INTRODUCTION:Whether early-life exposure to persistent organic pollutants (POPs) associates with adult cognitive function is unknown. We examined the association of childhood serum POPs levels with cognitive function in midlife. METHODS:This was a prospective cohort study of 1304 children aged 3-18 years. Childhood serum levels of 18 POPs including p,p'-dichlorodiphenyltrichloroethane (p,p'-DDT), p,p'-dichlorodiphenyldichloroethylene (pp'-DDE), pentachlorobenzene (PeCB), hexachlorobenzene (HCB), hexachlorocyclohexanes (HCHs), polychlorinated biphenyls (PCBs), trans-nonachlor were measured in childhood and early adulthoood. In mid-adulthood, cognitive function was measured using a computerized test battery (CANTAB) including tests for 1) memory and learning, 2) working memory, 3) reaction time, and 4) information processing. We assessed the overall association of the 18 POPs with cognitive function (normalized with mean 0 and standard deviation 1) by deriving a POP mixture index using weighted quantile sum (WQS) regression. RESULTS:For every unit-increase in the derived POP index (range 0-3, SD = 0.7), 0.129 (95% CI: -0.244, -0.014) SD-units lower memory and learning in midlife was observed when adjusting for covariates and adult POP index. This association was stable as shown by repeated holdout validation (β = -0.086, 95% confidence interval: -0.160 to -0.011), corresponding to 1.7 years additional aging on memory and learning. The POP mixture index was predominated by HCB (23%), p,p'-DDT (21%), PCB99 (10%), and p,p'-DDE (10%). CONCLUSIONS:Childhood exposure to a high level of multiple POPs, such as HCB, p,p'-DDT and PCB99, was associated with poorer memory and learning in midlife, independent of adult exposure to those POPs.

AIMS:The role of adult HDL-C in atherosclerotic cardiovascular disease (ASCVD) faces challenges from Mendelian randomizations and drug trials. However, the association between childhood HDL-C and its changes and adult ASCVD remains undefined. This study aimed to determine this association. METHODS AND RESULTS:Participants: Children in the International Childhood Cardiovascular Cohort (i3C) Consortium with childhood HDL-C and adult ASCVD follow-up. Age- and sex-standardized HDL-C z-scores were calculated for childhood (3-19 years), early childhood (3-11 years), and adolescence (12-19 years); low HDL-C defined as <1.03 mmol/L; participants classified as consistently normal, low to normal, normal to low, and consistently low based on HDL-C status at early childhood and adolescence. ASCVD events: Identified using self-reports adjudicated by medical records or death registries. Analysis: Cox proportional hazards models quantified the associations between childhood HDL-C and adult ASCVD. The study included 38 589 participants (49.7% males, mean age in 2016: 46.4 years) with 779 ASCVD and 784 imputed ASCVD events. After adjusting for sex, cohort, age, and HDL-C measurement year, higher HDL-C z-scores in childhood, early childhood, and adolescence were associated with lower adult ASCVD risk [hazard ratio (HR): 0.81-0.82], with the lowest risk at HDL-C > 1.50 mmol/L. Normal to low [HR 1.38, 95% confidence intervaI (CI) 1.04-1.82] and consistently low (HR 1.94, 95% CI 1.45-2.63) childhood HDL-C increased adult ASCVD risk compared to consistently normal HDL-C. Adjusting for body mass index and triglycerides weakened these associations. CONCLUSION:Childhood and adolescent HDL-C were prospectively and inversely associated with adult ASCVD, suggesting that low HDL-C could be a risk marker of adult ASCVD. Future replications, mechanistic studies, and Mendelian randomizations on childhood HDL-C may clarify its causal effects on adult ASCVD. LAY SUMMARY:We examined the association between childhood HDL-C measurement and adult atherosclerotic cardiovascular disease (ASCVD) at follow-up in data from the International Childhood Cardiovascular Cohort (i3C) Consortium.Higher HDL-C levels in childhood were associated with lower risk of a ASCVD event, irrespective of age (early childhood vs. adolescence). The lowest risk was observed at HDL-C concentrations of around and above 1.50 mmol/L (58 mg/dL). A decrease in HDL-C from early childhood to adolescence was associated with an increased risk of adult ASCVD.When additionally adjusted for body mass index z-score, attenuated associations were noted. Adding triglycerides to models attenuated associations towards null.

