Objective: To evaluate and compare the predictive value of eight dementia risk scores for late-life cognitive function and cognitive decline; ANU-ADRI, CAIDE, CogDrisk, LIBRA, LIBRA2, UKBDRS(-APOE), and a Lancet commission-based risk score. Methods: Using Norwegian Trøndelag Health Study (HUNT) data, we calculated risk scores from lifestyle and health data of 7221 dementia-free participants (mean age: 76.8 years, 54.1% female) collected in HUNT3 (2006–2008). Cognitive function was assessed using the Montreal Cognitive Assessment scale (MoCA) 11 years later in HUNT4 70+, and reassessed in 4716 participants 4 years thereafter. Associations between continuous risk scores or risk score tertiles, cognition and cognitive decline were examined using linear mixed-effects models. Logistic regression models were used to test associations between risk scores and a ≥ 3-point decline in MoCA scores. Results: All risk scores were significantly associated with cognitive function and cognitive decline. Associations with cognitive function ranged from UKBDRS β per 1SD=-1.61(95%CI:-1.72,-1.51) to CAIDE (β=-0.74;95%CI:-0.82,-0.67), and with yearly cognitive decline from Lancet (β=-0.23;95%CI:-0.27,-0.18) to CAIDE (β=-0.04;95%CI:-0.07,-0.02). High-low risk group differences in cognitive function were largest for CogDrisk (β=-3.04;95%CI:-3.27,-2.81), LIBRA (β=-3.04;95%CI:-3.27,-2.80) and lowest for CAIDE (β=-1.65;95%CI:-1.86,-1.44). High-risk groups showed the steepest decline for UKBDRS-APOE (β=-0.43;95%CI:-0.52,-0.34), Lancet (β=-0.39;95%CI:-0.48,-0.30), and LIBRA (β=-0.38;95%CI:-0.47,-0.28). All scores predicted ≥3-point decline modestly: AUCs were highest for UKBDRS (AUC=0.61;95%CI:0.60,0.63), UKBDRS-APOE (0.61;95%CI:0.60,0.63), CogDrisk (0.60;95%CI:0.58,0.62), and Lancet (0.60;95%CI:0.58,0.61), but none outperformed a model including age and education alone (0.61;95%CI:0.60,0.63). Conclusion: Risk scores captured meaningful gradients in cognition and decline but offered limited discriminatory accuracy beyond demographics, supporting their use for prevention-oriented risk profiling rather than prediction.

Severe infections have been implicated in dementia risk, but their associations with detailed patterns of cognitive performance, and whether poorer cognition in turn increases risk for certain infections, remain unclear. We examined bidirectional associations between hospital-treated infections and domain-specific cognitive function in a cohort of older adults. We analysed data from the English Longitudinal Study of Ageing Harmonised Cognitive Assessment Protocol (ELSA-HCAP), conducted in 2018 and linked to national inpatient records. Pre-HCAP hospital-treated infections were identified from 1997 to 2018; post-HCAP incident infections were ascertained from 2018 to 2024. Cognitive performance was assessed at HCAP using 21 standardised neuropsychological tests summarised into general and four domain-specific scores (executive function, memory, language, and visuospatial ability). Linear regression assessed associations between pre-HCAP hospital-treated infections and standardised cognitive scores; Cox models estimated associations between cognition and risk of incident hospital-treated infections after HCAP. All models were adjusted for sociodemographic, lifestyle, and health covariates. Of 1,159 participants aged ≥65 at HCAP (631 [54.1%] female; mean [SD] age, 75.6 [7.2] years), 351 (30.3%) had a hospital-treated infection before HCAP. Prior hospitalisation for any infection was associated with lower general cognition (β = –0.11 SD, 95% CI –0.21 to –0.02) and poorer executive function (β = –0.19, –0.28 to –0.09), with similar patterns across infection types. Lower respiratory tract infections were additionally associated with poorer memory (β = –0.20, –0.36 to –0.04). Cognitive scores were progressively lower among individuals with more frequent or prolonged infection-related hospitalisations, sepsis, or cardiovascular disease. Prospectively, over a mean (SD) 4.8 (1.9) years of follow-up, 271 incident hospital-treated infections occurred. Each 1-SD higher general cognition was associated with a 36% lower risk of any subsequent hospital-treated infection (HR 0.64, 0.53 to 0.78), and with consistent associations across cognitive domains for all-cause and bacterial infections. Executive function alone showed a strong association with viral infections, especially COVID-19 (HR 0.59, 0.44 to 0.80). Severe infections were primarily associated with poorer executive function. Conversely, cognitive vulnerability across multiple domains was associated with increased susceptibility to infections requiring hospital care, while poorer executive function was specifically associated with viral infection risk. These findings support a reinforcing infection–cognition cycle in later life and cognitively tailored infection-prevention strategies.

