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.

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.

Do subjective components of disease activity contribute to heterogeneity in opioid prescriptions in inflammatory rheumatic diseases? Results from ESPOIR and DESIR cohorts.

OBJECTIVES: To determine whether subjective components of disease activity are associated with heterogeneity in opioid prescription in inflammatory rheumatic diseases (IRDs) after accounting for objective inflammatory markers. METHODS: Data from two prospective observational cohorts of early IRDs (ESPOIR for rheumatoid arthritis (RA) and DESIR for spondyloarthritis (SpA)) were included. Opioid prescription duration (converted to monthly binary opioid prescription), disease activity (Disease activity score 28 (DAS28) for RA; Axial spondyloarthritis disease activity score-C-reactive protein (ASDAS-CRP) for SpA) and its components were measured respectively at 13 and 9 occasions spanning 10- and 6-years of follow-up. Group-based trajectory modelling defined opioid-prescription trajectories and mixed-models characterised the evolution of disease activity and its subjective components by opioid-prescription trajectories. RESULTS: Four distinct opioid-prescription trajectories: no/low (60.5% and 54.3%), declining (14.7% and 15.8%), augmenting (11.9% and 10.7%), and persistent (12.9% and 19.1%) were identified in RA and SpA respectively (60% were prescribed opioids at least once). Those with regular opioid prescriptions (up to 30%) are often older, less educated, have higher BMI and worse disease. No/low trajectory was the reference for examining evolution of disease activity and subjective components (n=810 RA, n=679 SpA). In IRDs, consistently higher disease activity throughout follow-up were seen with persistent (DAS28(ß=0.4-0.8); ASDAS-CRP(ß=0.4-0.6)), and augmenting (DAS28(ß=0.2-0.5); ASDAS-CRP(ß=0.3-0.6)) trajectories and until 3- or 4-years of follow-up (DAS28(ß=0.3-0.4); ASDAS-CRP(ß=0.2-0.3)) with declining trajectory. Likewise, despite accounting for objective inflammation, subjective components had worse scores over follow-up in augmenting and persistent trajectory. CONCLUSIONS: Non-inflammatory pain mechanisms amplify subjective outcomes, thus, worsening composite measures like disease activity.

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.

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.

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.

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.

Association of sleep duration at age 50, 60, and 70 years with risk of multimorbidity in the UK: 25-year follow-up of the Whitehall II cohort study.

BACKGROUND: Sleep duration has been shown to be associated with individual chronic diseases but its association with multimorbidity, common in older adults, remains poorly understood. We examined whether sleep duration is associated with incidence of a first chronic disease, subsequent multimorbidity and mortality using data spanning 25 years. METHODS AND FINDINGS: Data were drawn from the prospective Whitehall II cohort study, established in 1985 on 10,308 persons employed in the London offices of the British civil service. Self-reported sleep duration was measured 6 times between 1985 and 2016, and data on sleep duration was extracted at age 50 (mean age (standard deviation) = 50.6 (2.6)), 60 (60.3 (2.2)), and 70 (69.2 (1.9)). Incidence of multimorbidity was defined as having 2 or more of 13 chronic diseases, follow-up up to March 2019. Cox regression, separate analyses at each age, was used to examine associations of sleep duration at age 50, 60, and 70 with incident multimorbidity. Multistate models were used to examine the association of sleep duration at age 50 with onset of a first chronic disease, progression to incident multimorbidity, and death. Analyses were adjusted for sociodemographic, behavioral, and health-related factors. A total of 7,864 (32.5% women) participants free of multimorbidity had data on sleep duration at age 50; 544 (6.9%) reported sleeping ≤5 hours, 2,562 (32.6%) 6 hours, 3,589 (45.6%) 7 hours, 1,092 (13.9%) 8 hours, and 77 (1.0%) ≥9 hours. Compared to 7-hour sleep, sleep duration ≤5 hours was associated with higher multimorbidity risk (hazard ratio: 1.30, 95% confidence interval = 1.12 to 1.50; p < 0.001). This was also the case for short sleep duration at age 60 (1.32, 1.13 to 1.55; p < 0.001) and 70 (1.40, 1.16 to 1.68; p < 0.001). Sleep duration ≥9 hours at age 60 (1.54, 1.15 to 2.06; p = 0.003) and 70 (1.51, 1.10 to 2.08; p = 0.01) but not 50 (1.39, 0.98 to 1.96; p = 0.07) was associated with incident multimorbidity. Among 7,217 participants free of chronic disease at age 50 (mean follow-up = 25.2 years), 4,446 developed a first chronic disease, 2,297 progressed to multimorbidity, and 787 subsequently died. Compared to 7-hour sleep, sleeping ≤5 hours at age 50 was associated with an increased risk of a first chronic disease (1.20, 1.06 to 1.35; p = 0.003) and, among those who developed a first disease, with subsequent multimorbidity (1.21, 1.03 to 1.42; p = 0.02). Sleep duration ≥9 hours was not associated with these transitions. No association was found between sleep duration and mortality among those with existing chronic diseases. The study limitations include the small number of cases in the long sleep category, not allowing conclusions to be drawn for this category, the self-reported nature of sleep data, the potential for reverse causality that could arise from undiagnosed conditions at sleep measures, and the small proportion of non-white participants, limiting generalization of findings. CONCLUSIONS: In this study, we observed short sleep duration to be associated with risk of chronic disease and subsequent multimorbidity but not with progression to death. There was no robust evidence of an increased risk of chronic disease among those with long sleep duration at age 50. Our findings suggest an association between short sleep duration and multimorbidity.

