Association analysis between an epigenetic risk score and blood pressure.

Background: Epigenome-wide association studies have revealed multiple DNA methylation sites (CpGs) associated with alcohol consumption, an important lifestyle risk factor for cardiovascular diseases. Results: We generated an alcohol consumption epigenetic risk score (ERS) based on previously reported 144 alcohol-associated CpGs and examined the association of the ERS with systolic blood pressure (SBP), diastolic blood pressure (DBP), and hypertension (HTN) in 3,898 Framingham Heart Study (FHS) participants. We found an association of alcohol intake with the ERS in the meta-analysis with 0.09 units higher ERS per drink consumed per day (p < 0.0001). Cross-sectional analyses in FHS revealed that a one-unit increment of the ERS was associated with 1.93 mm Hg higher SBP (p = 4.64E-07), 0.68 mm Hg higher DBP (p = 0.006), and an odds ratio of 1.78 for HTN (p < 2E-16). Meta-analysis of the cross-sectional association of the ERS with BP traits in eight independent external cohorts (n = 11,544) showed similar relationships with blood pressure levels, i.e., a one-unit increase in ERS was associated with 0.74 (p = 0.002) and 0.50 (p = 0.0006) mm Hg higher SBP and DBP, but could not confirm the association with hypertension. Longitudinal analyses in FHS (n = 3,260) and five independent external cohorts (n = 4,021) showed that the baseline ERS was not associated with a change in blood pressure over time or with incident HTN. Conclusions: Our findings provide proof-of-concept that utilizing an ERS is a useful approach to capture the recent health consequences of lifestyle behaviors such as alcohol consumption.

Weight-Bearing Physical Activity, Lower-Limb Muscle Mass, and Risk of Knee Osteoarthritis.

Importance: It has been demonstrated that total physical activity is not associated with risk of osteoarthritis. However, the association of different types of physical activity with incident knee osteoarthritis remains unclear. Objective: To determine whether weight-bearing recreational physical activities are associated with increased risk of incident knee osteoarthritis. Design, Setting, and Participants: This prospective cohort study used data from the Rotterdam Study (1996 to 2009), including participants with knee x-ray measurements at baseline and follow-up examinations. Participants with knee osteoarthritis at baseline were excluded. Residents aged 45 years and older of the Ommoord district in the city of Rotterdam in The Netherlands were invited to join the Rotterdam Study (78% response rate). Analysis was conducted in June 2023. Exposure: Total, weight-bearing, and non-weight-bearing recreational physical activities collected by questionnaires at baseline. Main Outcomes and Measures: Incident radiographic knee osteoarthritis measured by knee x-ray was the primary outcome, and incident symptomatic knee osteoarthritis defined by x-ray and knee pain questionnaire was the secondary outcome. The association of different types of recreational physical activity with radiographic knee osteoarthritis was examined using logistic regression within generalized estimating equation framework after adjusting for potential confounders. A prespecified stratification analysis was planned on the basis of lower-limb muscle mass index (LMI) tertiles, measured by dual-energy x-ray absorptiometry. Results: A total of 5003 individuals (2804 women [56.0%]; mean [SD] age, 64.5 [7.9] years) were included. The knee osteoarthritis incident rate was 8.4% (793 of 9483 knees) for a mean (SD) follow-up time of 6.33 (2.46) years. Higher weight-bearing activity was associated with increased odds of incident knee osteoarthritis (odds ratio [OR], 1.22; 95% CI, 1.10-1.35; P < .001), but non-weight-bearing activity was not (OR, 1.04; 95% CI, 0.95-1.15; P = .37). In the analysis stratified by LMI tertiles, the association of weight-bearing activity with incident osteoarthritis was found only among 431 patients in the lowest LMI tertile (OR, 1.53; 95% CI, 1.15-2.04; P = .003), but not among patients in the middle or high LMI tertile. Conclusions and Relevance: The findings of this study suggest that weight-bearing activity is associated with incident knee osteoarthritis in people with low levels of lower-limb muscle mass, which might be a promising avenue for tailored advice for physical activity.

Association analysis between an epigenetic alcohol risk score and blood pressure.