Early identification of individuals at risk of dementia is essential for effective prevention and timely intervention. Existing risk scores rely heavily on age, which limits their discriminative power at clinically relevant thresholds such as 65 years, when preventive strategies might be most impactful. We analysed 76 427 adults aged 65 years (52·1% women) from the UK and French THIN primary care databases. Using routinely collected diagnoses, prescriptions, and clinical characteristics, we developed and validated a transparent risk algorithm for incident Alzheimer’s disease and all-cause dementia. Logistic regression was compared with random forests, support vector machines, and neural networks to predict dementia risk at 2, 5, and 10 years. Model calibration was assessed using the Brier score. Key predictors included medication classes (eg, laxatives, urological drugs, antidepressants), sex, BMI, and number of comorbidities. At 65 years, calibration to a 5% false-positive rate identified 54·6%, 34·8%, and 23·6% of incident dementia cases at 2, 5, and 10 years, respectively. Conversely, calibration to a 50% detection rate yielded false-positive rates of 3·1%, 16·2%, and 20·8%. Precision among the top 1% of predicted risk ranged from 16·9% to 18·0%, representing a 10·7–46·2-fold enrichment of a hypothetical prevention randomised controlled trial over baseline prevalence. A simple, deployable algorithm based on prescriptions and clinical records, without laboratory data, can identify patients at high near-term risk of dementia at age 65. This approach is cost-effective, readily deployable in primary care, and offers substantial potential to enrich prevention trials and targeted screening programmes. Dementia is easier to prevent when people at risk are found early, but most existing tools rely mainly on age, so they work poorly when everyone is the same age. We wanted a way to spot higher-risk people at age 65, when prevention may help most. Using anonymous health records from more than 76,000 adults in the UK and France, we built a simple computer tool that looks only at routine information a family doctor already has, such as prescribed medicines and basic health details. The tool could pick out many of the people who later developed dementia. Because it is cheap and easy to use, it could help doctors and speed up research into ways to prevent dementia. Nedelec et al. developed a simple algorithm that uses routine primary care records, such as prescribed medicines, to identify people at higher risk of dementia at age 65. The tool detects some cases years in advance and could help enrich prevention trials and target screening.

Physical multimorbidity and loneliness are increasingly recognised as public health concerns, but the nature of their potential relationships remains unclear. Here we report bidirectional associations between physical multimorbidity and loneliness in middle-aged and older adults and the mediating role of social inactivity. Longitudinal data from adults aged ≥45 years are analysed across 19 countries from five prospective cohorts: US Health and Retirement Study; English Longitudinal Study on Ageing; Survey of Health, Ageing and Retirement in Europe; China Health and Retirement Longitudinal Study; and Korean Longitudinal Study of Aging. Cox regression models suggest longitudinal associations between physical multimorbidity and loneliness in both directions (from physical multimorbidity to loneliness: adjusted hazard ratio (HR) = 1.25, 95% confidence interval (CI) = 1.20 to 1.30; from loneliness to physical multimorbidity: adjusted HR = 1.10, 95% CI = 1.05 to 1.17). Random-intercept cross-lagged panel models confirm significant association between T1 physical multimorbidity and T3 loneliness, with T2 social inactivity serving as a mediator. These findings suggest that physical multimorbidity and loneliness may create a vicious cycle where each condition exacerbates the other, with social inactivity mediating the direction from physical multimorbidity and loneliness. Both multimorbidity and loneliness are major public health issues. Here, the authors show that physical multimorbidity and loneliness are bidirectionally linked and social inactivity partially mediates the pathway from physical multimorbidity to loneliness.

