The impacts of social restrictions during the COVID-19 pandemic on the physical activity levels of over 50-year olds: The CHARIOT COVID-19 Rapid Response (CCRR) cohort study.

OBJECTIVES: To quantify the associations between shielding status and loneliness at the start of the COVID-19 pandemic, and physical activity (PA) levels throughout the pandemic. METHODS: Demographic, health and lifestyle characteristics of 7748 cognitively healthy adults aged >50, and living in London, were surveyed from April 2020 to March 2021. The International Physical Activity Questionnaire (IPAQ) short-form assessed PA before COVID-19 restrictions, and up to 6 times over 11 months. Linear mixed models investigated associations between shielding status and loneliness at the onset of the pandemic, with PA over time. RESULTS: Participants who felt 'often lonely' at the outset of the pandemic completed an average of 522 and 547 fewer Metabolic Equivalent of Task (MET) minutes/week during the pandemic (95% CI: -809, -236, p<0.001) (95% CI: -818, -275, p<0.001) than those who felt 'never lonely' in univariable and multivariable models adjusted for demographic factors respectively. Those who felt 'sometimes lonely' completed 112 fewer MET minutes/week (95% CI: -219, -5, p = 0.041) than those who felt 'never lonely' following adjustment for demographic factors. Participants who were shielding at the outset of the pandemic completed an average of 352 fewer MET minutes/week during the pandemic than those who were not (95% CI: -432, -273; p<0.001) in univariable models and 228 fewer MET minutes/week (95% CI: -307, -150, p<0.001) following adjustment for demographic factors. No significant associations were found after further adjustment for health and lifestyle factors. CONCLUSIONS: Those shielding or lonely at pandemic onset were likely to have completed low levels of PA during the pandemic. These associations are influenced by co-morbidities and health status.

Impact of hypertension prevalence trend on mortality and burdens of dementia and disability in England and Wales to 2060: a simulation modelling study.

BACKGROUND: Previous estimates of the impact of public health interventions targeting hypertension usually focus on one health outcome. This study aims to consider the effects of change in future hypertension prevalence on mortality, dementia, and disability simultaneously. METHODS: We modelled three plausible scenarios based on observed trends of hypertension prevalence from 2003 to 2017 in England: observed trends continue (baseline scenario); 2017 prevalence remains unchanged; and 2017 prevalence decreases by 50% by 2060. We used a probabilistic Markov model to integrate calendar trends in incidence of cardiovascular disease, dementia, disability, and mortality to forecast their future occurrence in the population of England and Wales. Assuming the hypertension prevalence trend modifies health transition probabilities, we compared mortality outcomes and the burden of dementia and disability to 2060 for the scenarios. FINDINGS: If the decline in hypertension prevalence stops, there would be a slight increase in the number of additional deaths to 2060 (22·9 [95% uncertainty interval 19·0-26·6] more deaths per 100 000 population), although the burdens of disability and dementia in absolute terms would change little. Alternatively, if the downward hypertension prevalence trend accelerates (with prevalence falling by 50% between 2017 and 2060), there would be a modest additional reduction in deaths (57·0 [50·4-63·5] fewer deaths per 100 000 population), a small increase in dementia burden (9·0 [5·1-13·2] more cases per 100 000 population), no significant effect on disability burden, and an 8% gain in healthy life expectancy at age 65 years from 2020 to 2060 (5·3 years vs 4·9 years) compared with the baseline scenario. INTERPRETATION: The major future impact of alternative hypertension prevention strategies appears to be on future life expectancy. The salutary effect of lower population blood pressure distribution on incidence of dementia and disability might not offset expansion of the susceptible population due to reduced mortality. FUNDING: British Heart Foundation and UK Economic and Social Research Council.

Dementia risk in patients with type 2 diabetes: Comparing metformin with no pharmacological treatment.

