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1.  Socioeconomic status as a risk factor for dementia death: individual participant meta-analysis of 86 508 men and women from the UK* 
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.
To examine the association between socioeconomic status in early life and adulthood with later dementia death.
Individual participant meta-analysis of 11 prospective cohort studies (1994-2004, n = 86 508).
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.
Lower educational attainment in women was associated with an increased risk of dementia-related death independently of common risk behaviours and comorbidities.
PMCID: PMC3696876  PMID: 23818534
2.  Clinical and Subclinical Macrovascular Disease as Predictors of Cognitive Decline in Older Patients With Type 2 Diabetes 
Diabetes Care  2013;36(9):2779-2786.
Macrovascular disease may contribute to increased risk of accelerated cognitive decline in patients with type 2 diabetes. We aimed to determine associations of measures of macrovascular disease with cognitive change in a cognitively healthy older population with type 2 diabetes.
Eight hundred thirty-one men and women (aged 60–75 years) attended two waves of the prospective Edinburgh Type 2 Diabetes Study (ET2DS). At baseline, clinical and subclinical macrovascular disease was measured, including cardiovascular event history, carotid intima-media thickness (cIMT), ankle brachial index (ABI), and serum N-terminal probrain natriuretic peptide (NT-proBNP). Seven neuropsychological tests were administered at baseline and after 4 years; scores were combined to a standardized general ability factor (g). Adjustment of follow-up g for baseline g assessed 4-year cognitive change. Adjustment for vocabulary (estimated premorbid ability) was used to estimate lifetime cognitive change.
Measures of cognitive decline were significantly associated with stroke, NT-proBNP, ABI, and cIMT, but not with nonstroke vascular events. The association of stroke with increased estimated lifetime cognitive decline (standardized β, −0.12) and of subclinical markers with actual 4-year decline (standardized β, −0.12, 0.12, and −0.15 for NT-proBNP, ABI, and cIMT, respectively) reached the Bonferroni-adjusted level of statistical significance (P < 0.006). Results altered only slightly on adjustment for vascular risk factors.
Stroke and subclinical markers of cardiac stress and generalized atherosclerosis are associated with cognitive decline in older patients with type 2 diabetes. Further investigation into the potential use of subclinical vascular disease markers in predicting cognitive decline is warranted.
PMCID: PMC3747922  PMID: 23579182
3.  Modifiable cardiovascular disease risk factors as predictors of dementia death: pooling of ten general population-based cohort studies 
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.
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.
In the present individual participant meta-analysis, there was limited evidence that cardiovascular disease risk factors were related to dementia death.
PMCID: PMC4036694  PMID: 24886432
4.  The effect of funding sources on donepezil randomised controlled trial outcome: a meta-analysis 
BMJ Open  2014;4(4):e004083.
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.
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).
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.
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.
PMCID: PMC3987717  PMID: 24710130
5.  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.
PMCID: PMC3429875  PMID: 22798662
Dementia; Alzheimer disease; epidemiology; geography; disease clustering
6.  Association between psychological distress and mortality: individual participant pooled analysis of 10 prospective cohort studies 
Objective To quantify the link between lower, subclinically symptomatic, levels of psychological distress and cause-specific mortality in a large scale, population based study.
Design Individual participant meta-analysis of 10 large prospective cohort studies from the Health Survey for England. Baseline psychological distress measured by the 12 item General Health Questionnaire score, and mortality from death certification.
Participants 68 222 people from general population samples of adults aged 35 years and over, free of cardiovascular disease and cancer, and living in private households in England at study baseline.
Main outcome measures Death from all causes (n=8365), cardiovascular disease including cerebrovascular disease (n=3382), all cancers (n=2552), and deaths from external causes (n=386). Mean follow-up was 8.2 years (standard deviation 3.5).
Results We found a dose-response association between psychological distress across the full range of severity and an increased risk of mortality (age and sex adjusted hazard ratio for General Health Questionnaire scores of 1-3 v score 0: 1.20, 95% confidence interval 1.13 to 1.27; scores 4-6: 1.43, 1.31 to 1.56; and scores 7-12: 1.94, 1.66 to 2.26; P<0.001 for trend). This association remained after adjustment for somatic comorbidity plus behavioural and socioeconomic factors. A similar association was found for cardiovascular disease deaths and deaths from external causes. Cancer death was only associated with psychological distress at higher levels.
Conclusions Psychological distress is associated with increased risk of mortality from several major causes in a dose-response pattern. Risk of mortality was raised even at lower levels of distress.
PMCID: PMC3409083  PMID: 22849956
7.  Explaining the excess mortality in Scotland compared with England: pooling of 18 cohort studies 
Mortality in Scotland is higher than in the rest of west and central Europe and is improving more slowly. Relative to England and Wales, the excess is only partially explained by area deprivation. We tested the extent to which sociodemographic, behavioural, anthropometric and biological factors explain the higher mortality in Scotland compared with England.
Pooled data from 18 nationally representative cohort studies comprising the Health Surveys for England (HSE) and the Scottish Health Survey (SHS). Cox regression analysis was used to quantify the excess mortality risk in Scotland relative to England with adjustment for baseline characteristics.
A total of 193 873 participants with a mean of 9.6 years follow-up gave rise to 21 345 deaths. The age-adjusted and sex-adjusted all-cause mortality HR for Scottish respondents compared with English respondents was 1.40 (95% CI 1.34 to 1.47), which attenuated to 1.29 (95% CI 1.23 to 1.36) with the addition of the baseline socioeconomic and behavioural characteristics. Cause-specific mortality HRs attenuated only marginally to 1.43 (95% 1.28 to 1.60) for ischaemic heart disease, 1.37 (95% CI 1.15 to 1.63) for stroke, 1.41 (95% CI 1.30 to 1.53) for all cancers, 3.43 (95% CI 1.85 to 6.36) for illicit drug-related poisoning and 4.64 (95% CI 3.55 to 6.05) for alcohol-related mortality. The excess was greatest among young adults (16–44 years) and was observed across all occupational social classes with the greatest excess in the unskilled group.
Only a quarter of the excess mortality among Scottish respondents could be explained by the available baseline risk factors. Greater understanding is required on the lived experience of poverty, the role of social support, and the historical, environmental, cultural and political influences on health in Scotland.
PMCID: PMC4283682  PMID: 25216666

Results 1-7 (7)