Importance:Disruptions in the sleep-wake cycle have been reported in the preclinical period of dementia; whether they contribute to dementia prediction remains unclear. Objective:To examine associations of accelerometer-derived sleep-wake cycle metrics with incident dementia and their contribution to dementia risk prediction in models containing age and known risk factors. Design, Setting, and Participants:This study included 2 prospective UK population-based cohort studies: (1) UK Biobank (derivation study) and (2) Whitehall II (validation study). A UK Biobank accelerometer substudy was undertaken from 2013 to 2015, yielding accelerometer data on 103 278 participants. A Whitehall II accelerometer substudy was undertaken from 2012 to 2013 that provided data on 4267 participants. Analyses were performed between August 2024 and November 2025. Included participants were 60 years and older, without dementia, and with valid accelerometer and covariate data. Exposures:Thirty-six accelerometer-derived sleep-wake cycle metrics were extracted. A machine learning approach identified and combined metrics predicting dementia risk. Main Outcome and Measure:Incident all-cause dementia, ascertained from electronic health records. Results:Analyses were based on 53 448 UK Biobank participants (mean [SD] age, 67.5 [4.2] years; 28 448 female [54.2%]; mean [SD] follow-up, 7.8 [1.1] years) and 3965 Whitehall II participants (mean [SD] age, 69.4 [5.7] years; 1025 female [25.9%]; mean [SD] follow-up, 10.6 [2.4] years). In UK Biobank, 9 sleep-wake cycle metrics were combined in 2 components. Higher values in component 1 represented shorter durations and less frequent bouts of moderate to vigorous physical activity, more time in low-intensity activity, lower diversity of activity intensities, and higher probabilities to transition from activity to rest during daytime. Higher component 2 corresponded to more extreme sleep durations, longer wake bouts during sleep, lower probabilities to transition from wake to sleep, and earlier waking time. Both components were associated with higher dementia risk (component 1: hazard ratio [HR], 1.43; 95% CI, 1.33-1.54; component 2: HR, 1.10; 95% CI, 1.04-1.17) and improved prediction of a model including sociodemographic, behavioral, and health-related factors (increase in C index = 0.018; 95% CI, 0.011-0.025). Results were confirmed in the Whitehall II cohort study. Compared with an age-only prediction model, adding the components led to an increase in C index equivalent to that for APOE genotype. Conclusions and Relevance:Results of this cohort study show that accelerometer-derived sleep-wake cycle measures were associated with dementia, and made a modest, statistically significant contribution to its prediction. Future studies should evaluate their clinical utility as scalable markers alongside established predictors for early identification of individuals at risk of dementia.

Abstract Background As a global health crisis, the COVID-19 pandemic offered a unique opportunity to identify sickness absence (SA) patterns consisting of long and short episodes and total number of SA days in a cohort of Finnish public sector employees while comparing to pre-pandemic timepoint. Methods Survey data from 39,791 employees in four Finnish cities in 2020 were linked to SA records between Jan-1 and Dec-31, 2021. We used K-means modelling on short (1–9 days) and long (10–365 days) episodes and total numbers of SA days. For comparison, we analysed 2019 (pre-pandemic) SA records. Employee and work characteristics associated with SA patterns were analysed using multinomial regression. Results Four distinct SA patterns during COVID-19 were identified: Low SA (n = 31,320, 79%), repeated short episodes (n = 5149, 13%), repeated long episodes (n = 2964, 7%), and very high SA (n = 358, 1%). Compared to others, employees with low SA were less likely to have had a first-wave COVID-19 infection, more frequently worked from home, were more often men in higher occupational positions, had lower body mass index, lower smoking and higher alcohol abstinence rates. Repeated short episodes were associated with younger age and team reorganization, whereas repeated long episodes and very high SA were linked to older age. Except for fewer overall SA days, the pre-pandemic SA pattern structure was similar. Conclusions We identified four distinct SA patterns with different employee correlates during the COVID-19 pandemic. These patterns appeared stable over time, as similar profiles – albeit with lower overall SA rates – were evident before the pandemic.