INTRODUCTION: Metformin has been suggested as a therapeutic agent for dementia, but the relevant evidence has been partial and inconsistent. METHODS: We established a national cohort of 210,237 type 2 diabetes patients in the UK Clinical Practice Research Datalink. Risks of incident dementia were compared between metformin initiators and those who were not prescribed any anti-diabetes medication during follow-up. RESULTS: Compared with metformin initiators (n = 114,628), patients who received no anti-diabetes medication (n = 95,609) had lower HbA1c and better cardiovascular health at baseline. Both Cox regression and propensity score weighting analysis showed metformin initiators had lower risk of dementia compared to those non-users (adjusted hazard ratio = 0.88 [95% confidence interval: 0.84-0.92] and 0.90 [0.84-0.96]). Patients on long-term metformin treatment had an even lower risk of dementia. DISCUSSION: Metformin may act beyond its glycemic effect and reduce dementia risk to an even lower level than that of patients with milder diabetes and better health profiles. HIGHLIGHTS: Metformin initiators had a significantly lower risk of dementia compared with patients not receiving anti-diabetes medication. Compared with metformin initiators, diabetes patients not receiving pharmacological treatment had better glycemic profiles at baseline and during follow-up. Patients on long-term metformin treatment had an even lower risk of subsequent dementia incidence. Metformin may act beyond its effect on hyperglycemia and has the potential of being repurposed for dementia prevention.

Practice Effect of Repeated Cognitive Tests Among Older Adults: Associations With Brain Amyloid Pathology and Other Influencing Factors.

Background: Practice effects (PE), after repeated cognitive measurements, may mask cognitive decline and represent a challenge in clinical and research settings. However, an attenuated practice effect may indicate the presence of brain pathologies. This study aimed to evaluate practice effects on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) scale, and their associations with brain amyloid status and other factors in a cohort of cognitively unimpaired older adults enrolled in the CHARIOT-PRO SubStudy. Materials and Methods: 502 cognitively unimpaired participants aged 60-85 years were assessed with RBANS in both screening and baseline clinic visits using alternate versions (median time gap of 3.5 months). We tested PE based on differences between test and retest scores in total scale and domain-specific indices. Multiple linear regressions were used to examine factors influencing PE, after adjusting for age, sex, education level, APOE-ε4 carriage and initial RBANS score. The latter and PE were also evaluated as predictors for amyloid positivity status based on defined thresholds, using logistic regression. Results: Participants' total scale, immediate memory and delayed memory indices were significantly higher in the second test than in the initial test (Cohen's dz = 0.48, 0.70 and 0.35, P < 0.001). On the immediate memory index, the PE was significantly lower in the amyloid positive group than the amyloid negative group (P = 0.022). Older participants (≥70 years), women, non-APOE-ε4 carriers, and those with worse initial RBANS test performance had larger PE. No associations were found between brain MRI parameters and PE. In addition, attenuated practice effects in immediate or delayed memory index were independent predictors for amyloid positivity (P < 0.05). Conclusion: Significant practice effects on RBANS total scale and memory indices were identified in cognitively unimpaired older adults. The association with amyloid status suggests that practice effects are not simply a source of measurement error but may be informative with regard to underlying neuropathology.

What will the cardiovascular disease slowdown cost? Modelling the impact of CVD trends on dementia, disability, and economic costs in England and Wales from 2020-2029.

BACKGROUND: There is uncertainty around the health impact and economic costs of the recent slowing of the historical decline in cardiovascular disease (CVD) incidence and the future impact on dementia and disability. METHODS: Previously validated IMPACT Better Ageing Markov model for England and Wales, integrating English Longitudinal Study of Ageing (ELSA) data for 17,906 ELSA participants followed from 1998 to 2012, linked to NHS Hospital Episode Statistics. Counterfactual design comparing two scenarios: Scenario 1. CVD Plateau-age-specific CVD incidence remains at 2011 levels, thus continuing recent trends. Scenario 2. CVD Fall-age-specific CVD incidence goes on declining, following longer-term trends. The main outcome measures were age-related healthcare costs, social care costs, opportunity costs of informal care, and quality adjusted life years (valued at £60,000 per QALY). FINDINGS: The total 10 year cumulative incremental net monetary cost associated with a persistent plateauing of CVD would be approximately £54 billion (95% uncertainty interval £14.3-£96.2 billion), made up of some £13 billion (£8.8-£16.7 billion) healthcare costs, £1.5 billion (-£0.9-£4.0 billion) social care costs, £8 billion (£3.4-£12.8 billion) informal care and £32 billion (£0.3-£67.6 billion) value of lost QALYs. INTERPRETATION: After previous, dramatic falls, CVD incidence has recently plateaued. That slowdown could substantially increase health and social care costs over the next ten years. Healthcare costs are likely to increase more than social care costs in absolute terms, but social care costs will increase more in relative terms. Given the links between COVID-19 and cardiovascular health, effective cardiovascular prevention policies need to be revitalised urgently.