Socioeconomic disadvantage at individual level is associated with poor cognitive outcomes but the link of neighborhood disadvantage with cognitive function is unclear. We used data from Young Finns Study, a population-based cohort, to examine the associations of neighborhood and individual-level disadvantage in childhood (age 3-21 years) and adulthood (age 22 up to the time of cognitive assessment) with cognitive function in mid-adulthood (age 35-49 years). Neighborhood disadvantage was ascertained based on register data, including geo-coded address history. Compared to individuals who experienced neither individual-level nor neighborhood disadvantage in childhood, those who experienced both had, on average, 0.236 SDs lower overall cognitive function scores (95% CI: -0.355 to -0.116) and those who experienced individual-level but not neighborhood disadvantage had 0.196 SDs lower scores (95% CI, -0.323 to -0.070). The estimates were slightly larger for adult individual-level and neighborhood disadvantage. The findings were similar across the cognitive domains and robust to adjustment for a polygenic risk score for cognitive ability. We found no clear evidence of sleep difficulties, depressive symptoms or cardiovascular health mediating the associations. Our findings suggest that socioeconomic disadvantage at individual-level but not neighborhood-level, from childhood to adulthood, may impact on cognitive function in mid-adulthood.

Abstract/Summary Innate immune responses are crucial for host defence but vary markedly between individuals. Although determinants of this variation are well characterised in adults, data from healthy children remain scarce. We therefore profiled whole-blood cytokine responses to innate immune stimulation in 286 children aged approximately four years and examined genetic, host-intrinsic, and environmental correlates of response. Cytokine responses showed marked inter-individual heterogeneity and stimulus-specific patterns. The top 50 genetic variants explained a substantial proportion (∼20-45%) of this variance across many stimulus conditions, including a biologically coherent association of the STING locus with cGAMP-induced cytokine production. In contrast, sex, age, adiposity, and perinatal variables showed limited or modest associations. Systemic inflammatory biomarkers of systemic inflammation (hsCRP, glycoprotein acetyls, granulocyte-to-lymphocyte ratio) were strongly positively associated with cytokine responses. Finally, seasonal population-level viral infection burden was positively associated with antiviral and inflammatory cytokine responses. Collectively, these findings advance our understanding of variation in early-life whole-blood cytokine responses, underscoring this developmental period as a critical window for understanding immune development trajectories relevant to long-term health.

Prospective studies have demonstrated an inverse association between lipoprotein(a) [Lp(a)] levels and the risk for type 2 diabetes, although the mechanisms underlying this relationship remain unclear. We examined the associations of Lp(a) with incident type 2 diabetes, fasting serum insulin, and fasting plasma glucose, in the prospective Young Finns Study cohort. Lp(a) measurements were first available in Young Finns Study participants in 1986 (N = 2 464). For type 2 diabetes analyses, the baseline was defined as the 2001 follow-up study (participants aged 24–39 years) when data on both Lp(a) and diabetes status were available (N = 2 263). The association between Lp(a) levels and incident type 2 diabetes was examined using the Fine-Gray model. Associations with fasting insulin and glucose were analyzed using repeated-measures linear regression, utilizing data from 1986, 2001, 2007, 2011, and 2018. During the mean follow-up period of 16.6 years from 2001, 144 participants (6.4