Background: Epigenome-wide association studies have revealed multiple DNA methylation sites (CpGs) associated with alcohol consumption, an important lifestyle risk factor for cardiovascular diseases. Results: We generated an alcohol consumption epigenetic risk score (ERS) based on previously reported 144 alcohol-associated CpGs and examined the association of the ERS with systolic blood pressure (SBP), diastolic blood pressure (DBP), and hypertension (HTN) in 3,898 Framingham Heart Study (FHS) participants. We found an association of alcohol intake with the ERS in the meta-analysis with 0.09 units higher ERS per drink consumed per day (p < 0.0001). Cross-sectional analyses in FHS revealed that a one-unit increment of the ERS was associated with 1.93 mm Hg higher SBP (p = 4.64E-07), 0.68 mm Hg higher DBP (p = 0.006), and an odds ratio of 1.78 for HTN (p < 2E-16). Meta-analysis of the cross-sectional association of the ERS with BP traits in eight independent external cohorts (n = 11,544) showed similar relationships with blood pressure levels, i.e., a one-unit increase in ERS was associated with 0.74 (p = 0.002) and 0.50 (p = 0.0006) mm Hg higher SBP and DBP, but could not confirm the association with hypertension. Longitudinal analyses in FHS (n = 3,260) and five independent external cohorts (n = 4,021) showed that the baseline ERS was not associated with a change in blood pressure over time or with incident HTN. Conclusions: Our findings provide proof-of-concept that utilizing an ERS is a useful approach to capture the recent health consequences of lifestyle behaviors such as alcohol consumption.

Sarcopenia and Sarcopenic Obesity and Mortality Among Older People.

Importance: Sarcopenia and obesity are 2 global concerns associated with adverse health outcomes in older people. Evidence on the population-based prevalence of the combination of sarcopenia with obesity (sarcopenic obesity [SO]) and its association with mortality are still limited. Objective: To investigate the prevalence of sarcopenia and SO and their association with all-cause mortality. Design, Setting, and Participants: This large-scale, population-based cohort study assessed participants from the Rotterdam Study from March 1, 2009, to June 1, 2014. Associations of sarcopenia and SO with all-cause mortality were studied using Kaplan-Meier curves, Cox proportional hazards regression, and accelerated failure time models fitted for sex, age, and body mass index (BMI). Data analysis was performed from January 1 to April 1, 2023. Exposures: The prevalence of sarcopenia and SO, measured based on handgrip strength and body composition (BC) (dual-energy x-ray absorptiometry) as recommended by current consensus criteria, with probable sarcopenia defined as having low handgrip strength and confirmed sarcopenia and SO defined as altered BC (high fat percentage and/or low appendicular skeletal muscle index) in addition to low handgrip strength. Main Outcome and Measure: The primary outcome was all-cause mortality, collected using linked mortality data from general practitioners and the central municipal records, until October 2022. Results: In the total population of 5888 participants (mean [SD] age, 69.5 [9.1] years; mean [SD] BMI, 27.5 [4.3]; 3343 [56.8%] female), 653 (11.1%; 95% CI, 10.3%-11.9%) had probable sarcopenia and 127 (2.2%; 95% CI, 1.8%-2.6%) had confirmed sarcopenia. Sarcopenic obesity with 1 altered component of BC was present in 295 participants (5.0%; 95% CI, 4.4%-5.6%) and with 2 altered components in 44 participants (0.8%; 95% CI, 0.6%-1.0%). An increased risk of all-cause mortality was observed in participants with probable sarcopenia (hazard ratio [HR], 1.29; 95% CI, 1.14-1.47) and confirmed sarcopenia (HR, 1.93; 95% CI, 1.53-2.43). Participants with SO plus 1 altered component of BC (HR, 1.94; 95% CI, 1.60-2.33]) or 2 altered components of BC (HR, 2.84; 95% CI, 1.97-4.11) had a higher risk of mortality than those without SO. Similar results for SO were obtained for participants with a BMI of 27 or greater. Conclusions and Relevance: In this study, sarcopenia and SO were found to be prevalent phenotypes in older people and were associated with all-cause mortality. Additional alterations of BC amplified this risk independently of age, sex, and BMI. The use of low muscle strength as a first step of both diagnoses may allow for early identification of individuals at risk for premature mortality.

Diet quality in relation to kidney function and its potential interaction with genetic risk of kidney disease among Dutch post-myocardial infarction patients.