Aortic Pulse Wave Velocity as Adjunct Risk Marker for Assessing Cardiovascular Disease Risk: Prospective Study.

BACKGROUND: Aortic pulse wave velocity is a noninvasive measure of aortic stiffness and arterial aging. Its current value in cardiovascular risk estimation practice is unknown. We aimed to establish whether aortic pulse wave velocity identified individuals with higher risk of incident major adverse cardiovascular events and improved performance of the American Heart Association/American College of Cardiology atherosclerotic cardiovascular disease risk score. METHODS: This prospective analysis included 3837 Whitehall II cohort participants screened in 2008 to 2009, and followed for 11.7 years (mean=10.3, SD=1.81), without history of stroke, myocardial infarction, or coronary heart disease. RESULTS: Mean age of the sample was 65.0 years (SD=5.6), 2831 participants (73.8%) were male and mean atherosclerotic cardiovascular disease risk score was 13.8%. At the end of follow-up, 411 individuals (10.7%) had suffered a major cardiovascular event. Those in the highest aortic pulse wave velocity quartile were at high risk (hazard ratio, 2.99 [95% CI, 2.25-3.97]) and reached the threshold for statin medication (7.5% risk) after 5 years whereas others reached it after 10 years (difference P<0.001). The addition of aortic pulse wave velocity to the risk score improved the C statistic (0.68 versus 0.67, P=0.03) and net reclassification index (4.6%, P=0.04 and 11.3%, P=0.02). CONCLUSIONS: Our results show that aortic stiffness predicted major adverse cardiovascular events in a cohort of elderly individuals, improving the performance of a widely used cardiovascular disease risk estimator. Aortic pulse wave velocity measurement is scalable, radiation-free, and easy to perform. Further studies on its applicability in cardiovascular disease risk assessment in primary care settings are needed.

Health, Lifestyle, and Psycho-Social Determinants of Poor Sleep Quality During the Early Phase of the COVID-19 Pandemic: A Focus on UK Older Adults Deemed Clinically Extremely Vulnerable.

Background: Several studies have assessed the impact of COVID-19-related lockdowns on sleep quality across global populations. However, no study to date has specifically assessed at-risk populations, particularly those at highest risk of complications from coronavirus infection deemed "clinically-extremely-vulnerable-(COVID-19CEV)" (as defined by Public Health England). Methods: In this cross-sectional study, we surveyed 5,558 adults aged ≥50 years (of whom 523 met criteria for COVID-19CEV) during the first pandemic wave that resulted in a nationwide-lockdown (April-June 2020) with assessments of sleep quality (an adapted sleep scale that captured multiple sleep indices before and during the lockdown), health/medical, lifestyle, psychosocial and socio-demographic factors. We examined associations between these variables and sleep quality; and explored interactions of COVID-19CEV status with significant predictors of poor sleep, to identify potential moderating factors. Results: Thirty-seven percent of participants reported poor sleep quality which was associated with younger age, female sex and multimorbidity. Significant associations with poor sleep included health/medical factors: COVID-19CEV status, higher BMI, arthritis, pulmonary disease, and mental health disorders; and the following lifestyle and psychosocial factors: living alone, higher alcohol consumption, an unhealthy diet and higher depressive and anxiety symptoms. Moderators of the negative relationship between COVID-19CEV status and good sleep quality were marital status, loneliness, anxiety and diet. Within this subgroup, less anxious and less lonely males, as well as females with healthier diets, reported better sleep. Conclusions: Sleep quality in older adults was compromised during the sudden unprecedented nation-wide lockdown due to distinct modifiable factors. An important contribution of our study is the assessment of a "clinically-extremely-vulnerable" population and the sex differences identified within this group. Male and female older adults deemed COVID-19CEV may benefit from targeted mental health and dietary interventions, respectively. This work extends the available evidence on the notable impact of lack of social interactions during the COVID-19 pandemic on sleep, and provides recommendations toward areas for future work, including research into vulnerability factors impacting sleep disruption and COVID-19-related complications. Study results may inform tailored interventions targeted at modifiable risk factors to promote optimal sleep; additionally, providing empirical data to support health policy development in this area.