Adolescent healthy behaviours may improve cardiometabolic health in adulthood differently across socioeconomic groups. We aimed to quantify the effects of adolescent healthy behaviours on multiple biomarkers of adult cardiometabolic health by socioeconomic backgrounds. We used a population-based cohort of Finnish adolescents from the Young Finns Study (1980–89, n = 2984) followed into adulthood (2001–11). Healthy behaviours (no smoking, no alcohol consumption, sufficient physical activity, daily fruit and vegetable consumption) and socioeconomic backgrounds (parental- and neighbourhood-related) were measured in adolescence (12–18 years). Biomarkers of adiposity [waist circumference, body mass index (BMI)], cardiovascular [blood pressure (BP), cholesterol, apolipoprotein B], and metabolic [plasma glucose, insulin resistance] outcomes were measured in adulthood (33–40 years). We estimated conditional average effects of healthy behaviours via inverse-probability-weighted marginal structural models. Sufficient physical activity lowered adiposity biomarkers to a greater extent among adolescents from disadvantaged neighbourhood, with additional decreases of 2.2 cm [95% confidence interval (CI): −0.1 to 4.7] in waist circumference and 1 kg/m2 (95% CI: 0.2 to 1.9) in BMI. In contrast, daily fruit and vegetable consumption lowered BP with additional 2.0–3.6 mmHg (95% CI: 0.3 to 6.1) among adolescents with advantaged either parental or neighbourhood socioeconomic backgrounds. There was little evidence for differential effects on other outcomes and for no smoking and alcohol. Socioeconomic backgrounds modified the effects of adolescent physical activity and fruit and vegetable consumption on adult cardiometabolic health. These findings indicate that population-wide interventions promoting healthy behaviours during adolescence have the potential to either mitigate or exacerbate long-term socioeconomic inequalities in cardiometabolic health.

BACKGROUND:Severe infections have been linked to an increased risk of dementia, but both conditions often coexist with other illnesses that may confound this association. Using nationwide Finnish health registry data, we examined the role of noninfectious mental and physical illnesses in the association between severe infections and dementia. METHODS AND FINDINGS:This register-based study included 62,555 individuals aged 65 or older in Finland in 2016 who were diagnosed with late-onset dementia between 2017 and 2020 and 312,772 dementia-free controls matched for year of birth, sex, and the follow-up period. Analyses were adjusted for education, marital status, employment, and area of residence, with age and sex accounted for through the matched conditional design and analysis. Applying a 1-year lag period, we identified 29 hospital-treated diseases that occurred 1-21 years before dementia diagnosis in cases (or index date in controls), had a prevalence of ≥ 1% prior to dementia, and were robustly associated with increased dementia risk (confounder-adjusted rate ratio ≥ 1.20, p < 0.000294). In addition to 2 infectious diseases (cystitis and bacterial infection of an unspecified site), these included 27 mental, behavioural, digestive, endocrine, cardiometabolic, neurological, and eye diseases, as well as injuries. 29,376 (47%) of the dementia cases had at least one of these diseases diagnosed before dementia. The associations between the two infectious diseases and dementia risk were not attributable to the 27 comorbid dementia-related diseases diagnosed before infections. The adjusted rate ratio for cystitis was 1.22 (95% confidence interval (CI) [1.17, 1.27]; p < 0.001) before and 1.19 (95% CI [1.14, 1.24]; p < 0.001) after adjustment for comorbidities, while for bacterial infections of an unspecified site, the rate ratios were 1.21 (95% CI [1.16, 1.28]; p < 0.001) and 1.19 (95% CI [1.13, 1.25]; p < 0.001), respectively. The findings were comparable across subgroups defined by sex and education, and stronger for cases of early onset dementia. We were not able to directly assess psychosocial, behavioural, or biological confounders that are not captured in nationwide registries. CONCLUSIONS:This nationwide Finnish study identified several mental and physical diseases that are associated with an increased risk of dementia and showed that the increased incidence of dementia among individuals with severe infections is not attributable to these comorbid conditions. These results support the role of severe infections as independent risk factors for dementia.

