Association between profiles of accelerometer-measured daily movement behaviour and mortality risk: a prospective cohort study of British older adults.

Objectives: We identified profiles of wake-time movement behaviours (sedentary behaviours, light intensity physical activity and moderate-to-vigorous physical activity) based on accelerometer-derived features among older adults and then examined their association with all-cause mortality. Methods: Data were drawn from a prospective cohort of 3991 Whitehall II accelerometer substudy participants aged 60-83 years in 2012-2013. Daily movement behaviour profiles were identified using k-means cluster analysis based on 13 accelerometer-assessed features characterising total duration, frequency, bout duration, timing and activity intensity distribution of movement behaviour. Cox regression models were used to assess the association between derived profiles and mortality risk. Results: Over a mean follow-up of 8.1 (SD 1.3) years, a total of 410 deaths were recorded. Five distinct profiles were identified and labelled as 'active' (healthiest), 'active sitters', 'light movers', 'prolonged sitters', and 'most sedentary' (most deleterious). In model adjusted for sociodemographic, lifestyle, and health-related factors, compared with the 'active' profile, 'active sitters' (HR 1.57, 95% CI 1.01 to 2.44), 'light movers' (HR 1.75, 95% CI 1.17 to 2.63), 'prolonged sitters' (HR 1.67, 95% CI 1.11 to 2.51), 'most sedentary' (HR 3.25, 95% CI 2.10 to 5.02) profiles were all associated with a higher risk of mortality. Conclusion: Given the threefold higher mortality risk among those with a 'most sedentary' profile, public health interventions may target this group wherein any improvement in physical activity and sedentary behaviour might be beneficial.

The role of dementia in the association between APOE4 and all-cause mortality: pooled analyses of two population-based cohort studies.

BACKGROUND: The ε4 allele of the apolipoprotein E gene (APOE4) plays a role in neurodegeneration and in cardiovascular disease, but findings on its association with mortality are inconsistent. We aimed to examine the association between APOE4 and mortality, and the role of dementia in this association. METHODS: In this pooled analysis, data on White participants aged 45-90 years who underwent APOE genotyping were drawn from two population-based cohorts: the Whitehall II study (UK), which began in 1985 and is ongoing, and the Three-City study (France), initiated in 1999 and ended in 2012. In the Three-City study, vital status was ascertained through linkage to the national registry of death Institut National de la Statistique des Études économiques, and dementia was ascertained via a neuropsychological evaluation and validation of diagnoses by an independent committee of neurologists and geriatricians. In the Whitehall II study, vital status was ascertained through linkage to the UK national mortality register, and dementia cases were ascertained by linkage to three national registers. Participants with prevalent dementia at baseline and participants missing an APOE genotype were excluded from analyses. Cox regression proportional hazard models were used to examine the association of APOE4 with all-cause, cardiovascular, and cancer mortality. The role of dementia in the association between APOE4 status and mortality was examined by excluding participants who developed dementia during follow-up from the analyses. An illness-death model was then used to examine the role of incident dementia in these associations. FINDINGS: 14 091 participants (8492 from the Three-City study and 5599 from the Whitehall II study; 6668 [47%] of participants were women and 7423 [53%] were men), with a median follow-up of 15·4 years (IQR 10·6-21·2), were included in the analyses. Of these participants, APOE4 carriers (3264 [23%] of the cohort carried at least one ε4 allele) had a higher risk of all-cause mortality compared with non-carriers, with hazard ratios (HR) of 1·16 (95% CI 1·07-1·26) for heterozygotes and 1·59 (1·24-2·06) for homozygotes. Compared with APOE3 homozygotes, higher cardiovascular mortality was observed in APOE4 carriers, with a HR of 1·23 (1·01-1·50) for heterozygotes, and no association was found between APOE4 and cancer mortality. Excluding cases of incident dementia over the follow-up resulted in attenuated associations with mortality in homozygotes but not in heterozygotes. The illness-death model indicated that the higher mortality risk in APOE4 carriers was not solely attributable to dementia. INTERPRETATION: We found a robust association between APOE4 and all-cause and cardiovascular mortality but not cancer mortality. Dementia explained a significant proportion of the association with all-cause mortality for APOE4 homozygotes, while non-dementia factors, such as cardiovascular disease mortality, are likely to play a role in shaping mortality outcomes in APOE4 heterozygotes. FUNDING: National Institutes of Health. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Measures of fragmentation of rest activity patterns: mathematical properties and interpretability based on accelerometer real life data.