Impact of social restrictions during the COVID-19 pandemic on the physical activity levels of adults aged 50-92 years: a baseline survey of the CHARIOT COVID-19 Rapid Response prospective cohort study.

OBJECTIVES: Physical inactivity is more common in older adults, is associated with social isolation and loneliness and contributes to increased morbidity and mortality. We examined the effect of social restrictions to reduce COVID-19 transmission in the UK (lockdown), on physical activity (PA) levels of older adults and the social predictors of any change. DESIGN: Baseline analysis of a survey-based prospective cohort study. SETTING: Adults enrolled in the Cognitive Health in Ageing Register for Investigational and Observational Trials cohort from general practitioner practices in North West London were invited to participate from April to July 2020. PARTICIPANTS: 6219 cognitively healthy adults aged 50-92 years completed the survey. MAIN OUTCOME MEASURES: Self-reported PA before and after the introduction of lockdown, as measured by metabolic equivalent of task (MET) minutes. Associations of PA with demographic, lifestyle and social factors, mood and frailty. RESULTS: Mean PA was significantly lower following the introduction of lockdown from 3519 to 3185 MET min/week (p<0.001). After adjustment for confounders and prelockdown PA, lower levels of PA after the introduction of lockdown were found in those who were over 85 years old (640 (95% CI 246 to 1034) MET min/week less); were divorced or single (240 (95% CI 120 to 360) MET min/week less); living alone (277 (95% CI 152 to 402) MET min/week less); reported feeling lonely often (306 (95% CI 60 to 552) MET min/week less); and showed symptoms of depression (1007 (95% CI 612 to 1401) MET min/week less) compared with those aged 50-64 years, married, cohabiting and not reporting loneliness or depression, respectively. CONCLUSIONS AND IMPLICATIONS: Markers of social isolation, loneliness and depression were associated with lower PA following the introduction of lockdown in the UK. Targeted interventions to increase PA in these groups should be considered.

Association between change in cardiovascular risk scores and future cardiovascular disease: analyses of data from the Whitehall II longitudinal, prospective cohort study.

BACKGROUND: Evaluation of cardiovascular disease risk in primary care, which is recommended every 5 years in middle-aged and older adults (typical age range 40-75 years), is based on risk scores, such as the European Society of Cardiology Systematic Coronary Risk Evaluation (SCORE) and American College of Cardiology/American Heart Association Atherosclerotic Cardiovascular Disease (ASCVD) algorithms. This evaluation currently uses only the most recent risk factor assessment. We aimed to examine whether 5-year changes in SCORE and ASCVD risk scores are associated with future cardiovascular disease risk. METHODS: We analysed data from the Whitehall II longitudinal, prospective cohort study for individuals with no history of stroke, myocardial infarction, coronary artery bypass graft, percutaneous coronary intervention, definite angina, heart failure, or peripheral artery disease. Participants underwent clinical examinations in 5-year intervals between Aug 7, 1991, and Dec 6, 2016, and were followed up for incident cardiovascular disease until Oct 2, 2019. Levels of, and 5-year changes in, cardiovascular disease risk were assessed using the SCORE and ASCVD risk scores and were analysed as predictors of cardiovascular disease. Harrell's C index, continuous net reclassification improvement, the Akaike information criterion, and calibration analysis were used to assess whether incorporating change in risk scores into a model including only a single risk score assessment improved the predictive performance. We assessed the levels of, and 5-year changes in, SCORE and ASCVD risk scores as predictors of cardiovascular disease and disease-free life-years using Cox proportional hazards and flexible parametric survival models. FINDINGS: 7574 participants (5233 [69·1%] men, 2341 [30·9%] women) aged 40-75 years were included in analyses of risk score change between April 24, 1997, and Oct 2, 2019. During a mean follow-up of 18·7 years (SD 5·5), 1441 (19·0%; 1042 [72·3%] men and 399 [27·7%] women) participants developed cardiovascular disease. Adding 5-year change in risk score to a model that included only a single risk score assessment improved model performance according to Harrell's C index (from 0·685 to 0·690, change 0·004 [95% CI 0·000 to 0·008] for SCORE; from 0·699 to 0·700, change 0·001 [0·000 to 0·003] for ASCVD), the Akaike information criterion (from 17 255 to 17 200, change -57 [95% CI -97 to -13] for SCORE; from 14 739 to 14 729, change -10 [-28 to 7] for ASCVD), and the continuous net reclassification index (0·353 [95% CI 0·234 to 0·447] for SCORE; 0·232 [0·030 to 0·344] for ASCVD). Both favourable and unfavourable changes in SCORE and ASCVD were associated with cardiovascular disease risk and disease-free life-years. The associations were seen in both sexes and all age groups up to the age of 75 years. At the age of 45 years, each 2-unit improvement in risk scores was associated with an additional 1·3 life-years (95% CI 0·4 to 2·2) free of cardiovascular disease for SCORE and an additional 0·9 life-years (95% CI 0·5 to 1·3) for ASCVD. At age 65 years, this same improvement was associated with an additional 0·4 life-years (95% CI 0·0 to 0·7) free of cardiovascular disease for SCORE and 0·3 life-years (95% CI 0·1 to 0·5) for ASCVD. These models were developed into an interactive calculator, which enables estimation of the number of cardiovascular disease-free life-years for an individual as a function of two risk score measurements. INTERPRETATION: Changes in the SCORE and ASCVD risk scores over time inform cardiovascular disease risk prediction beyond a single risk score assessment. Repeat data might allow more accurate cardiovascular risk stratification and strengthen the evidence base for decisions on preventive interventions. FUNDING: UK Medical Research Council, British Heart Foundation, Wellcome Trust, and US National Institute on Aging.