Contribution of smoking towards the association between socioeconomic position and dementia: 32-year follow-up of the Whitehall II prospective cohort study.

Background: There is consistent evidence of social inequalities in dementia but the mechanisms underlying this association remain unclear. We examined the role of smoking in midlife in socioeconomic differences in dementia at older ages. Methods: Analyses were based on 9951 (67% men) participants, median age 44.3 [IQR=39.6, 50.3] years at baseline in 1985-1988, from the Whitehall II cohort study. Socioeconomic position (SEP) and smoking (smoking status (current, ex-, never-smoker), pack years of smoking, and smoking history score (combining status and pack-years)) were measured at baseline. Counterfactual mediation analysis was used to examine the contribution of smoking to the association between SEP and dementia. Findings: During a median follow-up of 31.6 (IQR 31.1, 32.6) years, 628 participants were diagnosed with dementia and 2110 died. Analyses adjusted for age, sex, ethnicity, education, and SEP showed smokers (hazard ratio [HR] 1.36 [95% CI 1.10-1.68]) but not ex-smokers (HR 0.95 [95% CI 0.79-1.14]) to have a higher risk of dementia compared to never-smokers; similar results for smoking were obtained for pack-years of smoking and smoking history score. Mediation analysis showed low SEP to be associated with higher risk of dementia (HRs between 1.97 and 2.02, depending on the measure of smoking in the model); estimate for the mediation effect was 16% for smoking status (Indirect Effect HR 1.09 [95% CI 1.03-1.15]), 7% for pack-years of smoking (Indirect Effect HR 1.03 [95% CI 1.01-1.06]) and 11% for smoking history score (Indirect Effect HR 1.06 [95% CI 1.02-1.10]). Interpretation: Our findings suggest that part of the social inequalities in dementia is mediated by smoking. Funding: NIH.

Circulating serum metabolites as predictors of dementia: a machine learning approach in a 21-year follow-up of the Whitehall II cohort study.