Accelerometers, devices that measure body movements, have become valuable tools for studying the fragmentation of rest-activity patterns, a core circadian rhythm dimension, using metrics such as inter-daily stability (IS), intradaily variability (IV), transition probability (TP), and self-similarity parameter (named α ). However, their use remains mainly empirical. Therefore, we investigated the mathematical properties and interpretability of rest-activity fragmentation metrics by providing mathematical proofs for the ranges of IS and IV, proposing maximum likelihood and Bayesian estimators for TP, introducing the activity balance index (ABI) metric, a transformation of α , and describing distributions of these metrics in real-life setting. Analysis of accelerometer data from 2,859 individuals (age=60-83 years, 21.1% women) from the Whitehall II cohort (UK) shows modest correlations between the metrics, except for ABI and α . Sociodemographic (age, sex, education, employment status) and clinical (body mass index (BMI), and number of morbidities) factors were associated with these metrics, with differences observed according to metrics. For example, a difference of 5 units in BMI was associated with all metrics (differences ranging between -0.261 (95% CI -0.302, -0.220) to 0.228 (0.18, 0.268) for standardised TP rest to activity during the awake period and TP activity to rest during the awake period, respectively). These results reinforce the value of these rest-activity fragmentation metrics in epidemiological and clinical studies to examine their role for health. This paper expands on a set of methods that have previously demonstrated empirical value, improves the theoretical foundation for these methods, and evaluates their empirical use in a large dataset.

Association between changes in cardiovascular health and the risk of multimorbidity: community-based cohort studies in the UK and Finland.

Background: Better cardiovascular health is associated with lower risk of various chronic diseases, but its association with multimorbidity is poorly understood. We aimed to examine whether change in cardiovascular health is associated with multimorbidity risk. Methods: The primary analysis was conducted in the Whitehall II multiwave prospective cohort study (UK) and the validation analysis in the Finnish Public Sector cohort study (Finland). Change in cardiovascular health was assessed using the American Heart Association Life's Simple 7 (LS7) and Life's Essential 8 (LE8) at baseline and re-assessments, using objective measures in Whitehall II and self-reports and pharmacy claims in the Finnish Public Sector cohort study, respectively. Multimorbidity was defined as the presence of two or more of 12 chronic diseases during follow-up. We estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox's proportional hazard models with age as time scale, adjusting for sex, education, occupation, marital status, and ethnicity. Findings: In the primary analysis among 9715 participants, mean age was 44.8 (standard deviation 6.0) years and 67.6% participants were men at baseline. During the median follow-up of 31.4 (interquartile range 26.8-32.3) years, 2751 participants developed multimorbidity. The hazard of multimorbidity decreased by 8% (HR 0.92, 95% CI 0.88-0.96) per ideal LS7 metric increment over 5 years and by 14% (HR 0.86, 95% CI 0.80-0.93) per ten points increase in LE8 score over 10 years. These findings were replicated in the validation analysis among 75,377 participants in terms of 4-year change in cardiovascular health. Interpretation: Improvement in cardiovascular health was associated with lower multimorbidity risk in two community-based cohort studies. Interventions improving cardiovascular health of the community may contribute to multimorbidity prevention. Funding: None.

Role of cardiovascular health factors in mediating social inequalities in the incidence of dementia in the UK: two prospective, population-based cohort studies.