Glycemic Control, Diabetic Complications, and Risk of Dementia in Patients With Diabetes: Results From a Large U.K. Cohort Study.

OBJECTIVE: Type 2 diabetes is an established risk factor for dementia. However, the roles of glycemic control and diabetic complications in the development of dementia have been less well substantiated. This large-scale cohort study aims to examine associations of longitudinal HbA1c levels and diabetic complications with the risk of dementia incidence among patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Data of eligible patients with diabetes, aged ≥50 years in the U.K. Clinical Practice Research Datalink from 1987 to 2018, were analyzed. Time-varying Cox regressions were used to estimate adjusted hazard ratios (HRs) and 95% CIs for dementia risk. RESULTS: Among 457,902 patients with diabetes, 28,627 (6.3%) incident dementia cases were observed during a median of 6 years' follow-up. Patients with recorded hypoglycemic events or microvascular complications were at higher risk of dementia incidence compared with those without such complications (HR 1.30 [95% CI 1.22-1.39] and 1.10 [1.06-1.14], respectively). The HbA1c level, modeled as a time-varying exposure, was associated with increased dementia risk (HR 1.08 [95% CI 1.07-1.09] per 1% HbA1c increment) among 372,287 patients with diabetes with postdiagnosis HbA1c records. Similarly, a higher coefficient of variation of HbA1c during the initial 3 years of follow-up was associated with higher subsequent dementia risk (HR 1.03 [95% CI 1.01-1.04] per 1-SD increment). CONCLUSIONS: Higher or unstable HbA1c levels and the presence of diabetic complications in patients with type 2 diabetes are associated with increased dementia risk. Effective management of glycemia might have a significant role in maintaining cognitive health among older adults with diabetes.

Associations of Social Isolation with Anxiety and Depression During the Early COVID-19 Pandemic: A Survey of Older Adults in London, UK.

The COVID-19 pandemic is imposing a profound negative impact on the health and wellbeing of societies and individuals, worldwide. One concern is the effect of social isolation as a result of social distancing on the mental health of vulnerable populations, including older people. Within six weeks of lockdown, we initiated the CHARIOT COVID-19 Rapid Response Study, a bespoke survey of cognitively healthy older people living in London, to investigate the impact of COVID-19 and associated social isolation on mental and physical wellbeing. The sample was drawn from CHARIOT, a register of people over 50 who have consented to be contacted for aging related research. A total of 7,127 men and women (mean age=70.7 [SD=7.4]) participated in the baseline survey, May-July 2020. Participants were asked about changes to the 14 components of the Hospital Anxiety Depression scale (HADS) after lockdown was introduced in the UK, on 23rd March. A total of 12.8% of participants reported feeling worse on the depression components of HADS (7.8% men and 17.3% women) and 12.3% reported feeling worse on the anxiety components (7.8% men and 16.5% women). Fewer participants reported feeling improved (1.5% for depression and 4.9% for anxiety). Women, younger participants, those single/widowed/divorced, reporting poor sleep, feelings of loneliness and who reported living alone were more likely to indicate feeling worse on both the depression and/or anxiety components of the HADS. There was a significant negative association between subjective loneliness and worsened components of both depression (OR 17.24, 95% CI 13.20, 22.50) and anxiety (OR 10.85, 95% CI 8.39, 14.03). Results may inform targeted interventions and help guide policy recommendations in reducing the effects of social isolation related to the pandemic, and beyond, on the mental health of older people.