BACKGROUND: Age is the strongest risk factor for dementia and there is considerable interest in identifying scalable, blood-based biomarkers in predicting dementia. We examined the role of midlife serum metabolites using a machine learning approach and determined whether the selected metabolites improved prediction accuracy beyond the effect of age. METHODS: Five thousand three hundred seventy-four participants from the Whitehall II study, mean age 55.8 (standard deviation (SD) 6.0) years in 1997-1999 when 233 metabolites were quantified using nuclear magnetic resonance metabolomics. Participants were followed for a median 21.0 (IQR 20.4, 21.7) years for clinically-diagnosed dementia (N=329). Elastic net penalized Cox regression with 100 repetitions of nested cross-validation was used to select models that improved prediction accuracy for incident dementia compared to an age-only model. Risk scores reflecting the frequency with which predictors appeared in the selected models were constructed, and their predictive accuracy was examined using Royston's R2, Akaike's information criterion, sensitivity, specificity, C-statistic and calibration. RESULTS: Sixteen of the 100 models had a better c-statistic compared to an age-only model and 15 metabolites were selected at least once in all 16 models with glucose present in all models. Five risk scores, reflecting the frequency of selection of metabolites, and a 1-SD increment in all five risk scores was associated with higher dementia risk (HR between 3.13 and 3.26). Three of these, constituted of 4, 5 and 15 metabolites, had better prediction accuracy (c-statistic from 0.788 to 0.796) compared to an age-only model (c-statistic 0.780), all p<0.05. CONCLUSIONS: Although there was robust evidence for the role of glucose in dementia, metabolites measured in midlife made only a modest contribution to dementia prediction once age was taken into account.

Pre-stroke Disability and Long-Term Functional Limitations in Stroke Survivors: Findings From More of 12 Years of Follow-Up Across Three International Surveys of Aging.

Background: Almost 50% of the post-stroke disabled population already have a premorbid disability before stroke. These patients may be offered a different care pathway in the acute and subacute phase than those without pre-morbid disability. Therefore, the aim of this study was to assess the association of the severity of premorbid disability with change of limitations in basic and instrumental activities of daily living (ADL/IADL) 1 year after stroke and over the following decade. Methods: Among 3,432 participants from HRS, SHARE and ELSA cohorts with a first stroke, ADL/IADL limitations were measured at 1-2 years prior to stroke, at 1 year post-stroke, and during the chronic phase. Modified Ranking Scale (P-mRS) was used to categorize the participants by level of premorbid disability (1-2 years pre-stroke). Change in ADL/IADL limitations by P-mRS level (0-1, 2-3, and 4-5) was assessed using a piecewise linear mixed model with a breakpoint set at 1 year post-stroke, stratified by median age groups. Results: Increase in ADL limitations at 1 year post-stroke was less pronounced in P-mRS ≥2 (p < 0.005). After years of relative stability, limitations of ADL increased for all P-mRS levels (p = 0.003). In those aged ≥75 years at stroke event, the increase was similar irrespective of P-mRS (p = 0.090). There were no significant differences in IADL trajectories between P-mRS levels (p ≥ 0.127). Conclusion: These results suggest similar trajectories of functional limitations between P-mRS levels up to 9 years post-stroke, highlighting the possible benefit of including patients with pre-morbid disability to certain treatments during the acute phase.

Association of APOE ε4 with cerebral gray matter volumes in non-demented older adults: The MEMENTO cohort study.

Data on 2,045 non-demented individuals with memory complaints were drawn from the Memento cohort study to examine the association between Apolipoprotein E ε4 allele (APOE4) and regional brain gray matter volumes. Linear regression was used to examine the association of APOE4 and measures of regional gray matter volumes in cross-sectional analysis and change therein using longitudinal analyses based on two brain MRI performed at baseline and at two-year follow-up. Overall, in analyses adjusted for age, sex, and intracranial volume, the presence of APOE4 was associated with lower total gray matter volume at baseline and with a higher atrophy rate over the follow-up. The hippocampus and entorhinal cortex were the two gray matter regions most associated with APOE4. Further adjustment for cardiovascular risk factors had little impact on these associations. There was an interaction between age, APOE4 status and total brain volume atrophy rate, with evidence of an earlier age at onset of atrophy in hippocampal volume in APOE4 carriers compared to non-carriers. Those results are in accordance with the role of medial temporal structures in the greater risk of dementia observed in people carrying the APOE4 allele.