AIMS:P-wave prolongation and left atrial (LA) enlargement are markers of atrial cardiomyopathy and increase the risk for atrial fibrillation, stroke, and mortality. We investigated whether the cumulative burden of cardiovascular risk factors in early life is associated with P-wave duration and LA size in middle age. METHODS AND RESULTS:The Cardiovascular Risk in Young Finns Study is a prospective, ongoing, multicentre cohort initiated in 1980. Traditional cardiovascular risk factors were assessed repeatedly between 1980 and 2001 (ages 6-24 years), and transthoracic echocardiography and electrocardiography were performed in 2011. Associations between cumulative early life risk factors and P-wave duration, LA diameter, and LA volume were analysed using logistic regression. Body mass index (BMI) was the main modifiable determinant of P-wave prolongation and LA enlargement. Each standard deviation (SD) increase in early life BMI burden was associated with longer P-wave duration (0.120 SD; 1.85 ms), larger LA diameter (0.264 SD; 0.11 cm), and greater LA volume (0.235 SD; 3.31 mL). Male sex associated with all studied P-wave and LA parameters and older age associated with larger LA diameter. Higher physical activity in middle age was associated with 0.116 SD increased LA volume (1.64 mL). Participants with persistent or adult-onset high BMI were more likely to have larger LA. CONCLUSION:Excess BMI from childhood through adulthood is a key determinant of atrial remodelling in middle age. These findings highlight the long-term impact of early life adiposity and underscore the importance of lifelong weight management in preventing atrial cardiomyopathy and its clinical sequelae.

Background and aims: Longitudinal data and tracking of serum lipoprotein(a) (Lp(a)) concentrations through childhood?s development from infancy to adolescence are lacking. We aimed to establish the strength of the tracking phenomenon from early infancy to adolescence and to examine whether a heart-healthy dietary intervention and individual dietary components influence serum concentrations of Lp(a). Methods: 1062 healthy children aged 7 months were recruited and randomized into control (N=522) and intervention (N=540) groups in the Special Turku Coronary Risk Factor Intervention Project (STRIP). Serum Lp(a) concentration was measured at 10 age points (0.7, 1.3, 2, 3, 4, 5, 9, 11, 13, and 15 years) and median serum Lp(a) levels were studied longitudinally. Tracking across age points was studied using Spearman's rank-order correlation. Sex differences and the effects of the dietary intervention and individual dietary components were analyzed with linear mixed-effects models for repeated measures. Results: A total of 7018 Lp(a) measurements were analyzed. Median serum Lp(a) concentrations increased from infancy until approximately age 13 years. After age 13, median Lp(a) declined in boys (−15.1%) but was largely unchanged in girls. Girls had higher Lp(a) concentrations at all age points (P=0.01). Spearman's correlation analysis indicated a strong tracking between age points in both sexes (r=0.854-0.956). Achievement of at least one dietary fat quality goal of the intervention corresponded to a 2.5% increase in serum Lp(a) concentration (P=0.0004). Higher sucrose intake was associated with modestly higher Lp(a), whereas fiber intake showed no association. At age 15 years, 16.2% of all participants with available measurements had elevated Lp(a) (≥ 30mg/dL). Conclusions: A rising trend was observed in median serum Lp(a) concentrations from infancy to adolescence. Due to strong tracking, these findings suggest that early-life measurements may provide valuable insight for longitudinal cardiovascular risk assessment. Heart-healthy diet does not meaningfully influence serum Lp(a). ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial The STRIP study is registered at ClinicalTrials.gov, [NCT00223600][1], https://www.clinicaltrials.gov. ### Funding Statement This research was funded by the Research Council of Finland (grant numbers: 206374, 251360, 275595, 307996, 322112, 26081148, 347640); the Juho Vainio Foundation; the Finnish Foundation for Cardiovascular Research; the Finnish Ministry of Education and Culture; the Finnish Cultural Foundation; the Sigrid Jusélius Foundation; Special Governmental grants for Health Sciences Research; the Yrjö Jahnsson Foundation; the Finnish Medical Foundation; the Turku University Foundation; The Olvi Foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the Joint commission ethics committee of Turku University and Turku University Central Hospital. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data sharing outside the STRIP group requires a data sharing agreement. Investigators can submit an expression of interest to the STRIP Steering Committee (https://stripstudy.utu.fi/en/strip-study/). [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00223600&atom=%2Fmedrxiv%2Fearly%2F2026%2F06%2F29%2F2026.06.25.26356629.atom