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.

Perspective: Clinical relevance of the dichotomous classification of Alzheimer's disease biomarkers: Should there be a "gray zone"?

The 2018 National Institute on Aging and the Alzheimer's Association (NIA-AA) research framework recently redefined Alzheimer's disease (AD) as a biological construct, based on in vivo biomarkers reflecting key neuropathologic features. Combinations of normal/abnormal levels of three biomarker categories, based on single thresholds, form the AD signature profile that defines the biological disease state as a continuum, independent of clinical symptomatology. While single thresholds may be useful in defining the biological signature profile, we provide evidence that their use in studies with cognitive outcomes merits further consideration. Using data from the Alzheimer's Disease Neuroimaging Initiative with a focus on cortical amyloid binding, we discuss the limitations of applying the biological definition of disease status as a tool to define the increased likelihood of the onset of the Alzheimer's clinical syndrome and the effects that this may have on trial study design. We also suggest potential research objectives going forward and what the related data requirements would be.

5-year versus risk-category-specific screening intervals for cardiovascular disease prevention: a cohort study.

BACKGROUND: Clinical guidelines suggest preventive interventions such as statin therapy for individuals with a high estimated 10-year risk of major cardiovascular events. For those with a low or intermediate estimated risk, risk-factor screenings are recommended at 5-year intervals; this interval is based on expert opinion rather than on direct research evidence. Using longitudinal data on the progression of cardiovascular disease risk over time, we compared different screening intervals in terms of timely detection of high-risk individuals, cardiovascular events prevented, and health-care costs. METHODS: We used data from participants in the British Whitehall II study (aged 40-64 years at baseline) who had repeated biomedical screenings at 5-year intervals and linked these data to electronic health records between baseline (Aug 7, 1991, to May 10, 1993) and June 30, 2015. We estimated participants' 10-year risk of a major cardiovascular event (myocardial infarction, cardiac death, and fatal or non-fatal stroke) using the revised Atherosclerotic Cardiovascular Disease (ASCVD) calculator. We used multistate Markov modelling to estimate optimum screening intervals on the basis of progression rates from low-risk and intermediate-risk categories to the high-risk category (ie, ≥7·5% 10-year risk of a major cardiovascular event). Our assessment criteria included person-years spent in a high-risk category before detection, the number of major cardiovascular events prevented and quality-adjusted life-years (QALYs) gained, and screening costs. FINDINGS: Of 6964 participants (mean age 50·0 years [SD 6·0] at baseline) with 152 700 person-years of follow-up (mean follow-up 22·0 years [SD 5·0]), 1686 participants progressed to the high-risk category and 617 had a major cardiovascular event. With the 5-year screening intervals, participants spent 7866 (95% CI 7130-8658) person-years unrecognised in the high-risk group. For individuals in the low, intermediate-low, and intermediate-high risk categories, 21 alternative risk category-based screening intervals outperformed the 5-yearly screening protocol. Screening intervals at 7 years, 4 years, and 1 year for those in the low, intermediate-low, and intermediate-high-risk category would reduce the number of person-years spent unrecognised in the high-risk group by 62% (95% CI 57-66; 4894 person-years), reduce the number of major cardiovascular events by 8% (7-9; 49 events), and raise 44 QALYs (40-49) for the study population. INTERPRETATION: In terms of timely preventive interventions, the 5-year screening intervals were unnecessarily frequent for low-risk individuals and insufficiently frequent for intermediate-risk individuals. Screening intervals based on risk-category-specific progression rates would perform better in terms of preventing major cardiovascular disease events and improving cost-effectiveness. FUNDING: Medical Research Council, British Heart Association, National Institutes on Aging, NordForsk, Academy of Finland.

Midlife contributors to socioeconomic differences in frailty during later life: a prospective cohort study.