PURPOSE: We examined the relation between diet quality, its components and kidney function decline in post-myocardial infarction (MI) patients, and we explored differences by genetic risk of chronic kidney disease (CKD). METHODS: We analysed 2169 patients from the Alpha Omega Cohort (aged 60-80 years, 81% male). Dietary intake was assessed at baseline (2002-2006) using a validated food-frequency questionnaire and diet quality was defined using the Dutch Healthy Diet Cardiovascular Disease (DHD-CVD) index. We calculated 40-months change in estimated glomerular filtration rate (eGFR, mL/min per 1.73m2). We constructed a weighted genetic risk score (GRS) for CKD using 88 single nucleotide polymorphisms previously linked to CKD. Betas with 95%-confidence intervals (CIs) were obtained using multivariable linear regression models for the association between DHD-CVD index and its components and eGFR change, by GRS. RESULTS: The average DHD-CVD index was 79 (SD 15) points and annual eGFR decline was 1.71 (SD 3.86) mL/min per 1.73 m2. The DHD-CVD index was not associated with annual eGFR change (per 1-SD increment in adherence score: -0.09 [95% CI -0.26,0.08]). Results for adherence to guidelines for red meat showed less annual eGFR decline (per 1-SD: 0.21 [0.04,0.38]), whereas more annual eGFR decline was found for legumes and dairy (per 1-SD: -0.20legumes [-0.37,-0.04] and - 0.18dairy [-0.34,-0.01]). Generally similar results were obtained in strata of GRS. CONCLUSION: The DHD-CVD index for overall adherence to Dutch dietary guidelines for CVD patients was not associated with kidney function decline after MI, irrespective of genetic CKD risk. The preferred dietary pattern for CKD prevention in CVD patients warrants further research.

The Rotterdam Study. Design update and major findings between 2020 and 2024.

The Rotterdam Study is a population-based cohort study, started in 1990 in the district of Ommoord in the city of Rotterdam, the Netherlands, with the aim to describe the prevalence and incidence, unravel the etiology, and identify targets for prediction, prevention or intervention of multifactorial diseases in mid-life and elderly. The study currently includes 17,931 participants (overall response rate 65%), aged 40 years and over, who are examined in-person every 3 to 5 years in a dedicated research facility, and who are followed-up continuously through automated linkage with health care providers, both regionally and nationally. Research within the Rotterdam Study is carried out along two axes. First, research lines are oriented around diseases and clinical conditions, which are reflective of medical specializations. Second, cross-cutting research lines transverse these clinical demarcations allowing for inter- and multidisciplinary research. These research lines generally reflect subdomains within epidemiology. This paper describes recent methodological updates and main findings from each of these research lines. Also, future perspective for coming years highlighted.

Animal and plant protein intake during infancy and childhood DNA methylation: a meta-analysis in the NutriPROGRAM consortium.

BACKGROUND: Higher early-life animal protein intake is associated with a higher childhood obesity risk compared to plant protein intake. Differential DNA methylation may represent an underlying mechanism. METHODS: We analysed associations of infant animal and plant protein intakes with DNA methylation in early (2-6 years, N = 579) and late (7̄-12 years, N = 604) childhood in two studies. Study-specific robust linear regression models adjusted for relevant confounders were run, and then meta-analysed using a fixed-effects model. We also performed sex-stratified meta-analyses. Follow-up analyses included pathway analysis and eQTM look-up. RESULTS: Infant animal protein intake was not associated with DNA methylation in early childhood, but was associated with late-childhood DNA methylation at cg21300373 (P = 4.27 × 10¯8, MARCHF1) and cg10633363 (P = 1.09 × 10¯7, HOXB9) after FDR correction. Infant plant protein intake was associated with early-childhood DNA methylation at cg25973293 (P = 2.26 × 10-7, C1orf159) and cg15407373 (P = 2.13 × 10-7, MBP) after FDR correction. There was no overlap between the findings from the animal and plant protein analyses. We did not find enriched functional pathways at either time point using CpGs associated with animal and plant protein. These CpGs were not previously associated with childhood gene expression. Sex-stratified meta-analyses showed sex-specific DNA methylation associations for both animal and plant protein intake. CONCLUSION: Infant animal protein intake was associated with DNA methylation at two CpGs in late childhood. Infant plant protein intake was associated with DNA methylation in early childhood at two CpGs. A potential mediating role of DNA methylation at these CpGs between infant protein intake and health outcomes requires further investigation.