Background: The contribution of modifiable risk factors to social inequalities in dementia, observed in longitudinal studies, remains unclear. We aimed to quantify the role of cardiovascular health factors, assessed using Life's Essential 8 (LE8) score, in mediating social inequalities in incidence of dementia and, for comparison, in incidence of stroke, coronary heart disease, and mortality. Methods: In this prospective, population-based cohort study, we collected data from the UK Whitehall II Study and UK Biobank databases. Participants were included if data were available on SEP, outcomes and LE8 (smoking, physical activity, diet, body mass index, blood pressure, fasting blood glucose, lipid levels, sleep duration). The primary outcome was incident dementia and secondary outcomes were stroke, coronary heart disease, and mortality. Outcomes were derived from electronic healthcare records. Socioeconomic position (SEP) was measured by occupation in Whitehall II and education in UK Biobank. Counterfactual mediation analysis was used to quantify the extent to which LE8 score explained the associations of SEP with all outcomes. Analyses involved Cox regression, accelerated failure time models, and linear regression; and were adjusted for age, sex, and ethnicity. Findings: Between 10.09.1985 and 29.03.1988, a total of 9688 participants (mean age ± SD 44.9 ± 6.0; 67% men) from the Whitehall II study, and between 19.12.2006 and 01.10.2010, 278,215 participants (mean age ± SD 56.0 ± 8.1; 47% men) from the UK Biobank were included. There were 606 and 4649 incident dementia cases over a median (interquartile range) follow-up of 31.7 (31.1-32.7) and 13.5 (12.7-14.1) years respectively in Whitehall II and UK Biobank. In Whitehall II, the hazard ratio was 1.85 [95% CI 1.42, 2.32] for the total effect of SEP on dementia and 1.20 [1.12, 1.28] for the indirect effect via the LE8, the proportion mediated being 36%. In UK Biobank, the total effect of SEP on dementia was 1.65 [1.54, 1.78]; the indirect effect was 1.11 [1.09, 1.12], and the proportion mediated was 24%. The proportions mediated for stroke, coronary heart disease, and mortality were higher, ranging between 34% and 63% in Whitehall II and between 36% and 50% in UK Biobank. Interpretation: In two well-characterised cohort studies, up to one third of the social inequalities in incidence of dementia was attributable to cardiovascular health factors. Promotion of cardiovascular health in midlife may contribute to reducing social inequalities in risk of dementia, in addition to cardiovascular diseases and all-cause mortality. This study used adult measures of SEP, further research is warranted using lifecourse measures of SEP. Funding: NIH (RF1AG062553).

Cross-sectional and longitudinal associations of obesity with disability between age 50 and 90 in the SHARE study.

BACKGROUND: Obesity is associated with disability but whether age and ageing modify this association remains unclear. We examined whether this association changes between 50 and 90 years, and whether change in disability rates over 14 years differs by body mass index (BMI) categories. METHODS: BMI and ADL-disability data on 28,453 individuals from 6 waves (2004-2018, SHARE study) were used to examine the cross-sectional absolute and relative associations, extracted at age 50, 60, 70, 80, and 90 years using logistic mixed models. Then baseline BMI and change in disability rates over 14-years were examined using logistic-mixed models. RESULTS: At age 50, the probabilities of ADL disability in individuals with BMI 30-34.9 and ≥35 kg/m² were 0.07 (0.06, 0.09) and 0.11 (0.09, 0.12), increasing to 0.47 (0.44, 0.50) and 0.55 (0.50, 0.60) at age 90; the increase in both these groups was greater than that in the normal-weight group (p for increase with age<0.001). On the relative scale the OR at age 50 in these obesity groups was 2.37 (1.79, 3.13) and 5.03 (3.38, 7.48), decreasing to 1.51 (1.20, 1.89) and 2.19 (1.50, 3.21) at age 90; p for decrease with age=0.05 and 0.02 respectively. The 14-year increase in probability of disability was greatest in those with BMI≥35 kg/m² at age 50, 60, and 70 at baseline: differences in increase compared to normal weight were 0.08 (0.02, 0.14), 0.11 (0.07, 0.15), and 0.09 (0.02, 0.16) respectively. CONCLUSIONS: ADL disability is increasingly prevalent with age in individuals with obesity. Relative measures of change obscure the association between obesity and disability due to age-related increase in disability rates in all groups.

Age at cardiovascular disease onset, dementia risk, and the role of lifestyle factors.

INTRODUCTION: We first examined the role of age at cardiovascular disease (CVD) onset for incident dementia, and then examined whether lifestyle factors at guideline-recommended levels in individuals with CVD mitigates dementia risk. METHODS: We used population-based data (Whitehall II: n = 10,308/baseline 1985-1988/examinations every 4-5 years). Lifestyle factors (non-smoking, body mass index [BMI], physical activity, diet) were extracted post-CVD. RESULTS: Over a median of 31.6 years, 3275 (32.1%) developed CVD. At age 70, risk of dementia was higher in individuals with CVD onset before (hazard ratio [HR] of incident dementia for participants with CVD before age 60, using participants without CVD at age 70 as the reference: 1.56, 95% confidence interal [CI] 1.18-2.08) but not after 60 years. In participants with CVD, a greater number of lifestyle factors at recommended levels post-CVD was associated with a lower dementia risk (per lifestyle factor at recommended level HR: 0.73, 95% CI 0.59-0.92). DISCUSSION: Our results suggest that early onset CVD is associated with a higher dementia risk at older ages. In those with CVD, the dementia risk was lower if lifestyle factors are at recommended levels following CVD diagnosis. HIGHLIGHTS: CVD in midlife but not in late life is associated with a higher risk of dementia. Dementia risk in CVD patients is lower if their lifestyle factors are at recommended levels. These findings provide evidence to promote CVD prevention in midlife or earlier. Study findings also show the importance of a healthy lifestyle in those with CVD.

