Risk of Macrovascular and Microvascular Disease in Diabetes Diagnosed Using Oral Glucose Tolerance Test With and Without Confirmation by Hemoglobin A1c: The Whitehall II Cohort Study.

BACKGROUND: It is unclear whether replacing oral glucose tolerance test (OGTT) with hemoglobin A1c (HbA1c) measurement for diagnosing diabetes is justified. We aimed to assess the proportion of OGTT-diagnosed diabetes cases that can be confirmed by HbA1c and to examine whether individuals with OGTT diagnosis but nondiagnostic HbA1c are at higher risk of macrovascular and microvascular disease. METHODS: Participants were 5773 men and women from the population-based Whitehall II prospective cohort study in the United Kingdom. New OGTT diabetes cases diagnosed in clinical examinations in 2002 to 2004 and 2007 to 2009 were assessed for HbA1c confirmation (≥6.5%) in these and subsequent clinical examinations in 2012 to 2013 and 2015 to 2016. All participants were followed up for major cardiovascular events through linkage to electronic health records until 2017 and for incident chronic kidney disease (estimated glomerular filtration rate <60 mL·min-1·1.73 m-2) until the last clinical examination. In analysis of vascular disease risk, new OGTT-diagnosed diabetes cases with and without diagnostic HbA1c and preexisting diabetes cases were compared with diabetes-free participants. RESULTS: Of the 378 (59.3%) participants with OGTT-diagnosed diabetes, 224 were confirmed by HbA1c during 4.1 years (SD, 4.1 years) of follow-up. We recorded 942 cardiovascular events over 12.1 years. After adjustment for nonmodifiable risk factors and compared with the 4997 diabetes-free participants, 371 participants with new HbA1c-confirmed diabetes and 405 participants with preexisting diabetes had increased risk of cardiovascular disease (hazard ratio, 1.53 [95% CI, 1.12-2.10] and 1.85 [95% CI, 1.50-2.28], respectively). The corresponding hazard ratios in the analysis of incident chronic kidney disease (487 cases; follow-up, 6.6 years) were 1.69 (95% CI, 1.09-2.62) for 282 participants with new HbA1c-confirmed diabetes and 1.67 (95% CI, 1.22-2.28) for 276 participants with preexisting diabetes. In both analyses, OGTT cases with nondiagnostic HbA1c (n=149 and 107) had a risk (hazard ratio, 0.99-1.07) similar to that of the diabetes-free population. CONCLUSIONS: More than 40% of OGTT-diagnosed diabetes cases were not confirmed by HbA1c during an extended follow-up. However, because these individuals have a risk of cardiovascular disease and chronic kidney disease similar to that of the diabetes-free population, replacement of OGTT with HbA1c-based diagnosis appears justified.

Serum transthyretin and risk of cognitive decline and dementia: 22-year longitudinal study.

Serum transthyretin (TTR) may be an early biomarker for Alzheimer's disease and related disorders (ADRD). We investigated associations of TTR measured at baseline with cognitive decline and incident ADRD and whether TTR trajectories differ between ADRD cases and non-cases, over 22 years before diagnosis. A total of 6024 adults aged 45-69 in 1997-1999 were followed up until 2019. TTR was assessed three times, and 297 cases of dementia were recorded. Higher TTR was associated with higher cognitive function at baseline; however, TTR was unrelated to subsequent change in cognitive function. TTR at baseline did not predict ADRD risk (hazard ratio per SD TTR (4.8 mg/dL) = 0.97; 95% confidence interval: 0.94-1.00). Among those later diagnosed with ADRD, there was a marginally steeper downward TTR trajectory than those free of ADRD over follow-up (P=0.050). Our findings suggest TTR is not neuroprotective. The relative decline in TTR level in the preclinical stage of ADRD is likely to be a consequence of disease processes.

Potential impact of diabetes prevention on mortality and future burden of dementia and disability: a modelling study.