Long-Term Evolution of Functional Limitations in Stroke Survivors Compared With Stroke-Free Controls: Findings From 15 Years of Follow-Up Across 3 International Surveys of Aging.

BACKGROUND AND PURPOSE: In the chronic phase 2 to 5 years poststroke, limitations in activities of daily living (ADL) and instrumental ADL (IADL) initially plateau before steady increasing. However, the impact of age and differences in initial levels of disability on the evolution of these limitations remains unclear. As such, this study aims to evaluate differences in long-term evolution of ADL/IADL limitations between stroke survivors and stroke-free population, and how limitations differ by initial level of disability for stroke survivors. METHODS: Thirty-three thousand six hundred sixty participants (5610 first-ever stroke cases with no recurrence during follow-up and 28 050 stroke-free controls) aged ≥50 from the Health and Retirement Study, Survey of Health, Ageing and Retirement in Europe, and English Longitudinal Study of Ageing were assessed for number of ADL/IADL limitations during the poststroke chronic phase (for cases) and over follow-up years 1996 to 2018 (for controls). Three thousand seven hundred eighteen stroke cases were additionally categorized by disability level using the modified Rankin Scale score of 1 to 2 years poststroke. Evolution of ADL/IADL limitations was assessed in stroke cases and controls and by modified Rankin Scale score (0-1, 2-3, 4-5) using linear mixed models. Models were stratified by age group (50-74 and ≥75 years) and adjusted for baseline characteristics, health behaviors, BMI, and comorbidities. RESULTS: Findings showed relative stability of ADL/IADL limitations during 3 to 6 years poststroke followed by an increase for both populations, which was faster for younger stroke cases, suggesting a differential age-effect (P<0.001). Disability level at 1 to 2 years poststroke influenced the evolution of limitations over time, especially for severe disability (modified Rankin Scale score, 4-5) associated with a reduction in limitations at 5 to 6 years poststroke. CONCLUSIONS: Our findings showed that during the poststroke chronic phase functional limitations first plateau and then increase and the evolution differs by disability severity. These results highlight the importance of adaptive long-term health and social care measures for stroke survivors.

How Selection Over Time Contributes to the Inconsistency of the Association Between Sex/Gender and Cognitive Decline Across Cognitive Aging Cohorts.

The association between sex/gender and aging-related cognitive decline remains poorly understood because of inconsistencies in findings. Such heterogeneity could be attributable to the cognitive functions studied and study population characteristics, but also to differential selection by dropout and death between men and women. We aimed to evaluate the impact of selection by dropout and death on the association between sex/gender and cognitive decline. We first compared the statistical methods most frequently used for longitudinal data, targeting either population estimands (marginal models fitted by generalized estimating equations) or subject-specific estimands (mixed/joint models fitted by likelihood maximization) in 8 studies of aging: 6 population-based studies (the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) Study (1996-2009), Personnes Âgées QUID (PAQUID; 1988-2014), the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study (2003-2016), the Three-City Study (Bordeaux only; 1999-2016), the Washington Heights-Inwood Community Aging Project (WHICAP; 1992-2017), and the Whitehall II Study (2007-2016)) and 2 clinic-based studies (the Alzheimer's Disease Neuroimaging Initiative (ADNI; 2004-2017) and a nationwide French cohort study, MEMENTO (2011-2016)). We illustrate differences in the estimands of the association between sex/gender and cognitive decline in selected examples and highlight the critical role of differential selection by dropout and death. Using the same estimand, we then contrast the sex/gender-cognitive decline associations across cohorts and cognitive measures suggesting a residual differential sex/gender association depending on the targeted cognitive measure (memory or animal fluency) and the initial cohort selection. We recommend focusing on subject-specific estimands in the living population for assessing sex/gender differences while handling differential selection over time.

Socio-demographic determinants in the evolution of pain in inflammatory rheumatic diseases: results from ESPOIR and DESIR cohorts.