Is metabolic-healthy obesity associated with risk of dementia? An age-stratified analysis of the Whitehall II cohort study.

BACKGROUND: Metabolically healthy obesity is hypothesized to be a benign condition but whether this is the case for dementia remains debated. We examined the role of age at assessment of metabolic-obesity phenotypes in associations with incident dementia. METHODS: Obesity (body mass index ≥ 30 kg/m2) and poor metabolic health (≥ 2 of elevated serum triglycerides, low HDL-C, elevated blood pressure, and elevated serum fasting glucose) were used to define four metabolic-obesity phenotypes (metabolically healthy (MHNO) and unhealthy non-obesity (MUNO), metabolically healthy (MHO) and unhealthy obesity (MUO)) at < 60, 60 to < 70, and ≥ 70 years using 6 waves of data from the Whitehall II study and their associations with incident dementia was examined using Cox regression. RESULTS: Analyses with exposures measured < 60, 60 to < 70, and ≥ 70 years involved 410 (5.8%), 379 (5.6%), and 262 (7.4%) incident dementia cases over a median follow-up of 20.8, 10.3, and 4.2 years respectively. In analyses of individual components, obesity before 60 years (HR 1.41, 95% CI: [1.08, 1.85]) but not at older ages was associated with dementia; unhealthy metabolic status when present < 60 years (HR 1.33, 95% CI: [1.08, 1.62]) and 60 to < 70 years (HR 1.32, 95% CI: [1.07, 1.62]) was associated with dementia. Compared to the metabolically healthy non-obesity group, the risk of dementia was higher in those with metabolically healthy obesity before 60 years (1.69; 95% CI: [1.16, 2.45]); this was not the case when metabolic-obesity phenotype was present at 60 to < 70 years or ≥ 70 years. Analyses at older ages were on smaller numbers due to death and drop-out but inverse probability weighting to account for missing data yielded similar results. CONCLUSIONS: Individuals with metabolically healthy obesity before age 60 had a higher risk of incident dementia over a 27-year follow-up; the excess risk dissipates when metabolic health and obesity are measured after 70 years.

Measures of fragmentation of rest activity patterns: mathematical properties and interpretability based on accelerometer real life data.

Accelerometers, devices that measure body movements, have become valuable tools for studying the fragmentation of rest-activity patterns, a core circadian rhythm dimension, using metrics such as inter-daily stability (IS), intradaily variability (IV), transition probability (TP), and self-similarity parameter (named α). However, their use remains mainly empirical. Therefore, we investigated the mathematical properties and interpretability of rest-activity fragmentation metrics by providing mathematical proofs for the ranges of IS and IV, proposing maximum likelihood and Bayesian estimators for TP, introducing the activity balance index metric, an adaptation of α, and describing distributions of these metrics in real-life setting. Analysis of accelerometer data from 2,859 individuals (age=60-83 years, 21.1% women) from the Whitehall II cohort (UK) shows modest correlations between the metrics, except for ABI and α. Sociodemographic (age, sex, education, employment status) and clinical (body mass index (BMI), and number of morbidities) factors were associated with these metrics, with differences observed according to metrics. For example, a difference of 5 units in BMI was associated with all metrics (differences ranging between -0.261 (95% CI -0.302, -0.220) to 0.228 (0.18, 0.268) for standardised TP rest to activity during the awake period and TP activity to rest during the awake period, respectively). These results reinforce the value of these rest-activity fragmentation metrics in epidemiological and clinical studies to examine their role for health. This paper expands on a set of methods that have previously demonstrated empirical value, improves the theoretical foundation for these methods, and evaluates their empirical worth in a large dataset.

Is the number of ideal cardiovascular health metrics in midlife associated with lower risk of cancer? Evidence from 3 European prospective cohorts.