Genome-Wide Interaction Analysis With DASH Diet Score Identified Novel Loci for Systolic Blood Pressure.

BACKGROUND: The Dietary Approaches to Stop Hypertension (DASH) diet score lowers blood pressure (BP). We examined interactions between genotype and the DASH diet score in relation to systolic BP. METHODS: We analyzed up to 9 420 585 single nucleotide polymorphisms in up to 127 282 individuals of 6 population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (n=35 660) and UK Biobank (n=91 622) and performed European population-specific and cross-population meta-analyses. RESULTS: We identified 3 loci in European-specific analyses and an additional 4 loci in cross-population analyses at Pinteraction<5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency, 0.03) and the DASH diet score (Pinteraction=4e-8; P for heterogeneity, 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg (Pinteraction=9.4e-7) and 0.20±0.06 mm Hg (Pinteraction=0.001) in Cohorts for Heart and Aging Research in Genomic Epidemiology and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with cis-expression quantitative trait loci (eQTL) variants (P=4e-273) and cis-DNA methylation quantitative trait loci variants (P=1e-300). Although the closest gene for rs117878928 is MTHFS, the highest narrow sense heritability accounted by single nucleotide polymorphisms potentially interacting with the DASH diet score in this locus was for gene ST20 at 15q25.1. CONCLUSIONS: We demonstrated gene-DASH diet score interaction effects on systolic BP in several loci. Studies with larger diverse populations are needed to validate our findings.

Body composition and plasma total-tau, neurofilament light chain, and amyloid-ß: A population-based study.

A higher body mass at older age has been linked to a lower risk of dementia. This unexpected trend may be explained by age-related lean mass depletion, or methodological issues such as the long preclinical phase of dementia or competing risks. Focusing on preclinical markers of dementia may overcome these issues. Between 2002 and 2005, body composition and plasma total-tau, neurofilament light chain (NfL), amyloid-ß40, and amyloid-ß42 were measured in 3408 dementia-free participants from the population-based Rotterdam Study. The cross-sectional associations between body composition and plasma markers were determined using linear regression models. Whole body and fat mass, but not lean mass, were positively associated with total-tau, while all these measures were inversely associated with NfL. Apart from an inverse association between lean mass and amyloid-ß40, body composition measures were not associated with plasma amyloid-ß. Our findings suggest distinct effects of body composition on neurodegeneration.

Cardiovascular risk burden, dementia risk and brain structural imaging markers: a study from UK Biobank.

Background: Cardiovascular risk burden is associated with dementia risk and neurodegeneration-related brain structure, while the role of genetics and incident cardiovascular disease (CVD) remains unclear. Aims: To examine the association of overall cardiovascular risk burden with the risk of major dementia subtypes and volumes of related brain regions in a large sample, and to explore the role of genetics and CVD onset. Methods: A prospective study among 354 654 participants free of CVD and dementia (2006-2010, mean age 56.4 years) was conducted within the UK Biobank, with brain magnetic resonance imaging (MRI) measurement available for 15 104 participants since 2014. CVD risk burden was evaluated by the Framingham General Cardiovascular Risk Score (FGCRS). Dementia diagnosis was ascertained from inpatient and death register data. Results: Over a median 12.0-year follow-up, 3998 all-cause dementia cases were identified. Higher FGCRS was associated with increased all-cause dementia risk after adjusting for demographic, major lifestyle, clinical factors and the polygenic risk score (PRS) of Alzheimer's disease. Comparing the high versus low tertile of FGCRS, the odds ratios (ORs) and 95% confidence intervals (CIs) were 1.26 (1.12 to 1.41) for all-cause dementia, 1.67 (1.33 to 2.09) for Alzheimer's disease and 1.53 (1.07 to 2.16) for vascular dementia (all ptrend<0.05). Incident stroke and coronary heart disease accounted for 14% (95% CI: 9% to 21%) of the association between FGCRS and all-cause dementia. Interactions were not detected for FGCRS and PRS on the risk of any dementia subtype. We observed an 83% (95% CI: 47% to 128%) higher all-cause dementia risk comparing the high-high versus low-low FGCRS-PRS category. For brain volumes, higher FGCRS was associated with greater log-transformed white matter hyperintensities, smaller cortical volume and smaller grey matter volume. Conclusions: Our findings suggest that the positive association of cardiovascular risk burden with dementia risk also applies to major dementia subtypes. The association of cardiovascular risk burden with all-cause dementia is largely independent of CVD onset and genetic predisposition to dementia.