AIMS/HYPOTHESIS: Diabetes is associated with an increased risk of dementia. We estimated the potential impact of trends in diabetes prevalence upon mortality and the future burden of dementia and disability in England and Wales. METHODS: We used a probabilistic multi-state, open cohort Markov model to integrate observed trends in diabetes, cardiovascular disease and dementia to forecast the occurrence of disability and dementia up to the year 2060. Model input data were taken from the English Longitudinal Study of Ageing, Office for National Statistics vital data and published effect estimates for health-state transition probabilities. The baseline scenario corresponded to recent trends in obesity: a 26% increase in the number of people with diabetes by 2060. This scenario was evaluated against three alternative projected trends in diabetes: increases of 49%, 20% and 7%. RESULTS: Our results suggest that changes in the trend in diabetes prevalence will lead to changes in mortality and incidence of dementia and disability, which will become visible after 10-15 years. If the relative prevalence of diabetes increases 49% by 2060, expected additional deaths would be approximately 255,000 (95% uncertainty interval [UI] 236,000-272,200), with 85,900 (71,500-101,600) cumulative additional cases of dementia and 104,900 (85,900-125,400) additional cases of disability. With a smaller relative increase in diabetes prevalence (7% increase by 2060), we estimated 222,200 (205,700-237,300) fewer deaths, and 77,000 (64,300-90,800) and 93,300 (76,700-111,400) fewer additional cases of dementia and disability, respectively, than the baseline case of a 26% increase in diabetes. CONCLUSIONS/INTERPRETATION: Reducing the burden of diabetes could result in substantial reductions in the incidence of dementia and disability over the medium to long term.

Associations between arterial stiffening and brain structure, perfusion, and cognition in the Whitehall II Imaging Sub-study: A retrospective cohort study.

BACKGROUND: Aortic stiffness is closely linked with cardiovascular diseases (CVDs), but recent studies suggest that it is also a risk factor for cognitive decline and dementia. However, the brain changes underlying this risk are unclear. We examined whether aortic stiffening during a 4-year follow-up in mid-to-late life was associated with brain structure and cognition in the Whitehall II Imaging Sub-study. METHODS AND FINDINGS: The Whitehall II Imaging cohort is a randomly selected subset of the ongoing Whitehall II Study, for which participants have received clinical follow-ups for 30 years, across 12 phases. Aortic pulse wave velocity (PWV) was measured in 2007-2009 (Phase 9) and at a 4-year follow-up in 2012-2013 (Phase 11). Between 2012 and 2016 (Imaging Phase), participants received a multimodal 3T brain magnetic resonance imaging (MRI) scan and cognitive tests. Participants were selected if they had no clinical diagnosis of dementia and no gross brain structural abnormalities. Voxel-based analyses were used to assess grey matter (GM) volume, white matter (WM) microstructure (fractional anisotropy (FA) and diffusivity), white matter lesions (WMLs), and cerebral blood flow (CBF). Cognitive outcomes were performance on verbal memory, semantic fluency, working memory, and executive function tests. Of 542 participants, 444 (81.9%) were men. The mean (SD) age was 63.9 (5.2) years at the baseline Phase 9 examination, 68.0 (5.2) at Phase 11, and 69.8 (5.2) at the Imaging Phase. Voxel-based analysis revealed that faster rates of aortic stiffening in mid-to-late life were associated with poor WM microstructure, viz. lower FA, higher mean, and radial diffusivity (RD) in 23.9%, 11.8%, and 22.2% of WM tracts, respectively, including the corpus callosum, corona radiata, superior longitudinal fasciculus, and corticospinal tracts. Similar voxel-wise associations were also observed with follow-up aortic stiffness. Moreover, lower mean global FA was associated with faster rates of aortic stiffening (B = -5.65, 95% CI -9.75, -1.54, Bonferroni-corrected p < 0.0125) and higher follow-up aortic stiffness (B = -1.12, 95% CI -1.95, -0.29, Bonferroni-corrected p < 0.0125). In a subset of 112 participants who received arterial spin labelling scans, faster aortic stiffening was also related to lower cerebral perfusion in 18.4% of GM, with associations surviving Bonferroni corrections in the frontal (B = -10.85, 95% CI -17.91, -3.79, p < 0.0125) and parietal lobes (B = -12.75, 95% CI -21.58, -3.91, p < 0.0125). No associations with GM volume or WMLs were observed. Further, higher baseline aortic stiffness was associated with poor semantic fluency (B = -0.47, 95% CI -0.76 to -0.18, Bonferroni-corrected p < 0.007) and verbal learning outcomes (B = -0.36, 95% CI -0.60 to -0.12, Bonferroni-corrected p < 0.007). As with all observational studies, it was not possible to infer causal associations. The generalisability of the findings may be limited by the gender imbalance, high educational attainment, survival bias, and lack of ethnic and socioeconomic diversity in this cohort. CONCLUSIONS: Our findings indicate that faster rates of aortic stiffening in mid-to-late life were associated with poor brain WM microstructural integrity and reduced cerebral perfusion, likely due to increased transmission of pulsatile energy to the delicate cerebral microvasculature. Strategies to prevent arterial stiffening prior to this point may be required to offer cognitive benefit in older age. TRIAL REGISTRATION: ClinicalTrials.gov NCT03335696.