BACKGROUND: Primordial prevention may be a relevant strategy for the prevention of cancer. Given the commonality of risk factors and mechanisms between cancer and cardiovascular disease, we examined the associations between the number of ideal cardiovascular health metrics in midlife and incident cancer. METHODS: In 3 European cohorts (NutriNet-Santé and GAZEL, France; Whitehall II, United Kingdom), the number of ideal cardiovascular health metrics was determined at baseline (range 0-7). Follow-up for cancer events was until October 2020 (NutriNet-Santé), March 2017 (Whitehall II) and December 2015 (GAZEL). Cox regression was conducted in each cohort, and results were thereafter pooled using a random-effects model. RESULTS: Data were available on 39 718 participants. A total of 16 237 were from NutriNet-Santé (mean age 51.3 yr; 28% men), 9418 were from Whitehall II (mean age 44.8 yr; 68% men) and 14 063 were from GAZEL (mean age 45.2 yr; 75% men). The median follow-up was 8.1 years in NutriNet-Santé, 29.6 years in Whitehall II and 24.8 years in GAZEL, and yielded a total of 4889 cancer events. A greater number of ideal cardiovascular health metrics was associated with a lower overall cancer risk in each cohort, with an aggregate hazard ratio (HR) per 1 increment in number of ideal metrics of 0.91 (95% confidence interval [CI] 0.88-0.93). This association remained after removal of the smoking metric (aggregate HR per unit increment in number of ideal metrics: 0.94, 95% CI 0.90-0.97), and site-specific analysis demonstrated a significant association with lung cancer. INTERPRETATION: A greater number of ideal cardiovascular health metrics in midlife was associated with lower cancer risk, notably lung cancer. Primordial prevention of cardiovascular risk factors in midlife may be a complementary strategy to prevent the onset of cancer.

Role of age and sex in the association between BMI and functional limitations in stroke patients: Cross-sectional analysis in three European and US cohorts.

BACKGROUND: A U- or J-shaped association between BMI and different post-stroke outcomes is suggested. Thus, the aim is to evaluate the association between BMI with ADL, IADL and mobility limitations in the ageing post-stroke population at different ages, as well as the differences in this association by sex. METHODS: A total of 5,468 participants with stroke and 21,872 without stroke over 50 years of age were assessed for the number of limitations in basic or instrumental activities of daily living (ADL/IADL) as well as mobility tasks. The association between BMI at the interview (continuous time-dependent variable) and the level of limitations was assessed using a linear mixed model stratified by sex and stroke status. RESULTS: The association between BMI and ADL/IADL and mobility limitations were found to be significant in both men and women regardless of stroke status (p<0.001 for all). The association differs between those who have suffered a stroke and those who have not (p<0.001 for all). In ADL/IADL limitations, men with stroke showed a transition from an inverted J-shape to a U-shape association with age. In women, the BMI showed a less pronounced association between BMI and ADL/IADL limitations compared to men but with similar trends. A effect of sex was observed in the association between BMI and mobility, with women with and without stroke showing a linear association that differed from the inverted J-shaped or U-shaped association of men. CONCLUSION: Our results suggest that BMI is associated with limitations in ADL, IADL and mobility in stroke patients. In addition, this association differs between men and women and is also influenced by age.

BPSD Patterns in Patients With Severe Neuropsychiatric Disturbances: Insight From the RECAGE Study.

OBJECTIVE: Behavioral and psychological symptoms of dementia (BPSD) profiles vary depending on etiology in patients with mild-to-moderate BPSD. It is not known if similar differences exist in patients with severe BPSD. METHODS: We analyzed data collected at baseline in 398 patients with severe BPSD (NPI ≥ 32) and defined diagnosis of dementia (Alzheimer's disease [AD] 297; frontotemporal dementia [FTD] 39; Lewy body disease/Parkinsonian dementia [LBD/PD] 31; and vascular dementia [VD] 31) included in the European multicenter cohort RECAGE. RESULTS: Mean total NPI was 52.11 (18.55). LBD/PD patients demonstrated more hallucinations, more anxiety and more delusions than patients with other dementia. FTD patients had less delusions and more disinhibition than patients with other neurodegenerative disorders. These profiles overlapped partially with those reported in the literature in patients with less severe symptoms. CONCLUSION: Patients with severe BPSD display different and specific profiles of neuropsychiatric symptoms depending on dementia etiology.

Change in lipids before onset of dementia, coronary heart disease, and mortality: A 28-year follow-up Whitehall II prospective cohort study.