Dairy Intake and Risk of Cognitive Decline and Dementia: A Systematic Review and Dose-Response Meta-Analysis of Prospective Studies.

Dairy intake may influence cognition through several molecular pathways. However, epidemiologic studies yield inconsistent results, and no dose-response meta-analysis has been conducted yet. Therefore, we performed a systematic review with a dose-response meta-analysis about the association between dairy intake and cognitive decline or incidence of dementia. We investigated prospective studies with a follow-up ≥6 mo on cognitive decline or dementia incidence in adults without known chronic conditions through a systematic search of Embase, Medline, Cochrane Library, Web of Science, and Google Scholar from inception to 11 July 2023. We evaluated the dose-response association using a random-effects model. We identified 15 eligible cohort studies with >300,000 participants and a median follow-up of 11.4 y. We observed a negative nonlinear association between cognitive decline/dementia incidence and dairy intake as assessed through the quantity of consumption, with the nadir at ∼150 g/d (risk ratio: 0.88; 95% confidence interval: 0.78, 0.99). Conversely, we found an almost linear negative association when we considered the frequency of consumption (risk ratio for linear trend: 0.84; 95% confidence interval: 0.77, 0.92 for 1 time/d increase of dairy products). Stratified analysis by dairy products showed different shapes of the association with linear inverse relationship for milk intake, whereas possibly nonlinear for cheese. The inverse association was limited to Asian populations characterized by generally lower intake of dairy products, compared with the null association reported by European studies. In conclusion, our study suggests a nonlinear inverse association between dairy intake and cognitive decline or dementia, also depending on dairy types and population characteristics, although the heterogeneity was still high in overall and several subgroup analyses. Additional studies should be performed on this topic, including a wider range of intake and types of dairy products, to confirm a potential preventing role of dairy intake on cognitive decline and identify ideal intake doses. This review was registered at PROSPERO as CRD42020192395.

Genome-Wide Interaction Analysis with DASH Diet Score Identified Novel Loci for Systolic Blood Pressure.

Objective: We examined interactions between genotype and a Dietary Approaches to Stop Hypertension (DASH) diet score in relation to systolic blood pressure (SBP). Methods: We analyzed up to 9,420,585 biallelic imputed single nucleotide polymorphisms (SNPs) in up to 127,282 individuals of six population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (CHARGE; n=35,660) and UK Biobank (n=91,622) and performed European population-specific and cross-population meta-analyses. Results: We identified three loci in European-specific analyses and an additional four loci in cross-population analyses at P for interaction < 5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency = 0.03) and the DASH diet score (P for interaction = 4e-8; P for heterogeneity = 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg (P for interaction = 9.4e-7) and 0.20±0.06 mm Hg (P for interaction = 0.001) in CHARGE and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with cis-expression quantitative trait loci (eQTL) variants (P = 4e-273) and cis-DNA methylation quantitative trait loci (mQTL) variants (P = 1e-300). While the closest gene for rs117878928 is MTHFS, the highest narrow sense heritability accounted by SNPs potentially interacting with the DASH diet score in this locus was for gene ST20 at 15q25.1. Conclusion: We demonstrated gene-DASH diet score interaction effects on SBP in several loci. Studies with larger diverse populations are needed to validate our findings.

Serum uric acid is related to liver and kidney disease and 12-year mortality risk after myocardial infarction.