Association of aortic stiffness with cognitive decline: Whitehall II longitudinal cohort study.

Aortic stiffness is associated with an increased risk of cardio- and cerebrovascular disease and mortality and may increase risk of dementia. The aim of the present study is to examine the association between arterial stiffness and cognitive decline in a large prospective cohort study with three repeated cognitive assessment over 7 years of follow-up. Aortic pulse wave velocity (PWV) was measured among 4300 participants (mean ± standard deviation age 65.1 ± 5.2 years) in 2007-2009 and categorized based on the tertiles: (lowest third: < 7.41 m/s), (middle third: 7.41-8.91 m/s), and (highest third: > 8.91 m/s). A global cognitive score was calculated in 2007-2009, 2012-2013, and 2015-2016 based on responses to memory, reasoning and fluency tests. Standardized global cognitive score (mean = 0, SD = 1) in highest third versus lowest third of PWV category was lower at baseline (- 0.12, 95% CI - 0.18, - 0.06). Accelerated 7-year cognitive decline was observed among individuals with the highest PWV [difference in 7-year cognitive change for highest third versus lowest third PWV: - 0.06, 95% CI - 0.11, - 0.01, P < 0.01]. Higher aortic stiffness was associated with faster cognitive decline. Clinicians may be able to use arterial stiffness severity as an indicator to administer prompt treatments to prevent or delay the onset of cognitive decline or dementia. Future studies need to determine whether early intervention of vascular stiffness is effective in delaying these outcomes.

Carotid artery wave intensity in mid- to late-life predicts cognitive decline: the Whitehall II study.

AIMS: Excessive arterial pulsatility may contribute to cognitive decline and risk of dementia via damage to the fragile cerebral microcirculation. We hypothesized that the intensity of downstream-travelling pulsatile waves measured by wave intensity analysis in the common carotid artery during mid- to late-life would be associated with subsequent cognitive decline. METHODS AND RESULTS: Duplex Doppler ultrasound was used to calculate peak forward-travelling compression wave intensity (FCWI) within the common carotid artery in 3191 individuals [mean ± standard deviation (SD), age = 61 ± 6 years; 75% male] assessed as part of the Whitehall II study in 2003-05. Serial measures of cognitive function were taken between 2002-04 and 2015-16. The relationship between FCWI and cognitive decline was adjusted for sociodemographic variables, genetic and health-related risk factors, and health behaviours. Mean (SD) 10-year change in standardized global cognitive score was -0.39 (0.18). Higher FCWI at baseline was associated with accelerated cognitive decline during follow-up [difference in 10-year change of global cognitive score per 1 SD higher FCWI = -0.02 (95% confidence interval -0.04 to -0.00); P = 0.03]. This association was largely driven by cognitive changes in individuals with the highest FCWI [Q4 vs. Q1-Q3 = -0.05 (-0.09 to -0.01), P = 0.01], equivalent to an age effect of 1.9 years. Compared to other participants, this group was ∼50% more likely to exhibit cognitive decline (defined as the top 15% most rapid reductions in cognitive function during follow-up) even after adjustments for multiple potential confounding factors [odds ratio 1.49 (1.17-1.88)]. CONCLUSION: Elevated carotid artery wave intensity in mid- to late-life predicts faster cognitive decline in long-term follow-up independent of other cardiovascular risk factors.

Long-term risk of dementia following hospitalization due to physical diseases: A multicohort study.

INTRODUCTION: Conventional risk factors targeted by prevention (e.g., low education, smoking, and obesity) are associated with a 1.2- to 2-fold increased risk of dementia. It is unclear whether having a physical disease is an equally important risk factor for dementia. METHODS: In this exploratory multicohort study of 283,414 community-dwelling participants, we examined 22 common hospital-treated physical diseases as risk factors for dementia. RESULTS: During a median follow-up of 19 years, a total of 3416 participants developed dementia. Those who had erysipelas (hazard ratio = 1.82; 95% confidence interval = 1.53 to 2.17), hypothyroidism (1.94; 1.59 to 2.38), myocardial infarction (1.41; 1.20 to 1.64), ischemic heart disease (1.32; 1.18 to 1.49), cerebral infarction (2.44; 2.14 to 2.77), duodenal ulcers (1.88; 1.42 to 2.49), gastritis and duodenitis (1.82; 1.46 to 2.27), or osteoporosis (2.38; 1.75 to 3.23) were at a significantly increased risk of dementia. These associations were not explained by conventional risk factors or reverse causation. DISCUSSION: In addition to conventional risk factors, several physical diseases may increase the long-term risk of dementia.