OBJECTIVE: To determine whether socio-demographic factors are associated with heterogeneity in pain evolution in inflammatory rheumatic diseases (IRDs) after accounting for disease-specific characteristics in a system with universal health care. METHODS: This analysis included the data from two prospective observational cohorts of early IRDs (ESPOIR for early RA and DESIR for early SpA). Data on pain was measured, respectively, on 13 and 9 occasions spanning 10 and 6 years of follow-up using the Short-Form 36 bodily pain score for 810 participants of ESPOIR, and 679 participants of DESIR. Linear mixed models were used to characterize differences in pain evolution as a function of age (tertiles), sex, ethnicity, education, marital, and professional status, after accounting for disease-related, treatment, lifestyle, and health factors. RESULTS: While transitioning from early (disease duration ≤6 months for RA and ≤3 years for SpA) to long-standing disease, differences in pain evolution emerged as a function of age (P < 0.001), sex (P = 0.050), and ethnicity (P = 0.001) in RA, and as a function of age (P = 0.048) in SpA; younger age, males, and Caucasians exhibited lower pain in the latter phases of both diseases. Highly educated participants (RA, ß = -3.8, P = 0.007; SpA, ß = -6.0, P < 0.001) for both diseases, and Caucasians (ß = -5.6, P = 0.021) for SpA presented with low pain early in the disease, with no changes throughout disease course. CONCLUSION: Being older, female, non-Caucasian and having lower education was found to be associated with worse pain in early and/or long-standing IRDs, despite universally accessible health-care. Early identification of at-risk populations and implementation of multidisciplinary strategies may reduce patient-reported health outcome disparities. TRIAL REGISTRATION REGISTRATIONS: ESPOIR: ClinicalTrials.gov, www.clinicaltrials.gov, NCT03666091. DESIR: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01648907.

Sex differences in functional limitations and the role of socioeconomic factors: a multi-cohort analysis.

BACKGROUND: Women are more likely to have functional limitations than are men, partly because of greater socioeconomic disadvantage. However, how sex differences vary by severity of functional limitations remains unclear. We examined sex differences in functional limitations, with attention to socioeconomic factors and severity of limitations. METHODS: Longitudinal data on limitations in basic activities of daily living (ADL) and instrumental activities of daily living (IADL) and mobility activities were drawn from 62 375 participants from 14 countries. For ADL, IADL, and mobility, participants were categorised based on number of limited activities (0, 1, 2, or ≥3). Sex differences in limitations in four birth cohorts (1895-1929, 1930-38, 1939-45, and 1946-60) were analysed before and after adjustment for socioeconomic factors (education and labour force status). FINDINGS: The prevalence of IADL and ADL limitations was higher in women than in men. After adjustment for socioeconomic factors, this sex difference was attenuated. The sex difference in IADL limitations at age 75 years (in the 1895-1929 cohort) was 3·7% before adjustment for socioeconomic factors (95% CI 2·6-4·7) and 1·7% (1·1-2·2) after adjustment. For ADL, the sex difference in limitations at age 75 years (in the 1895-1929 cohort) was 3·2% (2·3-4·1) before adjustment for socioeconomic factors and 1·4% (0·9-1·8) after adjustment. Sex differences in mobility limitations (16·1%, 95% CI 14·4-17·7) remained after adjustment for socioeconomic factors (14·3%, 12·7-15·9). After age 85 years, women were more likely to have three or more IADL or mobility limitations and men were more likely to have one or two limitations. INTERPRETATION: Socioeconomic factors largely explain sex differences in IADL and ADL limitations but not mobility. Sex differences in mobility limitations in midlife are important targets for future research and interventions. FUNDING: National Institute on Aging, UK National Institute for Health Research, European Commission, and US Social Security Administration.

Association of daily composition of physical activity and sedentary behaviour with incidence of cardiovascular disease in older adults.