BACKGROUND: Health inequalities persist into old age. We aimed to investigate risk factors for socioeconomic differences in frailty that could potentially be modified through policy measures. METHODS: In this multi-wave longitudinal cohort study (Whitehall II study), we assessed participants' socioeconomic status, behavioural and biomedical risk factors, and disease status at age 45-55 years, and frailty (defined according to the Fried phenotype) at baseline and at one or more of three clinic visits about 18 years later (mean age 69 years [SD 5·9]). We used logistic mixed models to examine the associations between socioeconomic status and risk factors at age 50 years and subsequent prevalence of frailty (adjusted for sex, ethnic origin, and age), with sensitivity analyses and multiple imputation for missing data. FINDINGS: Between Sept 9, 2007, and Dec 8, 2016, 6233 middle-aged adults were measured for frailty. Frailty was present in 562 (3%) of 16 164 person-observations, and varied by socioeconomic status: 145 (2%) person-observations had high socioeconomic status, 241 (4%) had intermediate status, and 176 (7%) had low socioeconomic status, adjusting for sex and age. Risk factors for frailty included cardiovascular disease, depression, smoking, high or abstinent alcohol consumption, low fruit and vegetable consumption, physical inactivity, poor lung function, hypertension, and overweight or obesity. Cardiometabolic markers for future frailty were high ratio of total to high-density lipoprotein cholesterol, and raised interleukin-6 and C-reactive protein concentrations. The five most important factors contributing to the frailty gradient, assessed by percent attenuation of the association between socioeconomic status and frailty, were physical activity (13%), interleukin-6 (13%), body-mass index category (11%), C-reactive protein (11%), and poor lung function (10%). Overall, socioeconomic differences in frailty were reduced by 40% in the maximally-adjusted model compared with the minimally-adjusted model. INTERPRETATION: Behavioural and cardiometabolic risk factors in midlife account for more than a third of socioeconomic differences in frailty. Our findings suggest that interventions targeting physical activity, obesity, smoking, and low-grade inflammation in middle age might reduce socioeconomic differences in later-life frailty. FUNDING: British Heart Foundation and British Medical Research Council.

Physical Activity, Sedentary Behavior, and Long-Term Changes in Aortic Stiffness: The Whitehall II Study.

BACKGROUND: Physical activity is associated with reduced cardiovascular disease risk, mainly through effects on atherosclerosis. Aortic stiffness may be an alternative mechanism. We examined whether patterns of physical activity and sedentary behavior are associated with rate of aortic stiffening. METHODS AND RESULTS: Carotid-femoral pulse wave velocity (PWV) was measured twice using applanation tonometry at mean ages 65 (in 2008/2009) and 70 (in 2012/2013) years in the Whitehall-II study (N=5196). Physical activity was self-reported at PWV baseline (2008/2009) and twice before (in 1997/1999 and 2002/2003). Sedentary time was defined as sitting time watching television or at work/commute. Linear mixed models adjusted for metabolic and lifestyle risk factors were used to analyze PWV change. Mean (SD) PWV (m/s) was 8.4 (2.4) at baseline and 9.2 (2.7) at follow-up, representing a 5-year increase of 0.76 m/s (95% CI 0.69, 0.83). A smaller 5-year increase in PWV was observed for each additional hour/week spent in sports activity (-0.02 m/s [95% CI -0.03, -0.001]) or cycling (-0.02 m/s [-0.03, -0.008]). Walking, housework, gardening, or do-it-yourself activities were not significantly associated with aortic stiffening. Each additional hour/week spent sitting was associated with faster PWV progression in models adjusted for physical activity (0.007 m/s [95% CI 0.001, 0.013]). Increasing physical activity over time was associated with a smaller subsequent increase in PWV (-0.16 m/s [-0.32, -0.002]) compared with not changing activity levels. CONCLUSIONS: Higher levels of moderate-to-vigorous physical activity and avoidance of sedentary behavior were each associated with a slower age-related progression of aortic stiffness independent of conventional vascular risk factors.

Forecasted trends in disability and life expectancy in England and Wales up to 2025: a modelling study.