Weight change increases the odds of psychological distress in middle age: bidirectional analyses from the Whitehall II Study.

BACKGROUND: Mood disorders and adiposity are major public health challenges. Few studies have investigated the bidirectional association of weight and waist circumference (WC) change with psychological distress in middle age, while taking into account the potential U-shape of the association. The aim of this study was to examine the bidirectional association between psychological distress and categorical change in objectively measured weight and WC. METHODS: We analysed repeated measures (up to 17 522 person-observations in adjusted analyses) of psychological distress, weight and WC from the Whitehall II cohort. Participants were recruited at age 35-55 and 67% male. Psychological distress was assessed using the General Health Questionnaire. We used random-effects regressions to model the association between weight and WC changes and psychological distress, with and without a 5-year lag period. RESULTS: Psychological distress was associated with weight and WC gain over the subsequent 5 years but not the second 5-year period. Weight gain and loss were associated with increased odds for incident psychological distress in models with and without time-lag [odds ratio (OR) for incident psychological distress after 5-year time-lag: loss 1.20, 95% confidence interval (CI) 1.00-1.43; gain>5% 1.20, 95% CI 1.02-1.40]. WC changes were only associated with psychological distress in models without time-lag (OR for incident psychological distress: loss 1.29, 95% CI 1.02-1.64; gain>5% 1.33, 95% CI 1.11-1.58). CONCLUSIONS: Weight gain and loss increase the odds for psychological distress compared with stable weight over subsequent 10 years. In contrast, the association between psychological distress and subsequent weight and WC changes was limited to the first 5 years of follow-up.

Socioeconomic status and the 25 × 25 risk factors as determinants of premature mortality: a multicohort study and meta-analysis of 1·7 million men and women.

BACKGROUND: In 2011, WHO member states signed up to the 25 × 25 initiative, a plan to cut mortality due to non-communicable diseases by 25% by 2025. However, socioeconomic factors influencing non-communicable diseases have not been included in the plan. In this study, we aimed to compare the contribution of socioeconomic status to mortality and years-of-life-lost with that of the 25 × 25 conventional risk factors. METHODS: We did a multicohort study and meta-analysis with individual-level data from 48 independent prospective cohort studies with information about socioeconomic status, indexed by occupational position, 25 × 25 risk factors (high alcohol intake, physical inactivity, current smoking, hypertension, diabetes, and obesity), and mortality, for a total population of 1 751 479 (54% women) from seven high-income WHO member countries. We estimated the association of socioeconomic status and the 25 × 25 risk factors with all-cause mortality and cause-specific mortality by calculating minimally adjusted and mutually adjusted hazard ratios [HR] and 95% CIs. We also estimated the population attributable fraction and the years of life lost due to suboptimal risk factors. FINDINGS: During 26·6 million person-years at risk (mean follow-up 13·3 years [SD 6·4 years]), 310 277 participants died. HR for the 25 × 25 risk factors and mortality varied between 1·04 (95% CI 0·98-1·11) for obesity in men and 2 ·17 (2·06-2·29) for current smoking in men. Participants with low socioeconomic status had greater mortality compared with those with high socioeconomic status (HR 1·42, 95% CI 1·38-1·45 for men; 1·34, 1·28-1·39 for women); this association remained significant in mutually adjusted models that included the 25 × 25 factors (HR 1·26, 1·21-1·32, men and women combined). The population attributable fraction was highest for smoking, followed by physical inactivity then socioeconomic status. Low socioeconomic status was associated with a 2·1-year reduction in life expectancy between ages 40 and 85 years, the corresponding years-of-life-lost were 0·5 years for high alcohol intake, 0·7 years for obesity, 3·9 years for diabetes, 1·6 years for hypertension, 2·4 years for physical inactivity, and 4·8 years for current smoking. INTERPRETATION: Socioeconomic circumstances, in addition to the 25 × 25 factors, should be targeted by local and global health strategies and health risk surveillance to reduce mortality. FUNDING: European Commission, Swiss State Secretariat for Education, Swiss National Science Foundation, the Medical Research Council, NordForsk, Portuguese Foundation for Science and Technology.

