change in healthy older people.
Methods
In a narrow-age sample population from the Lothian Birth Cohort 1936 who were all aged approximately 72 years when tested, participants underwent RNFL measurements using OCT. General linear modeling was used to calculate the effect of RNFL thickness on three domains; general cognitive ability (g-factor), general processing speed (g-speed) and general memory ability (g-memory) using age at time of assessment and gender as co-variates.
Results
Of 105 participants, 96 completed OCT scans that were of suitable quality for assessment were analyzed. Using age and gender as covariates, we found only one significant association, between the inferior area RNFL thickness and g-speed (p = 0.049, η2 = 0.045). Interestingly, when we included age 11 IQ as a covariate in addition to age and gender, there were several statistically significant associations (p = 0.029 to 0.048, η2 = 0.00 to 0.059) in a negative direction; decreasing scores on measures of g-factor and g-speed were associated with increasing RNFL thickness (r = −0.229 to −0.243, p < 0.05). No significant associations were found between RNFL thickness and g-memory ability. When we considered the number of years of education as a covariate, we found no significant associations between the RNFL thickness and cognitive scores.
Conclusions
In a community dwelling cohort of healthy older people, increased RNFL thickness appeared to be associated with lower general processing speed and lower general cognitive ability when age 11 IQ scores were included as a covariate.
doi:10.1186/1471-2415-13-28
PMCID: PMC3706226  PMID: 23822668
Cognitive; Elderly; Principal components analysis; Optical coherence tomography; Retinal nerve fiber layer
18.  Physical capability and subsequent positive mental wellbeing in older people: findings from five HALCyon cohorts 
Age  2013;36(1):445-456.
Objective measures of physical capability are being used in a growing number of studies as biomarkers of healthy ageing. However, very little research has been done to assess the impact of physical capability on subsequent positive mental wellbeing, the maintenance of which is widely considered to be an essential component of healthy ageing. We aimed to test the associations of grip strength and walking, timed get up and go and chair rise speeds (assessed at ages 53 to 82 years) with positive mental wellbeing assessed using the Warwick–Edinburgh Mental Wellbeing Scale (WEMWBS) 5 to 10 years later. Data were drawn from five British cohorts participating in the Healthy Ageing across the Life Course research collaboration. Data from each study were analysed separately and then combined using random-effects meta-analyses. Higher levels of physical capability were consistently associated with higher subsequent levels of wellbeing; for example, a 1SD increase in grip strength was associated with an age and sex-adjusted mean difference in WEMWBS score of 0.81 (0.25, 1.37), equivalent to 10 % of a standard deviation (three studies, N = 3,096). When adjusted for body size, health status, living alone, socioeconomic position and neuroticism the associations remained albeit attenuated. The finding of these consistent modest associations across five studies, spanning early and later old age, highlights the importance of maintaining physical capability in later life and provides additional justification for using objective measures of physical capability as markers of healthy ageing.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-013-9553-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-013-9553-8
PMCID: PMC3818137  PMID: 23818103
Physical capability; Positive mental wellbeing; Grip strength; Walking speed; Chair rise time
19.  Age-related Changes in Memory and Fluid Reasoning in a Sample of Healthy Old People 
Participants in the Healthy Old People in Edinburgh (HOPE) study (N = 398) were assessed on Raven’s Progressive Matrices and Logical Memory on up to three occasions. Covariates included education, social class, disease and medication status, blood pressure and study outcome. Raven’s score declined linearly with age, whereas decline in Logical Memory was accelerating. There was significant variation in individuals’ rates of decline for Ravens but not Logical Memory. Slope–intercept covariances were not significant. Those who later developed dementia already exhibited lower scores, more so for Logical Memory than Raven’s. Death and study attrition were related to performance, again greater for Logical Memory. Conclusions: The HOPE approach of progressive screening is a feasible and practical method for studying healthy cognitive ageing. As predicted for an initially healthy sample, rates of decline were relatively homogeneous. The hypothesis of differential decline was not supported, nor was a strict interpretation of the hypothesis that cognitive ageing is entirely pathology driven.
doi:10.1080/13825580903009071
PMCID: PMC3623685  PMID: 19572219
Cognitive ageing; Ravens matrices; Logical memory; Physical health
20.  Brain lesions, hypertension and cognitive ageing in the 1921 and 1936 Aberdeen birth cohorts 
Age  2011;34(2):451-459.