Abstract Background Social frailty, a state of vulnerability to social risk factors, has been linked to adverse physical, psychological, and cognitive outcomes. However, evidence on its role in the progression of multimorbidity across these domains is limited. This study examined social frailty in relation to transitions from a healthy state to physical, psychological, and cognitive conditions and to multimorbidity. Methods In this multi-cohort study across 24 countries in the USA, Europe, and Asia, middle-aged and older individuals with no preexisting physical, psychological, or cognitive conditions were included. Social frailty, assessed through baseline questionnaires, was defined across four domains: general resources, social behaviors, social resources, and basic social needs. Physical, psychological, and cognitive conditions were ascertained at baseline and reassessed four times during a mean follow-up of 7 years. Multi-state models and the group-based multi-trajectory model were used to examine the role of social frailty in the development of physical, psychological, and cognitive conditions and their progression to multimorbidity. Results Among the 7119 participants (mean age, 59.6 years [SD 8.5]; 3575 [50.2%] women), 778 (10.9%) were socially frail at baseline. During 49,648 person-years at risk, 2981 (41.9%) individuals progressed from a healthy state to one physical, psychological, or cognitive condition, and 1592 (22.4%) progressed to multimorbidity. Compared with socially robust participants, those with social frailty had a higher risk of progressing to any of these conditions (hazard ratio, 1.30; 95% CI, 1.17–1.44) and to multimorbidity (2.10, 1.67–2.65). Four outcome trajectories were identified, including “stably no physical, psychological or cognitive conditions” (48.0%), “increased physical conditions” (16.4%), “increased physical and psychological conditions” (8.7%), and “increased physical and cognitive conditions” (26.9%). Social frailty was associated with more than a twofold increase in risk for the latter three trajectories (odds ratios 2.34, 1.76–3.09, 2.27, 1.63–3.15 and 2.69, 2.11–3.44, respectively). The strongest associations were observed for frailty in the domains of general resources and basic social needs. Conclusions Social frailty is associated with faster transitions from a healthy state to physical, psychological, and cognitive conditions and further progression to multimorbidity. Early identification and interventions to address social frailty may help improve health in middle-aged and older adults.

Objective Preterm birth is a major cause of childhood mortality and morbidity, but the aetiology of preterm delivery remains incompletely understood. We sought to examine whether cumulative exposure to neighbourhood socioeconomic disadvantage is associated with preterm delivery risk.Methods The association between neighbourhood socioeconomic disadvantage over the 20 years preceding delivery and risk of preterm delivery was assessed in a population-based cohort of 11 979 deliveries in Southwest Finland in 2008–2010. The statistical analyses were adjusted for a large number of potential individual-level confounding or mediating factors obtained from the national registry on parturients, deliveries and births.Results Altogether 615/11 979 deliveries (5.1%) occurred before 37 weeks of gestation. The incidence of preterm delivery was 6.2% (95% CI 5.0% to 7.7%) in the women with the highest cumulative exposure to neighbourhood disadvantage as compared with 3.6% (95% CI 2.8% to 4.5%) in women who had lived in the most affluent neighbourhoods adjusted for the covariates; OR 1.74 (95% CI 1.26 to 2.40). Smoking during pregnancy, prepregnancy body mass index, gestational diabetes, pre-eclampsia and other medical problems during pregnancy explained 27.4% of this association. Shorter exposure to neighbourhood disadvantage was associated with lower excess risk of preterm births.Conclusions Women with long-term exposure to neighbourhood socioeconomic disadvantage are at increased risk for preterm delivery in a dose-dependent fashion. Improving deprived neighbourhoods may offer means to reduce the risk of preterm birth and, consequently, the intergenerational transfer of health inequality.