INTRODUCTION: The association of lipids with dementia remains a subject of debate. Using data from 7,672 participants of the Whitehall II prospective cohort study, we examined whether timing of exposure, length of follow-up, or sex modifies this association. METHODS: Twelve markers of lipid levels were measured from fasting blood and eight among them a further five times. We performed time-to-event as well as trajectory analyses. RESULTS: No associations were observed in men; in women most lipids were associated with the risk of dementia, but only for events occurring after the first 20 years of follow-up. Differences in lipid trajectories in men emerged only in the years immediately before diagnosis whereas in women total cholesterol (TC), LDL-cholesterol (LDL-C), non-HDL-cholesterol (non-HDL-C), TC/HDL-C, and LDL-C/HDL-C were higher in midlife among dementia cases before declining progressively. DISCUSSION: Abnormal lipid levels in midlife seem to be associated with a higher risk of dementia in women.

Association between ATN profiles and mortality in a clinical cohort of patients with cognitive disorders.

BACKGROUND: Alzheimer's disease (AD) is the 5th leading cause of death in people 65 years and older. The ATN classification reflects a biological definition of AD pathology with markers of Aß deposition (A), pathologic tau (T), and neurodegeneration (N). Little is known about the relationship between ATN status and the risk of mortality, leading us to examine this association in a relatively large population of patients seen at a memory clinic for cognitive disorders. METHODS: Data were drawn from the BioCogBank Study, including patients seen for cognitive disorders in Lariboisiere Hospital (Paris, France), followed up to 15 years. All participants underwent a lumbar puncture for an assessment of the levels of CSF tau (tau), phosphorylated tau (p-tau181), and ß-amyloid 42 peptide (Aß42). Vital status on July 1, 2020, was recorded for each participant using the national mortality register. Individuals were categorized according to their ATN profiles based on CSF Aß42 or Aß42/40 ratio, p-tau181, and tau. Kaplan-Meier and multivariate Cox analyses were performed with A-T-N - participants as the reference using a short (5 years) and long follow-up (15 years). RESULTS: Of the 1353 patients in the study (mean age: 68 years old, 53% of women, mean MMSE score: 22.6), 262 died during the follow-up. At 5 years of follow-up, A-T-N + individuals had the highest risk of mortality in Kaplan-Meier and adjusted Cox analyses [HR (95% CI) = 2.93 (1.31-6.56)]. At 15 years of follow-up, patients in the AD spectrum had a higher mortality risk with a gradient effect for biomarker positivity: A-T + [HR = 1.63 (1.04-2.55)], A + T - [HR = 2.17 (1.44-3.26)], and A + T + individuals [HR = 2.38 (1.66-3.39)], compared to A-T-N - patients. Adjustments on potential confounders had little impact on these associations. CONCLUSION: This study shows ATN profiles to be associated with mortality in a relatively large patient cohort based on a memory clinic. Patients with isolated evidence of neurodegeneration had a higher mortality rate in the short follow-up, and patients with the AD profile had the highest mortality rate in the long follow-up.

Comparison of sex differences in cognitive function in older adults between high- and middle-income countries and the role of education: a population-based multicohort study.

BACKGROUND: The extent to which education explains variations in sex differences in cognitive function between countries at different levels of economic development is unknown. We examined the role of education in sex differences in four cognitive domains in high- and middle-income countries. METHODS: Analyses were based on 70,846 participants, aged 60 years and older, in cohort studies from a high-income (United States) and four middle-income countries (Mexico, Brazil, China, and India). We used weighted linear models to allow nationally-representative comparisons of sex differences in orientation, memory, attention, and fluency using the United States as the reference, before and after adjustment for education, and after stratification by education. RESULTS: Females had lower levels of education than males in all countries, particularly in India. Before adjustment for education, sex differences in orientation and attention in all middle-income countries, memory in Brazil, China, and India, and fluency in India were less favourable to females than in the United States (P < 0.010). For example, females outperformed males in memory in the United States (mean difference [male-female scores] = -0.26 standard deviations [95% CI -0.30, -0.22]) but not in China (0.15 [0.09, 0.21]) or India (0.16 [0.13, 0.19]). Adjustment for education attenuated these sex differences. In analyses stratified by education, there were minimal sex differences in the high education group in all countries. CONCLUSION: Education contributes to larger female disadvantages in cognitive function at older ages in middle-income countries compared with the United States. Gender equity in education is an important target to reduce sex disparities in cognitive function globally.

Identification of physical activity and sedentary behaviour dimensions that predict mortality risk in older adults: Development of a machine learning model in the Whitehall II accelerometer sub-study and external validation in the CoLaus study.