High-Sugar, High-Saturated-Fat Dietary Patterns Are Not Associated with Depressive Symptoms in Middle-Aged Adults in a Prospective Study.

Background: The consumption of unhealthy "Western" dietary patterns has been previously associated with depressive symptoms in different populations. Objective: We examined whether high-sugar and high-saturated-fat dietary patterns are associated with depressive symptoms over 5 y in a British cohort of men and women. Methods: We used data from the Whitehall II study in 5044 individuals (aged 35-55 y). Diet was assessed at phase 7 (2003-2004) using a validated food-frequency questionnaire. Dietary patterns were derived by using reduced rank regression with sugar, saturated fat, and total fat as response variables. The Center for Epidemiological Studies-Depression (CES-D) scale was used to assess depressive symptoms (CES-D sum score ≥16 and/or use of antidepressant medication) at phase 7 and at phase 9 (2008-2009). We applied logistic regression analyses to test the association between dietary patterns and depressive symptoms. All analyses were stratified by sex. Results: In total, 398 cases of recurrent and 295 cases of incident depressive symptoms were observed. We identified 2 dietary patterns: a combined high-sugar and high-saturated-fat (HSHF) and a high-sugar dietary pattern. No association was observed between the dietary patterns and either incidence of or recurrent depressive symptoms in men or women. For example, higher consumption of the HSHF dietary pattern was not associated with recurrent depressive symptoms in men (model 3, quartile 4: OR: 0.67; 95% CI: 0.36, 1.23; P-trend = 0.13) or in women (model 3, quartile 4: OR: 1.26; 95% CI: 0.58, 2.77; P-trend = 0.97). Conclusion: Among middle-aged men and women living in the United Kingdom, dietary patterns containing high amounts of sugar and saturated fat are not associated with new onset or recurrence of depressive symptoms.

Does pattern mixture modelling reduce bias due to informative attrition compared to fitting a mixed effects model to the available cases or data imputed using multiple imputation?: a simulation study.

BACKGROUND: Informative attrition occurs when the reason participants drop out from a study is associated with the study outcome. Analysing data with informative attrition can bias longitudinal study inferences. Approaches exist to reduce bias when analysing longitudinal data with monotone missingness (once participants drop out they do not return). However, findings may differ when using these approaches to analyse longitudinal data with non-monotone missingness. METHODS: Different approaches to reduce bias due to informative attrition in non-monotone longitudinal data were compared. To achieve this aim, we simulated data from a Whitehall II cohort epidemiological study, which used the slope coefficients from a linear mixed effects model to investigate the association between smoking status at baseline and subsequent decline in cognition scores. Participants with lower cognitive scores were thought to be more likely to drop out. By using a simulation study, a range of scenarios using distributions of variables which exist in real data were compared. Informative attrition that would introduce a known bias to the simulated data was specified and the estimates from a mixed effects model with random intercept and slopes when fitted to: available cases; data imputed using multiple imputation (MI); imputed data adjusted using pattern mixture modelling (PMM) were compared. The two-fold fully conditional specification MI approach, previously validated for non-monotone longitudinal data under ignorable missing data assumption, was used. However, MI may not reduce bias because informative attrition is non-ignorable missing. Therefore, PMM was applied to reduce the bias, usually unknown, by adjusting the values imputed with MI by a fixed value equal to the introduced bias. RESULTS: With highly correlated repeated outcome measures, the slope coefficients from a mixed effects model were found to have least bias when fitted to available cases. However, for moderately correlated outcome measurements, the slope coefficients from fitting a mixed effects model to data adjusted using PMM were least biased but still underestimated the true coefficients. CONCLUSIONS: PMM may potentially reduce bias in studies analysing longitudinal data with suspected informative attrition and moderately correlated repeated outcome measurements. Including additional auxiliary variables in the imputation model may also reduce any remaining bias.

Long working hours as a risk factor for atrial fibrillation: a multi-cohort study.