Background: Lipoprotein(a) [Lp(a)] can be reported as mass concentration (mg/dL) or particle concentration (nmol/L). Because Lp(a) biology is likely mediated at the particle level, molar concentration may better reflect biologically relevant exposure. We compared molar- and mass-based Lp(a) measurements in relation to cardiovascular outcomes, LPA genetic variation, and apo(a) isoform phenotype in a population-based cohort. Methods: Lp(a) was measured in 6,182 participants in the Young Finns Study. Among participants aged ≥40 years, associations with prevalent coronary artery disease (CAD) and composite cardiovascular disease (CVD) were assessed using logistic regression models. Lp(a) was modeled as quintiles, inverse-normal transformed continuous variables, and clinically relevant cut-points. Discrimination and model fit were evaluated using c-statistics and Akaike?s Information Criterion. Associations with an LPA genetic risk score (GRS) and apo(a) isoform phenotype were examined using Spearman?s correlation analyses. Results: The relation between molar and mass Lp(a) was not constant across the concentration range. The molar-to-mass ratio increased across higher clinically relevant Lp(a) categories, indicating concentration-dependent correspondence between nmol/L and mg/dL. The molar-to-mass ratio was directly associated with the LPA GRS and inversely associated with apo(a) isoform size, and these associations were more strongly attenuated after adjustment for molar than for mass Lp(a). Across CAD and composite CVD, molar- and mass-based Lp(a) showed broadly similar associations. In fully adjusted CAD models, the odds ratio for the highest versus lowest quintile was 1.55 for molar Lp(a) and 1.67 for mass Lp(a); corresponding continuous-model ORs were 1.20 and 1.22 per 1-unit increase in inverse-normal transformed Lp(a). Discrimination and global model fit were essentially identical between the two measurement scales. Conclusions: Molar- and mass-based Lp(a) measurements showed comparable epidemiologic associations with prevalent cardiovascular outcomes. However, molar reporting aligned somewhat more closely with the genetic and structural determinants of Lp(a), supporting continued standardization toward particle-based reporting. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial This is not a clinical trial. ### Funding Statement The Young Finns Study has been financially supported by the Academy of Finland: grants 356405, 322098, 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117797 (Gendi), and 141071 (Skidi); the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; The Sigrid Juselius Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjö Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; Diabetes Research Foundation of Finnish Diabetes Association; EU Horizon 2020 (grant 755320 for TAXINOMISIS and grant 848146 for To Aition); European Research Council (grant 742927 for MULTIEPIGEN project); Tampere University Hospital Supporting Foundation; Finnish Society of Clinical Chemistry; the Cancer Foundation Finland; pBETTER4U_EU (Preventing obesity through Biologically and bEhaviorally Tailored inTERventions for you; project number: 101080117); CVDLink (EU grant nro. 101137278) and the Jane and Aatos Erkko Foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Regional Medical Research Ethics Committee of the Wellbeing Services County of Southwest Finland I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Anonymized data are available upon reasonable request from the YFS research group (https://youngfinnsstudy.utu.fi/).

MicroRNAs have been suggested as essential hypertension biomarkers, but evidence remains inconclusive due to limited high-throughput studies in population cohorts. We analyzed data from the Young Finns Study (YFS) from 2011 and 2018-2020 to assess cross-sectional and prospective associations between circulatory microRNAs, blood pressure (BP), and hypertension. Hypertension risk prediction potential was assessed using nested logistic and Weibull survival models; model performance was evaluated with likelihood ratio (LR) test and c-statistic. All models were adjusted with relevant risk factors. In 2011, whole blood microRNAs were profiled for 871 individuals (83 with hypertension); in 2018-2020, 760 were re-examined, with 67 newly diagnosed. Cross-sectionally, 16 miRNAs correlated with BP (Spearman, PFDR  < 0.05); miR-122-5p (fold change = 1.33) and miR-144-5p (fold change = -1.10) differentiated hypertensive individuals ( U test, PFDR  < 0.05). Associations persisted in adjusted regression models and some replicated in LURIC ( n  = 999) and YFS serum data ( n  = 126). Prospectively, miR-19a-3p [odds ratio (OR) = 1.51, 95% confidence interval (95% CI): 1.14-2.18], miR-19b-3p (OR = 1.50, 95% CI:1.11-2.04), and miR-329-3p (OR = 0.58, 95% CI: 0.39-0.74) levels prognosed hypertension incident. miR-329-3p improved model fit (LR test, P  = 2.85×10 -4 ) and discrimination (c-statistic = 0.849, Δ = 0.026). miR-19b-3p predicted time to onset (hazard ratio = 2.13, 95% CI: 1.38-4.45), improving model fit (LR test, P  = 0.0012) and time-dependent discrimination at 7 and 8-year horizons. Our findings highlight both novel and previously reported miRNAs associating with BP and hypertension and suggest that miR-329-3p, miR-19a-3p, and miR-19b-3p as promising candidates for further investigation in hypertension risk prediction.