BACKGROUND:Impairments in physical, psychological, and cognitive functioning are associated with an increased risk of falls. However, how these functional domains change longitudinally before and after fall events remains unclear. We examined individual and joint trajectories of these outcomes preceding and following falls. METHODS AND FINDINGS:Using data collected between 2010 and 2021 from three national cohorts in China, the UK, and the USA, we included 28,773 adults aged ≥60 years and performed 1:1 matching between participants who reported falls during follow-up and those who did not. Physical function, depressive symptoms, and cognitive performance were assessed repeatedly using measures of activities of daily living, standardized depression scales, and cognitive test performance, respectively. Falls were self-reported, and fall-related characteristics were evaluated by the need for medical attention, the number of falls, and hip fracture. Statistical analyses included piecewise linear mixed-effects models and group-based multi-trajectory models, with adjustment for age, sex, cohort, socioeconomic status, lifestyle factors, sensory function, and major chronic conditions. A total of 10,990 matched participants who experienced falls and those who did not were included (5,495:5,495; mean age 71.0 [SD 7.2]; 5,010 women and 5,980 men). Compared with participants who did not experience falls, those who experienced falls had poorer physical function, more severe depressive symptoms, and poorer cognitive performance at the time of the fall; these differences were apparent up to 5 years before a fall event and persisted thereafter. Participants who experienced falls also exhibited faster worsening of physical function both before (βfall * pre-time -0.116, 95% CI [-0.142, -0.089]) and after the fall event (βfall * post-time -0.039, 95% CI [-0.050, -0.028]). Faster worsening of depressive symptoms was observed only before the fall event (βfall * pre-time -0.018, 95% CI [-0.026, -0.011]), whereas faster decline in cognitive performance was observed only thereafter (βfall * post-time -0.008, 95% CI [-0.016, 0.000]). In joint trajectory analyses, participants who experienced falls were more likely to experience progressive multidomain functional decline, with the highest odds ratio (2.45, 95% CI [1.97, 3.05]) observed for concurrent worsening across all three domains. Associations were stronger among participants who experienced more severe falls. The main limitations of this study were the reliance on self-reported falls and some functional measures, and the observational design, which precluded causal inference. CONCLUSIONS:In older adults, multidomain functional decline appears to precede falls by several years and worsens further after fall events. Falls may therefore signal broader functional deterioration and highlight the need for prevention and management strategies addressing physical, psychological, and cognitive domains.

Despite growing evidence related diet quality to depression, the extent to which the dietary risk factors proposed by the Global Burden of Diseases (GBD) are associated with depression at international level remains unknow. To address this gap, a harmonised protocol has been developed by the Global Burden of Disease Lifestyle And mental Disorder (GLAD) project and we aimed to contribute to the GLAD project by assessing associations between the 15 Global Burden of Diseases (GBD) dietary risk factors, and ultra processed foods (UPF) intakes—and recurrence of depressive symptoms (DepS) over 13 years of follow-up in the British Whitehall II study. Analyses carried out on 4099 participants with no prior history of DepS (73.6

INTRODUCTION:Changes in mental health symptoms, and their timing in the preclinical period of dementia, are not well characterised. METHODS:We followed 5,495 Whitehall II participants (median age 68.5; 72.1% male) from their mental health symptoms assessment using the Clinical Interview Schedule-Revised (CIS-R) starting in 2012/13 to dementia diagnosis, death, or 2024. Linear mixed effects regression assessed CIS-R score changes preceding dementia. Flexible parametric models estimated associations of mental health symptoms with dementia. RESULTS:Total CIS-R score increased (2.56 points [0.85-4.27]) in the 12 years preceding dementia. Having any mental health condition was associated with dementia in the short-term (HR at 3 years=4.04 [2.53-6.50]) but not the long-term (HR at 6 years=1.26 [0.63-2.49]). This pattern held for severe mental health conditions, concentration problems, depression, irritability, fatigue, anxiety, and worry. DISCUSSION:Awareness of mental health symptoms as preclinical indicators of dementia in the short-term may support timely diagnosis of dementia.