AIMS: Studies suggest that people who work long hours are at increased risk of stroke, but the association of long working hours with atrial fibrillation, the most common cardiac arrhythmia and a risk factor for stroke, is unknown. We examined the risk of atrial fibrillation in individuals working long hours (≥55 per week) and those working standard 35-40 h/week. METHODS AND RESULTS: In this prospective multi-cohort study from the Individual-Participant-Data Meta-analysis in Working Populations (IPD-Work) Consortium, the study population was 85 494 working men and women (mean age 43.4 years) with no recorded atrial fibrillation. Working hours were assessed at study baseline (1991-2004). Mean follow-up for incident atrial fibrillation was 10 years and cases were defined using data on electrocardiograms, hospital records, drug reimbursement registers, and death certificates. We identified 1061 new cases of atrial fibrillation (10-year cumulative incidence 12.4 per 1000). After adjustment for age, sex and socioeconomic status, individuals working long hours had a 1.4-fold increased risk of atrial fibrillation compared with those working standard hours (hazard ratio = 1.42, 95% CI = 1.13-1.80, P = 0.003). There was no significant heterogeneity between the cohort-specific effect estimates (I2 = 0%, P = 0.66) and the finding remained after excluding participants with coronary heart disease or stroke at baseline or during the follow-up (N = 2006, hazard ratio = 1.36, 95% CI = 1.05-1.76, P = 0.0180). Adjustment for potential confounding factors, such as obesity, risky alcohol use and high blood pressure, had little impact on this association. CONCLUSION: Individuals who worked long hours were more likely to develop atrial fibrillation than those working standard hours.

Body mass index and risk of dementia: Analysis of individual-level data from 1.3 million individuals.

INTRODUCTION: Higher midlife body mass index (BMI) is suggested to increase the risk of dementia, but weight loss during the preclinical dementia phase may mask such effects. METHODS: We examined this hypothesis in 1,349,857 dementia-free participants from 39 cohort studies. BMI was assessed at baseline. Dementia was ascertained at follow-up using linkage to electronic health records (N = 6894). We assumed BMI is little affected by preclinical dementia when assessed decades before dementia onset and much affected when assessed nearer diagnosis. RESULTS: Hazard ratios per 5-kg/m2 increase in BMI for dementia were 0.71 (95% confidence interval = 0.66-0.77), 0.94 (0.89-0.99), and 1.16 (1.05-1.27) when BMI was assessed 10 years, 10-20 years, and >20 years before dementia diagnosis. CONCLUSIONS: The association between BMI and dementia is likely to be attributable to two different processes: a harmful effect of higher BMI, which is observable in long follow-up, and a reverse-causation effect that makes a higher BMI to appear protective when the follow-up is short.

Association of branched-chain amino acids and other circulating metabolites with risk of incident dementia and Alzheimer's disease: A prospective study in eight cohorts.

INTRODUCTION: Metabolite, lipid, and lipoprotein lipid profiling can provide novel insights into mechanisms underlying incident dementia and Alzheimer's disease. METHODS: We studied eight prospective cohorts with 22,623 participants profiled by nuclear magnetic resonance or mass spectrometry metabolomics. Four cohorts were used for discovery with replication undertaken in the other four to avoid false positives. For metabolites that survived replication, combined association results are presented. RESULTS: Over 246,698 person-years, 995 and 745 cases of incident dementia and Alzheimer's disease were detected, respectively. Three branched-chain amino acids (isoleucine, leucine, and valine), creatinine and two very low density lipoprotein (VLDL)-specific lipoprotein lipid subclasses were associated with lower dementia risk. One high density lipoprotein (HDL; the concentration of cholesterol esters relative to total lipids in large HDL) and one VLDL (total cholesterol to total lipids ratio in very large VLDL) lipoprotein lipid subclass was associated with increased dementia risk. Branched-chain amino acids were also associated with decreased Alzheimer's disease risk and the concentration of cholesterol esters relative to total lipids in large HDL with increased Alzheimer's disease risk. DISCUSSION: Further studies can clarify whether these molecules play a causal role in dementia pathogenesis or are merely markers of early pathology.

Circulating metabolites and general cognitive ability and dementia: Evidence from 11 cohort studies.