BACKGROUND:Fatty liver is the most common chronic liver disease globally and is associated with increased cardiovascular risk. Evidence specifically addressing fatty liver and cardiovascular outcomes in young adults from European population-based cohorts remains scarce. METHODS:Fatty liver was assessed by abdominal ultrasound in 2008 participants of the Young Finns Study (age 34-49 years) in 2011. Incident composite cardiovascular disease (CVD) and coronary heart disease (CHD) were ascertained from national registries through 2024. Cox proportional hazards regression was used to examine associations between fatty liver and incident outcomes, with sequential adjustment for sex, age, waist circumference, apolipoprotein B (apoB), and C-reactive protein (CRP). RESULTS:Fatty liver was detected in 377 participants (19%). Over a median follow-up of 13 years, 124 CVD events and 71 CHD events occurred. Fatty liver was associated with incident CVD (HR 1.76, 95% CI 1.20-2.57) and CHD (HR 2.10, 95% CI 1.30-3.39) after adjustment for sex and age. The CVD association was attenuated to non-significance after further adjustment for apoB (HR 1.39, 95% CI 0.91-2.13, p = 0.134). The CHD association remained significant after adjustment for apoB (HR 1.82, 95% CI 1.06-3.12, p = 0.031) and was unchanged after additional adjustment for CRP (HR 1.81, 95% CI 1.06-3.10, p = 0.031), but was slightly attenuated after additional adjustment for markers of insulin resistance, such as HOMA-IR (HR 1.72, p = 0.056). CONCLUSIONS:Fatty liver in young adults was associated with incident CHD after adjustment for atherogenic dyslipidaemia and systemic inflammation, with modest attenuation after adjustment for insulin resistance. The association with composite CVD was substantially attenuated after adjustment for apoB. These findings support fatty liver as a marker of later CVD risk in young adults.