Background: Identification of new physical activity (PA) and sedentary behaviour (SB) features relevant for health at older age is important to diversify PA targets in guidelines, as older adults rarely adhere to current recommendations focusing on total duration. We aimed to identify accelerometer-derived dimensions of movement behaviours that predict mortality risk in older populations. Methods: We used data on 21 accelerometer-derived features of daily movement behaviours in 3991 participants of the UK-based Whitehall II accelerometer sub-study (25.8% women, 60-83 years, follow-up: 2012-2013 to 2021, mean = 8.3 years). A machine-learning procedure was used to identify core PA and SB features predicting mortality risk and derive a composite score. We estimated the added predictive value of the score compared to traditional sociodemographic, behavioural, and health-related risk factors. External validation in the Switzerland-based CoLaus study (N = 1329, 56.7% women, 60-86 years, follow-up: 2014-2017 to 2021, mean = 3.8 years) was conducted. Findings: In total, 11 features related to overall activity level, intensity distribution, bouts duration, frequency, and total duration of PA and SB, were identified as predictors of mortality in older adults and included in a composite score. Both in the derivation and validation cohorts, the score was associated with mortality (hazard ratio = 1.10 (95% confidence interval = 1.05-1.15) and 1.18 (1.10-1.26), respectively) and improved the predictive value of a model including traditional risk factors (increase in C-index = 0.007 (0.002-0.014) and 0.029 (0.002-0.055), respectively). Interpretation: The identified accelerometer-derived PA and SB features, beyond the currently recommended total duration, might be useful for screening of older adults at higher mortality risk and for diversifying PA and SB targets in older populations whose adherence to current guidelines is low. Funding: National Institute on Aging; UK Medical Research Council; British Heart Foundation; Wellcome Trust; French National Research Agency; GlaxoSmithKline; Lausanne Faculty of Biology and Medicine; Swiss National Science Foundation.

Trajectories of physical and mental functioning over 25 years before onset of frailty: results from the Whitehall II cohort study.

BACKGROUND: Research on frailty, a major contributor to heterogeneity in health, is undertaken on older adults although the processes leading to frailty are likely to begin earlier in the life course. Using repeat data spanning 25 years, we examined changes in physical and mental functioning before the onset of frailty, defined using Fried's frailty phenotype (FFP). METHODS: Functioning was measured using the Short-Form 36 General Health Survey (SF-36) on nine occasions from 1991 (age range 40-63 years) to 2015 (age range 63-85 years). The poorest of four FFP scores from 2002, 2007, 2012 and 2015 was used to classify participants as frail, pre-frail, or robust. We used linear mixed models with a backward timescale such that time 0 was the person-specific date of frailty classification for frail and pre-frail participants and the end of follow-up for robust participants. Analyses adjusted for socio-demographic factors, health behaviours, body mass index and multi-morbidity status were used to compare SF-36 physical (PCS) and mental (MCS) component summary scores over 25 years before time 0 as a function of FFP classification, with estimates extracted at time 0, -5, -10, -15, -20 and -25 years. We also used illness-death models to examine the prospective association between SF-36 component summary scores at age 50 and incident FFP-defined frailty. RESULTS: Among 7044 participants of the Whitehall II cohort study included in the analysis [29% female, mean age 49.7 (SD = 6.0) at baseline in 1991], 2055 (29%) participants remained robust, and 4476 (64%) became pre-frail and 513 (7%) frail during follow-up. Frail compared with robust participants had lower SF-36 scores at t = -25 before onset of frailty with a difference of 3.4 [95% confidence interval (CI) 1.6, 5.1] in PCS and 1.8 (-0.2, 3.8) in MCS. At t = 0, the differences increased to 11.5 (10.5, 12.5) and 9.1 (8.0, 10.2), respectively. The differences in SF-36 between the robust and pre-frail groups, although smaller [at t = 0, 1.7 (1.2, 2.2) in PCS and 4.0 (3.4, 4.5) in MCS], were already observed 20 and 25 years, respectively, before the onset of pre-frailty. Prospective analyses showed that at age 50, scores in the bottom quartiles of PCS [hazard ratio (HR) compared with the top quartile = 2.39, 95% CI 1.85, 3.07] and MCS [HR = 1.49 (1.15, 1.93)] were associated with a higher risk of FFP-defined frailty at older ages. CONCLUSIONS: Differences in trajectories of physical and mental functioning in individuals who developed physical frailty at older ages were observable 25 years before onset of FFP-defined frailty. These findings highlight the need for a life course approach in efforts to prevent frailty.