INTRODUCTION: Identifying circulating metabolites that are associated with cognition and dementia may improve our understanding of the pathogenesis of dementia and provide crucial readouts for preventive and therapeutic interventions. METHODS: We studied 299 metabolites in relation to cognition (general cognitive ability) in two discovery cohorts (N total = 5658). Metabolites significantly associated with cognition after adjusting for multiple testing were replicated in four independent cohorts (N total = 6652), and the associations with dementia and Alzheimer's disease (N = 25,872) and lifestyle factors (N = 5168) were examined. RESULTS: We discovered and replicated 15 metabolites associated with cognition including subfractions of high-density lipoprotein, docosahexaenoic acid, ornithine, glutamine, and glycoprotein acetyls. These associations were independent of classical risk factors including high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, and apolipoprotein E (APOE) genotypes. Six of the cognition-associated metabolites were related to the risk of dementia and lifestyle factors. DISCUSSION: Circulating metabolites were consistently associated with cognition, dementia, and lifestyle factors, opening new avenues for prevention of cognitive decline and dementia.

Validity of Cardiovascular Disease Event Ascertainment Using Linkage to UK Hospital Records.

BACKGROUND: Use of electronic health records for ascertainment of disease outcomes in large population-based studies holds much promise due to low costs, diminished study participant burden, and reduced selection bias. However, the validity of cardiovascular disease endpoints derived from electronic records is unclear. METHODS: Participants were 7860 study members of the UK Whitehall II cohort study. We compared cardiovascular disease ascertainment using linkage to the National Health Service's Hospital Episode Statistics database records (hereafter, "HES-ascertainment") against repeated biomedical examinations-our gold standard ascertainment method (Whitehall-ascertainment). Follow-up for both methods was from 1997 to 2013 for coronary heart disease and from 1997 to 2009 for stroke. RESULTS: We identified 950 prevalent or incident nonfatal coronary heart disease cases and 118 prevalent or incident nonfatal stroke cases using Whitehall-ascertainment. The corresponding figures for HES-ascertainment were 926 and 107. For coronary heart disease, the sensitivity of HES-ascertainment was 70%, positive predictive value 72%, specificity 96%, and the negative predictive value 96%. The pattern of results for stroke was similar. These statistics did not differ in analyses stratified by age, sex, baseline risk factor status, or after exclusion of prevalent cases. Estimates of risk factor-disease associations were similar between the two ascertainment methods. Including fatal cardiovascular disease in the outcomes improved the agreement between the methods. CONCLUSION: Our analyses support the validity of cardiovascular disease ascertainment using linkage to the UK Hospital Episode Statistics database records by showing agreement with high resolution disease data collected in the Whitehall II cohort.

Association between inflammatory biomarkers and all-cause, cardiovascular and cancer-related mortality.

BACKGROUND: The inflammatory biomarker α1-acid glycoprotein (AGP) was found to have the strongest association with 5-year mortality in a recent study of 106 biomarkers. We examined whether AGP is a better biomarker of mortality risk than the more widely used inflammatory biomarkers interleukin-6 (IL-6) and C-reactive protein (CRP). METHODS: We analyzed data for 6545 men and women aged 45-69 (mean 55.7) years from the Whitehall II cohort study. We assayed AGP, IL-6 and CRP levels from fasting serum samples collected in 1997-1999. Mortality followup was until June 2015. Cox regression analysis was used to model associations of inflammatory biomarkers with all-cause, cardiovascular and cancer-related mortality. RESULTS: Over the mean follow-up of 16.7 years, 736 deaths occurred, of which 181 were from cardiovascular disease and 347 from cancer. In the model adjusted for all covariates (age, sex, socioeconomic status, body mass index, health behaviours and chronic disease), AGP did not predict mortality beyond the first 5 years of follow-up; over this period, IL-6 and CRP had stronger associations with mortality. When we considered all covariates and biomarkers simultaneously, AGP no longer predicted all-cause mortality over the entire follow-up period (adjusted hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.90-1.08). Only IL-6 predicted all-cause mortality (adjusted HR 1.22, 95% CI 1.12-1.33) and cancer-related mortality (adjusted HR 1.13, 95% CI 1.00-1.29) over the entire follow-up period, whereas CRP predicted only cardiovascular mortality (adjusted HR 1.30, 95% CI 1.06-1.61). INTERPRETATION: Our findings suggest that AGP is not a better marker of short-or long-term mortality risk than the more commonly used biomarkers IL-6 and CRP.

Long working hours and cancer risk: a multi-cohort study.