Objective: To study the associations of non-alcoholic fatty liver disease (NAFLD), chronic kidney disease (CKD), and serum uric acid (SUA) in patients with post-myocardial infarction (MI) patients, and the relationship of SUA with 12-year mortality risk. Methods: We included 3,396 patients (60-80 years old, 78% men) of the Alpha Omega Cohort. Multivariable prevalence ratios (PRs) were obtained for the association of NAFLD [fatty liver index (FLI), ≥77 (women) and ≥79 (men)] with CKD [estimated glomerular filtration rate (eGFR), <60 mL/min per 1.73 m2]. We calculated sensitivity and specificity of SUA to detect the (combined) presence and absence of NAFLD and CKD. Cause-specific mortality was monitored from enrolment (2002-2006) through December 2018. Hazard ratios (HRs) for all-cause and cardiovascular disease (CVD) mortality in SUA categories were obtained from multivariable Cox models. Results: Median baseline FLI was 67 (men, 68; women, 64), and mean ± SD eGFR was 81 ± 20 mL/min per 1.73 m2 (17% with CKD). Sex-specific FLI was associated with higher CKD prevalence (PRtertile3 vs. tertile1, 1.94; 95% confidence interval: 1.57, 2.39). Baseline SUA was 0.36 ± 0.09 mmol/L. With increasing SUA concentrations, specificity for the presence of NAFLD, CKD, or both increased, and sensitivity decreased. During 12 (interquartile range, 9-14) years of follow-up, 1,592 patients died (713 from CVD). HRs ranged from 1.08 (0.88, 1.32) for SUA ≤0.25 mmol/L to 2.13 (1.75, 2.60) for SUA >0.50 mmol/L vs. SUA >0.30-0.35 mmol/L for all-cause mortality. For CVD mortality, HRs ranged from 1.05 (0.77, 1.44) to 2.43 (1.83, 3.25). Conclusions: NAFLD and CKD were strongly associated, which was reflected by higher SUA concentrations. SUA was a strong predictor of 12-year mortality risk after MI.

The inflammatory potential of diet is associated with the risk of age-related eye diseases.

BACKGROUND & AIMS: Inflammation is involved in the pathogenesis of cataract, age-related macular degeneration (AMD), and possibly open-angle glaucoma (OAG). We assessed whether the inflammatory potential of diet (quantified using the dietary inflammatory index; DII) affects the incidence of these common blinding age-related eye diseases. Serum inflammation markers were investigated as possible mediators. METHODS: Participants aged >45 years were selected from the prospective, population-based Rotterdam Study. From 1991 onwards, every 4-5 years, participants underwent extensive eye examinations. At baseline, blood samples and dietary data (using food frequency questionnaires) were collected. The DII was adapted based on the data available. Of the 7436 participants free of eye diseases at baseline, 4036 developed incident eye diseases during follow-up (cataract = 2895, early-intermediate AMD = 891, late AMD = 81, OAG = 169). RESULTS: The adapted DII (aDII) ranged from -4.26 (i.e., anti-inflammatory) to 4.53 (i.e., pro-inflammatory). A higher aDII was significantly associated with increased inflammation. A higher neutrophil-lymphocyte ratio (NLR) was associated with an increased risk of cataract and AMD. Additionally, complement component 3c (C3c) and systemic immune-inflammation index (SII) were associated with increased risks of cataract and late AMD, respectively. Every point increase in the aDII was associated with a 9% increased risk of cataract (Odds ratio [95% confidence interval]: 1.09 [1.04-1.14]). The NLR and C3c partly mediated this association. We also identified associations of the aDII with risk of AMD (early-intermediate AMD, OR [95% CI]: 1.11 [1.03-1.19]; late AMD, OR [95% CI]: 1.24 [1.02-1.53]). The NLR partly mediated these associations. The aDII was not associated with OAG. CONCLUSIONS: A pro-inflammatory diet was associated with increased risks of cataract and AMD. Particularly the NLR, a marker of subclinical inflammation, appears to be implicated. These findings are relevant for patients with AMD and substantiate the current recommendations to strive for a healthy lifestyle to prevent blindness.

Cross-sectional association between metabolic parameters and psychotic-like experiences in a population-based sample of middle-aged and elderly individuals.

BACKGROUND: Metabolic alterations are often found in patients with clinical psychosis early in the course of the disorder. Psychotic-like experiences are observed in the general population, but it is unclear whether these are associated with markers of metabolism. METHODS: A population-based cohort of 1890 individuals (mean age 58.0 years; 56.3% women) was included. Metabolic parameters were measured by body-mass index (BMI), concentrations of low-density and high-density lipoprotein cholesterol (LDL-C and HDL-C), total cholesterol, triglycerides, and fasting glucose and insulin in blood. Frequency and distress ratings of psychotic-like experiences from the positive symptom dimension of the Community Assessment of Psychic Experience questionnaire were assessed. Cross-sectional associations were analysed using linear regression analyses. RESULTS: Higher BMI was associated with higher frequency of psychotic-like experiences (adjusted mean difference: 0.04, 95% CI 0.02-0.06) and more distress (adjusted mean difference: 0.02, 95% CI 0.01-0.03). Lower LDL-C was associated with more psychotic-like experiences (adjusted mean difference: -0.23, 95% CI -0.40 to -0.06). When restricting the sample to those not using lipid-lowering medication, the results of BMI and LDL-C remained and an association between lower HDL-C and higher frequency of psychotic-like experiences was found (adjusted mean difference: -0.37, 95% CI -0.69 to -0.05). We observed no significant associations between cholesterol, triglycerides, glucose, insulin or homeostatic model assessment and psychotic-like experiences. CONCLUSIONS: In a population-based sample of middle-aged and elderly individuals, higher BMI and lower LDL-C were associated with psychotic-like experiences. This suggests that metabolic markers are associated with psychotic-like experiences across the vulnerability spectrum.