BACKGROUND: Reliable estimation of future trends in life expectancy and the burden of disability is crucial for ageing societies. Previous forecasts have not considered the potential impact of trends in disease incidence. The present prediction model combines population trends in cardiovascular disease, dementia, disability, and mortality to forecast trends in life expectancy and the burden of disability in England and Wales up to 2025. METHODS: We developed and validated the IMPACT-Better Ageing Model-a probabilistic model that tracks the population aged 35-100 years through ten health states characterised by the presence or absence of cardiovascular disease, dementia, disability (difficulty with one or more activities of daily living) or death up to 2025, by use of evidence-based age-specific, sex-specific, and year-specific transition probabilities. As shown in the English Longitudinal Study of Ageing, we projected continuing declines in dementia incidence (2·7% per annum), cardiovascular incidence, and mortality. The model estimates disability prevalence and disabled and disability-free life expectancy by year. FINDINGS: Between 2015 and 2025, the number of people aged 65 years and older will increase by 19·4% (95% uncertainty interval [UI] 17·7-20·9), from 10·4 million (10·37-10·41 million) to 12·4 million (12·23-12·57 million). The number living with disability will increase by 25·0% (95% UI 21·3-28·2), from 2·25 million (2·24-2·27 million) to 2·81 million (2·72-2·89 million). The age-standardised prevalence of disability among this population will remain constant, at 21·7% (95% UI 21·5-21·8) in 2015 and 21·6% (21·3-21·8) in 2025. Total life expectancy at age 65 years will increase by 1·7 years (95% UI 0·1-3·6), from 20·1 years (19·9-20·3) to 21·8 years (20·2-23·6). Disability-free life expectancy at age 65 years will increase by 1·0 years (95% UI 0·1-1·9), from 15·4 years (15·3-15·5) to 16·4 years (15·5-17·3). However, life expectancy with disability will increase more in relative terms, with an increase of roughly 15% from 2015 (4·7 years, 95% UI 4·6-4·8) to 2025 (5·4 years, 4·7-6·4). INTERPRETATION: The number of older people with care needs will expand by 25% by 2025, mainly reflecting population ageing rather than an increase in prevalence of disability. Lifespans will increase further in the next decade, but a quarter of life expectancy at age 65 years will involve disability. FUNDING: British Heart Foundation.

Temporal trend in dementia incidence since 2002 and projections for prevalence in England and Wales to 2040: modelling study.

Objective To forecast dementia prevalence with a dynamic modelling approach that integrates calendar trends in dementia incidence with those for mortality and cardiovascular disease.Design Modelling study.Setting General adult population of England and Wales.Participants The English Longitudinal Study of Ageing (ELSA) is a representative panel study with six waves of data across 2002-13. Men and women aged 50 or more years, selected randomly, and their cohabiting partners were recruited to the first wave of ELSA (2002-03). 11392 adults participated (response rate 67%). To maintain representativeness, refreshment participants were recruited to the study at subsequent waves. The total analytical sample constituted 17 906 people. Constant objective criteria based on cognitive and functional impairment were used to ascertain dementia cases at each wave.Main outcome measures To estimate calendar trends in dementia incidence, correcting for bias due to loss to follow-up of study participants, a joint model of longitudinal and time-to-event data was fitted to ELSA data. To forecast future dementia prevalence, the probabilistic Markov model IMPACT-BAM (IMPACT-Better Ageing Model) was developed. IMPACT-BAM models transitions of the population aged 35 or more years through states of cardiovascular disease, cognitive and functional impairment, and dementia, to death. It enables prediction of dementia prevalence while accounting for the growing pool of susceptible people as a result of increased life expectancy and the competing effects due to changes in mortality, and incidence of cardiovascular disease.Results In ELSA, dementia incidence was estimated at 14.3 per 1000 person years in men and 17.0/1000 person years in women aged 50 or more in 2010. Dementia incidence declined at a relative rate of 2.7% (95% confidence interval 2.4% to 2.9%) for each year during 2002-13. Using IMPACT-BAM, we estimated there were approximately 767 000 (95% uncertainty interval 735 000 to 797 000) people with dementia in England and Wales in 2016. Despite the decrease in incidence and age specific prevalence, the number of people with dementia is projected to increase to 872 000, 1 092 000, and 1 205 000 in 2020, 2030, and 2040, respectively. A sensitivity analysis without the incidence decline gave a much larger projected growth, of more than 1.9 million people with dementia in 2040.Conclusions Age specific dementia incidence is declining. The number of people with dementia in England and Wales is likely to increase by 57% from 2016 to 2040. This increase is mainly driven by improved life expectancy.