OBJECTIVE: This study aimed to examine the associations between work-related psychosocial factors and working life expectancy (WLE) across occupational groups among Finnish public sector employees aged ≥50 years. METHODS: In this cohort study, 70 662 Finnish public sector employees completed surveys on work-related psychosocial factors in 2000–2002, 2004, 2008, 2011–2012, 2013–2014, and 2015–2016, with each participant responding at least once at age ≥50 years (response rates 66–71%; 80% female). Survey data were linked to pensionable earnings records to verify work participation until 31 December 2018. WLE WLE between ages 50 and 68 was estimated using a multi-state life tables approach. Analyses were conducted among three occupational groups: managers and specialized professionals, non-manual professionals, and service and manual workers. RESULTS: The overall WLE at age 50 was 13.1 years [95% confidence interval (CI) 13.1–13.2]. Work-related psychosocial factors were associated with shorter WLE across all occupational groups, with WLE shortening from the highest to the lowest occupational group. High effort–reward imbalance (ERI) was associated with the shortest WLE, approximately five months shorter than among employees with low ERI. Compared with managers and specialized professionals with low psychosocial risks, high ERI, high job strain, high relational or procedural injustice were each associated with an approximately 1-year shorter WLE among service and manual workers. Occupational group showed a stronger association with WLE than the accumulation of psychosocial risk factors. No sex differences in WLE were observed. CONCLUSION: These findings suggest that promoting favorable psychosocial working conditions may extend working careers and reduce inequalities in working life participation, particularly among service and manual workers.

BACKGROUND:Severe infections have been linked to an increased risk of dementia, but whether this association reflects pre-existing conditions that predispose individuals to infections and dementia remains unclear. We assessed whether the association between severe infections and dementia risk is explained by pre-existing frailty, comorbidities, or other age-related physical diseases. METHODS:This prospective, multicohort, observational study included participants without severe infections or dementia (between Dec 19, 2006, and Oct 1, 2010, from the UK Biobank study and between Oct 8, 2002, and Nov 30, 2004, from the Whitehall II prospective cohort study). The primary analysis was conducted in the UK Biobank cohort. Frailty was assessed at baseline using the widely used phenotypic Fried Frailty Scale and comorbidities were assessed using the Charlson Comorbidity Index and 78 age-related diseases. Incident severe (hospital-treated) infections were identified from linked hospital discharge diagnoses. Follow-up included a 5-year exposure period from baseline, a 2-year washout period; and a final period extending to the end of follow-up. Incident dementia occurring after the exposure and washout periods was ascertained from hospital records and death certificates until 2022 (Oct 31 in England, Sept 30 in Scotland, and May 31 in Wales). Participants with a record of dementia during the exposure period or subsequent washout period were excluded. We repeated the main analyses in the Whitehall II study and conducted several supplementary analyses with follow-up until March 1, 2023. FINDINGS:We included 449 223 participants without severe infection or dementia from the UK Biobank study and 6106 from the Whitehall II study. Most participants were White (424 405 [94·5%] in UK Biobank and 5616 [92·0%] in the Whitehall II study). In UK Biobank, the mean age of participants was 56·5 years (SD 8·1), of whom 245 139 (54·6%) were female and 204 084 (45·4%) were male. Of 435 957 participants with dementia follow-up, 23 860 (5·5%) had a record of severe infection during the 5-year exposure period. After a 2-year washout period, the remaining follow-up for dementia occurred for a mean of 6·5 years (SD 1·2). 6756 participants developed incident dementia, corresponding to an incidence of 2·37 (95% CI 2·31-2·43) per 1000 person-years. Adjustment for frailty resulted in no statistically significant attenuation of the infection and dementia association (adjusted hazard ratio [HR] 1·54 [95% CI 1·43-1·67] for presence vs absence of severe infections before adjustment for frailty and 1·49 [1·37-1·61] after adjustment). The association was also evident within a subgroup of non-frail participants (1·34 [1·18-1·53]). Pre-frail and frail participants had a higher corresponding adjusted HR (1·62 [1·47-1·79]). In the Whitehall II study, the mean age of participants was 60·6 years (SD 6·0), of whom 1772 (29·0%) of 6106 were female and 4334 (71·0%) were male. Of 5824 participants available for dementia follow-up, 237 (4·1%) had a record of infection during the 5-year exposure period. After a 2-year washout period, the remaining mean follow-up for dementia was 11·3 years (SD 2·9). 545 incident cases of dementia were recorded (incidence 8·3 per 1000 person-years). Findings in the Whitehall II study, using an alternative proteomic measure of frailty and cognitive decline as a surrogate outcome, were consistent but less precise. INTERPRETATION:Frailty, comorbidities, and other age-related diseases were associated with a higher risk of dementia but did not account for the elevated dementia risk observed after severe infections. Interventional research to test whether targeting infections lowers dementia incidence is needed. FUNDING:Finnish Medical Foundation, Päivikki and Sakari Sohlberg Foundation, Research Council of Finland, Wellcome Trust, UK Medical Research Council, and National Institutes of Health.