Plant-based dietary patterns and the risk of dementia: a population-based study.

BACKGROUND: Plant-based dietary patterns are increasingly popular in western countries and are supported by many governments and health organisations for their potential beneficial role in the prevention of chronic diseases. Yet, the potential role of plant-based dietary patterns in the development of dementia remains unclear. OBJECTIVE: To evaluate the association between plant-based dietary patterns and the risk of dementia. METHODS: Dietary intake was measured at baseline in 9,543 dementia-free participants (mean age 64 years, birth years 1897-1960, 58% women) of the prospective population-based Rotterdam Study, using food frequency questionnaires. Based on these questionnaires, we calculated an overall plant-based dietary index (PDI), healthy PDI (hPDI) and unhealthy PDI (uPDI), with higher scores reflecting higher consumption of (any, healthy and unhealthy, respectively) plant-based foods and lower consumption of animal-based foods. We analysed the association of the PDIs with incident dementia using Cox proportional hazard models. RESULTS: During a mean follow-up of 14.5 years, 1,472 participants developed dementia. Overall, the PDIs were not associated with the risk of dementia (hazard ratio [95% confidence interval] per 10-point increase: 0.99 [0.91-1.08] for PDI, 0.93 [0.86-1.01] for hPDI, 1.02 [0.94-1.10] for uPDI). However, among men and APOE ε4 carriers, a higher hPDI was linearly associated with a lower risk of dementia (0.86 [0.75-0.99] and 0.83 [0.73-0.95], respectively), while this association was U-shaped among APOE ε4 non-carriers (P value for non-linearity = 0.01). CONCLUSIONS: We found no strong evidence for an overall association between plant-based eating and the risk of dementia. Our findings in stratified analyses warranted further investigation.

n-6 fatty acid biomarkers and incident atrial fibrillation: an individual participant-level pooled analysis of 11 international prospective studies.

BACKGROUND: The presence of atrial fibrillation (AF) is associated with an over 2-fold increased risk of stroke, heart failure, and cardiovascular mortality. Long chain n-6 PUFAs have been suggested to have a variety of beneficial biologic effects that may reduce AF development; however, prior studies evaluating this relationship are limited. OBJECTIVES: We prospectively evaluated the association between circulating levels of linoleic acid (LA) and arachidonic acid (AA) with incident AF. METHODS: We used participant-level data from a global consortium of 11 prospective cohort studies with measurements of LA and AA in adults (aged ≥18 y). Participating studies conducted de novo analyses using a prespecified analytical plan with harmonized definitions for exposures, outcomes, covariates, and subgroups. Associations were pooled using inverse-variance weighted meta-analysis. RESULTS: Among 41,335 participants, 6173 incident cases of AF were ascertained, with median follow-up time of 14 y. In multivariable analysis, per interquintile range (difference between the 10th and 90th percentiles for each fatty acid), circulating n-6 levels were not associated with incident AF. For LA, the hazard ratio per interquintile range was 0.96 (95% confidence interval [CI]: 0.89, 1.04), and for AA, 1.02 (95% CI: 0.94, 1.10), with little evidence of heterogeneity between cohorts. Associations were similarly nonsignificant across subgroups of age, race, and biomarker fraction. CONCLUSIONS: Biomarkers of n-6 fatty acids including LA and AA are not associated with incident AF. These findings suggest that overall effects of n-6 PUFAs on influencing AF development are neutral.

Fatty Liver Index and mortality after myocardial infarction: A prospective analysis in the Alpha Omega Cohort.