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.
doi:10.1007/s11357-011-9233-5
PMCID: PMC3312630  PMID: 21424787
Ageing; White matter hyperintensity; Cohort study; Fluid intelligence; Cognitive decline; MRI
21.  Vascular risk factors, large-artery atheroma, and brain white matter hyperintensities 
Neurology  2014;82(15):1331-1338.
Objective:
To determine the magnitude of potentially causal relationships among vascular risk factors (VRFs), large-artery atheromatous disease (LAD), and cerebral white matter hyperintensities (WMH) in 2 prospective cohorts.
Methods:
We assessed VRFs (history and measured variables), LAD (in carotid, coronary, and leg arteries), and WMH (on structural MRI, visual scores and volume) in: (a) community-dwelling older subjects of the Lothian Birth Cohort 1936, and (b) patients with recent nondisabling stroke. We analyzed correlations, developed structural equation models, and performed mediation analysis to test interrelationships among VRFs, LAD, and WMH.
Results:
In subjects of the Lothian Birth Cohort 1936 (n = 881, mean age 72.5 years [SD ±0.7 years], 49% with hypertension, 33% with moderate/severe WMH), VRFs explained 70% of the LAD variance but only 1.4% to 2% of WMH variance, of which hypertension explained the most. In stroke patients (n = 257, mean age 74 years [SD ±11.6 years], 61% hypertensive, 43% moderate/severe WMH), VRFs explained only 0.1% of WMH variance. There was no direct association between LAD and WMH in either sample. The results were the same for all WMH measures used.
Conclusions:
The small effect of VRFs and LAD on WMH suggests that WMH have a large “nonvascular,” nonatheromatous etiology. VRF modification, although important, may be limited in preventing WMH and their stroke and dementia consequences. Investigation of, and interventions against, other suspected small-vessel disease mechanisms should be addressed.
doi:10.1212/WNL.0000000000000312
PMCID: PMC4001185  PMID: 24623838
22.  Genetic Variants Influencing Biomarkers of Nutrition Are Not Associated with Cognitive Capability in Middle-Aged and Older Adults123 
The Journal of Nutrition  2013;143(5):606-612.
Several investigations have observed positive associations between good nutritional status, as indicated by micronutrients, and cognitive measures; however, these associations may not be causal. Genetic polymorphisms that affect nutritional biomarkers may be useful for providing evidence for associations between micronutrients and cognitive measures. As part of the Healthy Ageing across the Life Course (HALCyon) program, men and women aged between 44 and 90 y from 6 UK cohorts were genotyped for polymorphisms associated with circulating concentrations of iron [rs4820268 transmembrane protease, serine 6 (TMPRSS6) and rs1800562 hemochromatosis (HFE)], vitamin B-12 [(rs492602 fucosyltransferase 2 (FUT2)], vitamin D ([rs2282679 group-specific component (GC)] and β-carotene ([rs6564851 beta-carotene 15,15'-monooxygenase 1 (BCMO1)]. Meta-analysis was used to pool within-study effects of the associations between these polymorphisms and the following measures of cognitive capability: word recall, phonemic fluency, semantic fluency, and search speed. Among the several statistical tests conducted, we found little evidence for associations. We found the minor allele of rs1800562 was associated with poorer word recall scores [pooled β on Z-score for carriers vs. noncarriers: −0.05 (95% CI: −0.09, −0.004); P = 0.03, n = 14,105] and poorer word recall scores for the vitamin D–raising allele of rs2282679 [pooled β per T allele: −0.03 (95% CI: −0.05, −0.003); P = 0.03, n = 16,527]. However, there was no evidence for other associations. Our findings provide little evidence to support associations between these genotypes and cognitive capability in older adults. Further investigations are required to elucidate whether the previous positive associations from observational studies between circulating measures of these micronutrients and cognitive performance are due to confounding and reverse causality.
doi:10.3945/jn.112.171520
PMCID: PMC3738233  PMID: 23468552
23.  Genetic markers of bone and joint health and physical capability in older adults: the HALCyon programme 
Bone  2013;52(1):278-285.