Association of physical activity, sedentary behaviour, and daylight exposure with sleep in an ageing population: findings from the Whitehall accelerometer sub-study.

BACKGROUND: Ageing is accompanied by changes in sleep, while poor sleep is suggested as a risk factor for several health outcomes. Non-pharmacological approaches have been proposed to improve sleep in elderly; their impact remains to be investigated. The aim of this study was to examine the independent day-to-day associations of physical behaviours and daylight exposure with sleep characteristics among older adults. METHODS: Data were drawn from 3942 participants (age range: 60-83 years; 27% women) from the Whitehall II accelerometer sub-study. Day-to-day associations of objectively-assessed daytime physical behaviours (sedentary behaviour, light-intensity physical activity (LIPA), moderate-to-vigorous physical activity (MVPA), mean acceleration, physical activity chronotype) and daylight exposure (proportion of waking window with light exposure > 1000 lx and light chronotype) with sleep characteristics were examined using mixed models. RESULTS: A 10%-increase in proportion of the waking period spent sedentary was associated with 5.12-minute (4.31, 5.92) later sleep onset and 1.76-minute shorter sleep duration (95%confidence interval: 0.86, 2.66). Similar increases in LIPA and MVPA were associated with 6.69 (5.67, 7.71) and 4.15 (2.49, 5.81) earlier sleep onset respectively and around 2-minute longer sleep duration (2.02 (0.87, 3.17) and 2.23 (0.36, 4.11), respectively), although the association was attenuated for MVPA after adjustment for daylight exposure (1.11 (- 0.84, 3.06)). A 3-hour later physical activity chronotype was associated with a 4.79-minute later sleep onset (4.15, 5.43) and 2.73-minute shorter sleep duration (1.99, 3.47). A 10%-increase in proportion of waking period exposed to light> 1000 lx was associated with 1.36-minute longer sleep (0.69, 2.03), independently from mean acceleration. Associations found for sleep duration were also evident for duration of the sleep windows with slightly larger effect size (for example, 3.60 (2.37, 4.82) minutes for 10%-increase in LIPA), resulting in associations with sleep efficiency in the opposite direction (for example, - 0.29% (- 0.42, - 0.16) for 10%-increase in LIPA). Overall, associations were stronger for women than for men. CONCLUSIONS: In this study, higher levels of physical activity and daylight exposure were associated with slightly longer sleep in older adults. Given the small effect sizes of the associations, increased physical activity and daylight exposure might not be enough to improve sleep.

The role of age, sex, and multimorbidity in 7-year change in prevalence of limitations in adults 60-94 years.

Recent data suggest a temporal trend in decline in functional limitations in older adults but whether this trend extends to the period after the 8th decade of life remains unclear. We examined change in prevalence of limitations in activities and instrumental activities of daily living (ADL and IADL) between 2008 and 2015 among adults of 60-94 years and the role of age, sex, multimorbidity; we also examined changes in severity of limitations. Data were drawn from two nationally representative surveys in 2008 (n = 13,593) and 2015 (n = 13,267). The 6-item scales of ADL and IADL were each categorized first as ≥ 1 limitations, and then to examine severity as 0, 1-2, and ≥ 3 limitations. Weighted logistic and multinomial regressions were used to estimate prevalence of limitations; the difference between surveys were extracted every 5 years between 60 and 90 years. The prevalence of ≥ 1 ADL declined between 2008 and 2015, from age 75 (- 1.2%; 95%CI = - 2.0, - 0.4%) to age 90 (- 8.8%; 95%CI = - 12.7, - 5.0%). This decline was more pronounced in men than women (p-value for interaction = 0.05) and observed primarily in those with multimorbidity (p-value for interaction = 0.06). Up to 2 ADL limitations declined from age 75 (- 1.0; 95%CI = - 1.7, - 0.3) to 90 (- 6.7; 95%CI = - 9.9, - 3.6) and from age 80 (- 0.6; 95%CI = - 1.1, 0.1) to 85 (- 1.2; 95%CI = - 2.2, - 0.1) for ≥ 3 ADL limitations. There was no substantial change in IADL limitations. These data from a high-income country with universal health care show improvement in ADL even after the 8th decade of life despite increase in multimorbidity.