BACKGROUND: Working longer than the maximum recommended hours is associated with an increased risk of cardiovascular disease, but the relationship of excess working hours with incident cancer is unclear. METHODS: This multi-cohort study examined the association between working hours and cancer risk in 116 462 men and women who were free of cancer at baseline. Incident cancers were ascertained from national cancer, hospitalisation and death registers; weekly working hours were self-reported. RESULTS: During median follow-up of 10.8 years, 4371 participants developed cancer (n colorectal cancer: 393; n lung cancer: 247; n breast cancer: 833; and n prostate cancer: 534). We found no clear evidence for an association between working hours and the overall cancer risk. Working hours were also unrelated the risk of incident colorectal, lung or prostate cancers. Working ⩾55 h per week was associated with 1.60-fold (95% confidence interval 1.12-2.29) increase in female breast cancer risk independently of age, socioeconomic position, shift- and night-time work and lifestyle factors, but this observation may have been influenced by residual confounding from parity. CONCLUSIONS: Our findings suggest that working long hours is unrelated to the overall cancer risk or the risk of lung, colorectal or prostate cancers. The observed association with breast cancer would warrant further research.

Long working hours and risk of coronary heart disease and stroke: a systematic review and meta-analysis of published and unpublished data for 603,838 individuals.

BACKGROUND: Long working hours might increase the risk of cardiovascular disease, but prospective evidence is scarce, imprecise, and mostly limited to coronary heart disease. We aimed to assess long working hours as a risk factor for incident coronary heart disease and stroke. METHODS: We identified published studies through a systematic review of PubMed and Embase from inception to Aug 20, 2014. We obtained unpublished data for 20 cohort studies from the Individual-Participant-Data Meta-analysis in Working Populations (IPD-Work) Consortium and open-access data archives. We used cumulative random-effects meta-analysis to combine effect estimates from published and unpublished data. FINDINGS: We included 25 studies from 24 cohorts in Europe, the USA, and Australia. The meta-analysis of coronary heart disease comprised data for 603,838 men and women who were free from coronary heart disease at baseline; the meta-analysis of stroke comprised data for 528,908 men and women who were free from stroke at baseline. Follow-up for coronary heart disease was 5·1 million person-years (mean 8·5 years), in which 4768 events were recorded, and for stroke was 3·8 million person-years (mean 7·2 years), in which 1722 events were recorded. In cumulative meta-analysis adjusted for age, sex, and socioeconomic status, compared with standard hours (35-40 h per week), working long hours (≥55 h per week) was associated with an increase in risk of incident coronary heart disease (relative risk [RR] 1·13, 95% CI 1·02-1·26; p=0·02) and incident stroke (1·33, 1·11-1·61; p=0·002). The excess risk of stroke remained unchanged in analyses that addressed reverse causation, multivariable adjustments for other risk factors, and different methods of stroke ascertainment (range of RR estimates 1·30-1·42). We recorded a dose-response association for stroke, with RR estimates of 1·10 (95% CI 0·94-1·28; p=0·24) for 41-48 working hours, 1·27 (1·03-1·56; p=0·03) for 49-54 working hours, and 1·33 (1·11-1·61; p=0·002) for 55 working hours or more per week compared with standard working hours (ptrend<0·0001). INTERPRETATION: Employees who work long hours have a higher risk of stroke than those working standard hours; the association with coronary heart disease is weaker. These findings suggest that more attention should be paid to the management of vascular risk factors in individuals who work long hours. FUNDING: Medical Research Council, Economic and Social Research Council, European Union New and Emerging Risks in Occupational Safety and Health research programme, Finnish Work Environment Fund, Swedish Research Council for Working Life and Social Research, German Social Accident Insurance, Danish National Research Centre for the Working Environment, Academy of Finland, Ministry of Social Affairs and Employment (Netherlands), US National Institutes of Health, British Heart Foundation.

Underweight as a risk factor for respiratory death in the Whitehall cohort study: exploring reverse causality using a 45-year follow-up.

Underweight adults have higher rates of respiratory death than the normal weight but it is unclear whether this association is causal or reflects illness-induced weight loss (reverse causality). Evidence from a 45-year follow-up of underweight participants for respiratory mortality in the Whitehall study (N=18 823; 2139 respiratory deaths) suggests that excess risk among the underweight is attributable to reverse causality. The age-adjusted and smoking-adjusted risk was 1.55-fold (95% CI 1.32 to 1.83) higher among underweight compared with normal weight participants, but attenuated in a stepwise manner to 1.14 (95% CI 0.76 to 1.71) after serial exclusions of deaths during the first 5-35 years of follow-up (P(trend)<0.001).