BACKGROUND: Moderate-to-vigorous physical activity (MVPA) is proposed as key for cardiovascular diseases (CVD) prevention. At older ages, the role of sedentary behaviour (SB) and light intensity physical activity (LIPA) remains unclear. Evidence so far is based on studies examining movement behaviours as independent entities ignoring their co-dependency. This study examines the association between daily composition of objectively-assessed movement behaviours (MVPA, LIPA, SB) and incident CVD in older adults. METHODS: Whitehall II accelerometer sub-study participants free of CVD at baseline (N = 3319, 26.7% women, mean age = 68.9 years in 2012-2013) wore a wrist-accelerometer from which times in SB, LIPA, and MVPA during waking period were extracted over 7 days. Compositional Cox regression was used to estimate the hazard ratio (HR) for incident CVD for daily compositions of movement behaviours characterized by 10 (20 or 30) minutes greater duration in one movement behaviour accompanied by decrease in another behaviour, while keeping the third behaviour constant, compared to reference composition. Analyses were adjusted for sociodemographic, lifestyle, cardiometabolic risk factors and multimorbidity index. RESULTS: Of the 3319 participants, 299 had an incident CVD over a mean (SD) follow-up of 6.2 (1.3) years. Compared to daily movement behaviour composition with MVPA at recommended 21 min per day (150 min/week), composition with additional 10 min of MVPA and 10 min less SB was associated with smaller risk reduction - 8% (HR, 0.92; 95% CI, 0.87-0.99) - than the 14% increase in risk associated with a composition of similarly reduced time in MVPA and more time in SB (HR, 1.14; 95% CI, 1.02-1.27). For a given MVPA duration, the CVD risk did not differ as a function of LIPA and SB durations. CONCLUSIONS: Among older adults, an increase in MVPA duration at the expense of time in either SB or LIPA was found associated with lower incidence of CVD. This study lends support to public health guidelines encouraging increase in MVPA or at least maintain MVPA at current duration.

Comparison of the predictive accuracy of multiple definitions of cognitive impairment for incident dementia: a 20-year follow-up of the Whitehall II cohort study.

BACKGROUND: Studies generally use cognitive assessment done at one timepoint to define cognitive impairment in order to examine conversion to dementia. Our objective was to examine the predictive accuracy and conversion rate of seven alternate definitions of cognitive impairment for dementia. METHODS: In this prospective study, we included participants from the Whitehall II cohort study who were assessed for cognitive impairment in 2007-09 and were followed up for clinically diagnosed dementia. Algorithms based on poor cognitive performance (defined using age-specific and sex-specific thresholds, and subsequently thresholds by education or occupation levels) and objective cognitive decline (using data from cognitive assessments in 1997-99, 2002-04, and 2007-09) were used to generate seven alternate definitions of cognitive impairment. We compared predictive accuracy using Royston's R 2, the Akaike information criterion (AIC), sensitivity, specificity, and Harrell's C-statistic. FINDINGS: 5687 participants, with a mean age of 65·7 years (SD 5·9) in 2007-09, were included and followed up for a median of 10·5 years (IQR 10·1-10·9). Over follow-up, 270 (4·7%) participants were clinically diagnosed with dementia. Cognitive impairment defined using both cognitive performance and decline had higher hazard ratios (from 5·08 [95% CI 3·82-6·76] to 5·48 [4·13-7·26]) for dementia than did definitions based on cognitive performance alone (from 3·25 [2·52-4·17] to 3·39 [2·64-4·36]) and cognitive decline alone (3·01 [2·37-3·82]). However, all definitions had poor predictive performance (C-statistic ranged from 0·591 [0·565-0·616] to 0·631 [0·601-0·660]), primarily due to low sensitivity (21·6-48·4%). A predictive model containing age, sex, and education without measures of cognitive impairment had better predictive performance (C-statistic 0·783 [0·758-0·809], sensitivity 74·2%, specificity 72·2%) than all seven definitions of cognitive impairment (all p<0·0001). INTERPRETATION: These findings suggest that cognitive impairment in early old age might not be useful for dementia prediction, even when it is defined using longitudinal data on cognitive decline and thresholds of poor cognitive performance additionally defined by education or occupation. FUNDING: National Institutes of Health, UK Medical Research Council.