Cardiovascular Risk in Young Finns Study (YFS) is a prospective cohort of 3596 males and females (baseline age 3-18 years) that was established in 1980 to study cardiovascular risk factors in children and adolescents. The YFS has been instrumental in demonstrating the links between childhood risk factors and adult cardiovascular outcomes with implications on paediatric cardiovascular preventive practise. In the latest follow-up in 2018-2020, the study was expanded into a three-generation cohort, including the original cohort members, as well as their parents and offspring. Altogether 7341 individuals aged 3-92 years participated; 2127 original cohort members (now aged 40-58 years), 2452 parents (aged 58-92 years) and 2762 offspring (aged 3-37 years) of the original cohort members. The main aim was to establish a multigenerational population data base, sample biobank and links to national health registries that would offer a unique platform to study familial transmission of health-related traits. The field studies and data collections were conducted as part of the ERC funded MULTIEPIGEN project designed testing a specific hypothesis that epigenetic markers in the semen play a role in the transmission of intergenerational information in the paternal lineage. It is a first a priori designed epidemiologic study assessing the role of paternal life exposures, including chemical and psychosocial stress, in the development of cardio-metabolic, cognitive and psychosocial outcomes in their offspring. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The Young Finns Study has been financially supported by the Academy of Finland: grants 356405, 322098, 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117797 (Gendi), and 141071 (Skidi); the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; The Sigrid Juselius Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjo Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; Diabetes Research Foundation of Finnish Diabetes Association; EU Horizon 2020 (grant 755320 for TAXINOMISIS and grant 848146 for To Aition); European Research Council (grant 742927 for MULTIEPIGEN project); Tampere University Hospital Supporting Foundation; Finnish Society of Clinical Chemistry; the Cancer Foundation Finland; pBETTER4U_EU (Preventing obesity through Biologically and bEhaviorally Tailored inTERventions for you; project number: 101080117); CVDLink (EU grant nro. 101137278) and the Jane and Aatos Erkko Foundation; Research Committee of the Kuopio University Hospital Catchment Area (State Research Funding, 5031364); Research Council of Finland Flagship InFLAMES (funding decision numbers 337530 and 357910). Pashupati P. Mishra was supported by the Academy of Finland (Grant number: 349708) and Emma Raitoharju (grants: 330809, 338395). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical committees of the Hospital District of Southwest Finland and the European Research Council have approved the study. All individuals and/or legal guardians have signed a written informed consent to take part in the study. They had the right to refuse any part of the study protocol or discontinue at any time without the need to give any explanation. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Due to the local legal restrictions concerning the distribution of all personal information, allowance of open access to the YFS data is not possible. Therefore, data sharing outside the study group requires a data-sharing agreement. Investigators can submit an expression of interest to the YFS Steering Group / Data Sharing Committee (PI of the YFS, Prof. Olli Raitakari, olli.raitakari@utu.fi).

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.

PURPOSE:To examine whether cumulative physical activity (PA) in youth, adulthood, or from childhood to midlife is associated with cognitive changes in midlife. We further investigated whether cumulative PA in youth or adulthood was independently related to cognitive changes and whether these associations differed by sex. METHODS:This study utilized data ( n = 1353, 57% females) from the longitudinal, population-based cardiovascular risk in Young Finns Study, initiated in 1980. Cognitive functions (learning and memory, working memory, reaction time, and information processing) were evaluated using the Cambridge Neuropsychological Test Automated Battery in 2011 and 2018. PA was assessed with a standardized questionnaire in all study phases (1980-2018), with repeated measurements conducted at 3- to 9-yr intervals. Cumulative PA was determined for youth (ages 9-24), adulthood (ages 24-48), and life course (ages 9-48). Associations were analyzed using linear regression models with standardized variables, adjusted for age, education, cardiometabolic risk factors, health behaviors, and a polygenic risk score for cognitive function. Models of cumulative PA in youth and adulthood were additionally adjusted for each other. RESULTS:Higher life-course PA was associated with a smaller decrease in information processing in midlife (β = 0.08, P = 0.003; each unit increase in PA corresponded to a predicted 3-yr advantage in information processing). Moreover, higher life-course PA was associated with a smaller decrease in working memory among males (β = 0.09, P = 0.040; a predicted 2.7-yr advantage in working memory). Life-course PA was not associated with other cognitive functions. Youth PA showed no association with cognitive changes after adjusting for adulthood PA, and vice versa. CONCLUSIONS:The results suggest that individuals with higher life-course PA experience a smaller decrease in executive aspects of cognitive function during midlife.

Late diagnosis of type 2 diabetes increases patient morbidity and healthcare burden, yet current prediction models use adult risk factors to estimate 5–10-year risk. In this manuscript, we evaluate long-term prediction of type 2 diabetes over 38 years using childhood factors and polygenic risk scores (PRSs). Data from the longitudinal Cardiovascular Risk in Young Finns Study were analyzed. Childhood features—including anthropometric, demographic, lifestyle, parental characteristics, blood biomarkers, and PRSs—were used to train machine learning models to predict type 2 diabetes. Multiple feature selection, imputation, and classification algorithms were applied. Results were validated using nested cross-validation and assessed by the area under the receiver operating characteristic curve (AUROC). Added value of genetic data was evaluated using category-free net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Feature importance was assessed with Shapley additive explanations (SHAP). Diabetes status was available for 2,144 of 3,596 participants; 249 (11.6%) developed type 2 diabetes, with a mean onset age of 44.3 years. Random forest achieved the highest performance in distinguishing high-risk individuals (AUROC 0.737 [95% CI, 0.706–0.766]). Including PRSs improved prediction (NRI 0.201 [95% CI, 0.121–0.280]; IDI 0.014 [95% CI, 0.002–0.025]). The top five predictors were the PRS for type 2 diabetes, maternal body mass index (BMI), PRS for BMI, subscapular skinfold thickness, and C-reactive protein. Combining childhood, adolescent, and genetic data with machine learning, particularly tree-based ensemble methods such as random forest, enables long-term prediction of type 2 diabetes risk and improves early identification of high-risk individuals to institute lifelong risk modification strategies.