Background
Good bone and joint health is essential for the physical tasks of daily living and poorer indicators of physical capability in older adults have been associated with increased mortality rates. Genetic variants of indicators of bone and joint health may be associated with measures of physical capability.
Methods
As part of the Healthy Ageing across the Life Course (HALCyon) programme, men and women aged between 52 and 90 + years from six UK cohorts were genotyped for a polymorphism associated with serum calcium (rs1801725, CASR), two polymorphisms associated with bone mineral density (BMD) (rs2941740, ESR1 and rs9594759, RANKL) and one associated with osteoarthritis risk rs3815148 (COG5). Meta-analysis was used to pool within-study effects of the associations between each of the polymorphisms and measures of physical capability: grip strength, timed walk or get up and go, chair rises and standing balance.
Results
Few important associations were observed among the several tests. We found that carriers of the serum calcium-raising allele had poorer grip strength compared with non-carriers (pooled p = 0.05, n = 11,239) after adjusting for age and sex. Inconsistent results were observed for the two variants associated with BMD and we found no evidence for an association between rs3815148 (COG5) and any of the physical capability measures.
Conclusion
Our findings suggest elevated serum calcium levels may lead to lower grip strength, though this requires further replication. Our results do not provide evidence for a substantial influence of these variants in ESR1, RANKL and COG5 on physical capability in older adults.
Highlights
► We examined associations between bone-related genotypes and physical capability. ► We conducted a meta-analysis on 12,836 middle-age adults. ► We found CASR may be associated with grip strength. ► No substantial support for specific bone mineral density variants and physical capability.
doi:10.1016/j.bone.2012.10.004
PMCID: PMC3526776  PMID: 23072920
BMD, bone mineral density; OA, osteoarthritis; BMI, body mass index; SNP, single nucleotide polymorphism; CaPS, Caerphilly Prospective Study; ELSA, English Longitudinal Study of Ageing; HAS, Hertfordshire Ageing Study; HCS, Hertfordshire Cohort Study; LBC1921, The Lothian Birth Cohort 1921; NSHD, National Survey of Health and Development; HWE, Hardy–Weinberg equilibrium; WHR, waist–hip ratio; GWAS, genome-wide association studies; Aging; Grip strength; Calcium; Bone mineral density; Osteoarthritis
24.  Functional Gene Group Analysis Indicates No Role for Heterotrimeric G Proteins in Cognitive Ability 
PLoS ONE  2014;9(3):e91690.
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.
doi:10.1371/journal.pone.0091690
PMCID: PMC3953514  PMID: 24626473
25.  Profiles of physical, emotional and psychosocial wellbeing in the Lothian birth cohort 1936 
BMC Geriatrics  2012;12:64.
Background
Physical, emotional, and psychosocial wellbeing are important domains of function. The aims of this study were to explore the existence of separable groups among 70-year olds with scores representing physical function, perceived quality of life, and emotional wellbeing, and to characterise any resulting groups using demographic, personality, cognition, health and lifestyle variables.
Methods
We used latent class analysis (LCA) to identify possible groups.
Results
Results suggested there were 5 groups. These included High (n = 515, 47.2% of the sample), Average (n = 417, 38.3%), and Poor Wellbeing (n = 37, 3.4%) groups. The two other groups had contrasting patterns of wellbeing: one group scored relatively well on physical function, but low on emotional wellbeing (Good Fitness/ Low Spirits,n = 60, 5.5%), whereas the other group showed low physical function but relatively well emotional wellbeing (Low Fitness/Good Spirits, n = 62, 5.7%). Salient characteristics that distinguished all the groups included smoking and drinking behaviours, personality, and illness.
Conclusions
Despite there being some evidence of these groups, the results also support a largely one-dimensional construct of wellbeing in old age—for the domains assessed here—though with some evidence that some individuals have uneven profiles.
doi:10.1186/1471-2318-12-64
PMCID: PMC3549742  PMID: 23088370
Physical wellbeing; Psychosocial wellbeing; Profiles; Latent class analysis

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