BACKGROUND:Neighbourhood socioeconomic disadvantage correlates with cardiovascular disease risk. However, its relationship with subclinical atherosclerosis from childhood to midlife is not well-defined. We examined whether cumulative neighbourhood disadvantage is associated with carotid artery plaques, a measure of subclinical atherosclerosis. METHODS:We analysed data from 1998 participants in the Cardiovascular Risk in Young Finns Study, a cohort followed from childhood (mean age 10.7 years in 1980) to adulthood (mean age 48.6 years in 2018-2020). Neighbourhood disadvantage was derived from national grid-based socioeconomic data and computed cumulatively across the life course. The number of carotid artery plaques (mean plaque count) was assessed by standardized ultrasound imaging. Multivariable Poisson regression models were used to evaluate the associations. Mediation analyses were used to assessed the role of ideal cardiovascular health (CVH) metrics. RESULTS:Higher cumulative neighbourhood disadvantage from childhood to mid-adulthood was associated with a 1.24-fold increase in mean plaque count for every 1 standard deviation increase in cumulative disadvantage. This relationship persisted after controlling for parental carotid artery plaques, polygenic coronary artery disease risk score, and Framingham risk score. The association was partially explained by ideal CVH metrics, particularly smoking and blood pressure, which collectively accounted for almost half of the association. CONCLUSIONS:Long-term exposure to neighbourhood socioeconomic disadvantage beginning in childhood is associated with subclinical atherosclerosis in midlife, independently of achieved socioeconomic position. These findings highlight the importance of cumulative socioeconomic environments across the life course and suggest that behavioural risk factors may partly explain observed neighbourhood-level associations with atherosclerosis.

BACKGROUND AND AIMS:This study hypothesizes that subclinical myocardial injury during midlife, indexed by increases in cardiac troponin I, is associated with accelerated cognitive decline, smaller structural brain volume, and higher risk of dementia. METHODS:Overall, 5985 participants in the Whitehall II study, aged 45-69 who had cardiac troponin I measured by a high-sensitivity assay at baseline (1997-99), were followed until March 2023. The outcome measure was incident dementia; cognitive testing was performed at six waves; and neuroimaging metrics were obtained from magnetic resonance imaging scans in 2012-16. Cox model and linear mixed model were used to examine the association of cardiac troponin with incident dementia and cognitive trajectory. A nested case-control sample of 3475 participants (695 dementia cases and 2780 matched controls) was used for backward trajectory analysis for cardiac troponin, measured at three waves (1997-99, 2007-09, 2012-13). RESULTS:A total of 606 (10.1%) cases of dementia were recorded over a median follow-up of 24.8 years. Doubling of cardiac troponin was associated with 10% (95% confidence interval 3%-17%) higher risk of dementia. Participants with increased cardiac troponin at baseline had a faster decline of cognitive function. Participants with dementia had increased cardiac troponin concentrations compared with those without dementia between 7 and 25 years before diagnosis. Compared with those with cardiac troponin levels < 2.5 ng/L at baseline, those with concentrations > 5.2 ng/L had lower grey matter volume and higher hippocampal atrophy 15 years later, equivalent to ageing effects of 2.7 and 3 years, respectively. CONCLUSIONS:Subclinical myocardial injury at midlife was associated with higher dementia risk in later life.