Abstract Background DNA methylation (DNAm) may capture cumulative genetic, environmental, and lifestyle influences on cardiovascular health. Composite DNAm score based on the American Heart Association Life’s Essential 8 (LE8) framework have been linked to clinical events, but their association with early vascular changes and intergenerational effects is unclear. Methods We studied up to 1432 participants from the multigenerational Young Finns Study (YFS-3G), including parents (G0) and adult offspring (G1). DNAm was measured using Illumina EPIC arrays in 2011 and/or 2018, and carotid intima–media thickness (cIMT) was assessed in 2018. The LE8 DNAm score was calculated as a weighted sum of methylation levels. Associations with cIMT were evaluated in intergenerational, prospective, and cross-sectional settings, adjusting for demographic, technical, and biological covariates and conventional cardiovascular risk factors. Results Higher parental LE8 DNAm score was associated with lower offspring cIMT (β = −0.022 mm/SD; p-value = 0.02), although the association was attenuated after adjustment for parental cardiovascular risk factors. In G1, a higher baseline DNAm score was associated with lower cIMT measured seven years later (β = −0.030 mm/SD; p-value = 1.1 × 10⁻⁵). This association remained significant after adjustment for follow-up cardiovascular risk factors (p-value=0.009) but not after additional adjustment for prior cIMT. Cross-sectionally, higher DNAm score was associated with lower cIMT in both generations, with attenuation after risk factor adjustment in G1 but not G0. Associations with carotid plaque were not significant. Genes associated with the DNAm score were enriched for immune and inflammatory pathways. Conclusions An LE8-derived DNAm score was associated with lower cIMT across the life course and, to a lesser extent, across generations. These findings suggest that blood DNAm reflects cumulative cardiovascular health and vascular burden and may complement conventional cardiovascular risk assessment.

Background:Neighbourhood socioeconomic disadvantage is a known determinant of cardiovascular disease (CVD) risk. However, its impact on subclinical atherosclerosis across the life course remains inadequately understood. This study examined the association between cumulative neighbourhood socioeconomic disadvantage from childhood to midlife and carotid artery plaques-a marker of subclinical atherosclerosis-independent of genetic and behavioral CVD risk factors. Methods:We analysed data from 2,051 participants in the Cardiovascular Risk in Young Finns Study, a prospective 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 childhood/adolescence, adulthood, and the entire life course. The number of carotid artery plaques (plaque count) were assessed by standardized ultrasound imaging. Multivariable Poisson regression models were used to evaluate associations, adjusting for age, sex, individual and parental socioeconomic status, genetic predisposition, and cardiovascular risk profiles. Mediation analyses assessed the role of ideal cardiovascular health (CVH) metrics. Results:No cross-sectional association was found between current neighbourhood disadvantage and carotid plaque count. However, higher cumulative neighbourhood disadvantage over the life course was associated with increased plaque count (rate ratio [RR] ≈ 1.20 per 1 SD increase). This relationship persisted after controlling for parental carotid artery plaques, polygenic coronary artery disease risk score, and Framingham risk score. The effect was partially mediated by ideal CVH metrics, particularly smoking and blood pressure, which collectively explained up to 50% 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. Behavioural risk factors partially mediate this link, highlighting the importance of early and sustained interventions targeting both social environments and health behaviours to mitigate cardiovascular risk.