Accumulating evidence shows that NAFLD might play a role in the etiology and progression of CVD, but little is known on the association of NAFLD and CVD mortality in patients with a history of a myocardial infarction (MI). Therefore, we studied the relationship of Fatty Liver Index (FLI), as indicator for non-alcoholic fatty liver disease (NAFLD), with 12-year risk of cardiovascular disease (CVD) and all-cause mortality in post-MI patients. We included 4165 Dutch patients from the Alpha Omega Cohort aged 60-80 years who had an MI ≤10 years prior to study enrolment. NAFLD was defined as FLI ≥60. Patients were followed for cause-specific mortality from enrolment (2002-2006) through December 2018. Hazard ratios for CVD and all-cause mortality were obtained by multivariable Cox regression using FLI <30 (indicating absence of NAFLD) as the reference. Baseline FLI as a continuous measure was studied with mortality using restricted cubic splines analyses. The median (IQR) FLI was 68 (48-84). Sixty percent of the patients had FLI ≥60, who were more likely to be male and more often had diabetes, high blood pressure, and high serum cholesterol levels. During 12 years of follow-up, 2042 deaths occurred of which 846 from CVD. Patients with NAFLD were at increased risk of CVD mortality (HR: 1.55 [1.19, 2.03]) and all-cause mortality (HR: 1.21 [1.03; 1.41]) compared to patients without NAFLD. Results remained consistent after excluding patients with obesity and diabetes. To conclude, the adverse association of FLI with CVD mortality was stronger in female than in male patients with conventional cut-off points. FLI ≥60, indicating NAFLD, was a predictor for CVD and all-cause mortality in post-MI patients, independent of other cardiometabolic risk factors. However, cut-off points might differ between male and female patients for predicting CVD mortality.

Dietary nitrate intake in relation to the risk of dementia and imaging markers of vascular brain health: a population-based study.

BACKGROUND: Nitric oxide is a free radical that can be produced from dietary nitrate and positively affects cardiovascular health. With cardiovascular health playing an important role in the etiology of dementia, we hypothesized a link between dietary nitrate intake and the risk of dementia. OBJECTIVES: This study aimed to find the association of total, vegetable, and nonvegetable dietary nitrate intake with the risk of dementia and imaging markers of vascular brain health, such as total brain volume, global cerebral perfusion, white matter hyperintensity volume, microbleeds, and lacunar infarcts. METHODS: Between 1990 and 2009, dietary intake was assessed using food-frequency questionnaires in 9543 dementia-free participants (mean age, 64 y; 58% female) from the prospective population-based Rotterdam Study. Participants were followed up for incidence dementia until January 2020. We used Cox models to determine the association between dietary nitrate intake and incident dementia. Using linear mixed models and logistic regression models, we assessed the association of dietary nitrate intake with changes in imaging markers across 3 consecutive examination rounds (mean interval between images 4.6 y). RESULTS: Participants median dietary nitrate consumption was 85 mg/d (interquartile range, 55 mg/d), derived on average for 81% from vegetable sources. During a mean follow-up of 14.5 y, 1472 participants developed dementia. A higher intake of total and vegetable dietary nitrate was associated with a lower risk of dementia per 50-mg/d increase [hazard ratio (HR): 0.92; 95% confidence interval (CI): 0.87, 0.98; and HR: 0.92; 95% CI: 0.86, 0.97, respectively] but not with changes in neuroimaging markers. No association between nonvegetable dietary nitrate intake and the risk of dementia (HR: 1.15; 95% CI: 0.64, 2.07) or changes in neuroimaging markers were observed. CONCLUSIONS: A higher dietary nitrate intake from vegetable sources was associated with a lower risk of dementia. We found no evidence that this association was driven by vascular brain health.

Methyl Donor Nutrient Intake and Incidence of Type 2 Diabetes: Results From Three Large U.S. Cohorts.

OBJECTIVE: We examined whether intake of methyl donor nutrients, including vitamins B2, B6, and B12 and folate, from foods and/or supplements is associated with type 2 diabetes risk. RESEARCH DESIGN AND METHODS: We included 203,644 women and men from the Nurses' Health Study (1984-2016), Nurses' Health Study 2 (1991-2017), and Health Professionals Follow-Up Study (1986-2016). Dietary data were collected every 2-4 years with use of semiquantitative food-frequency questionnaires. Cox proportional hazards models with time-varying covariates were used to evaluate associations between each nutrient and type 2 diabetes risk. We combined cohort-specific hazard ratios (HRs) using inverse variance-weighted fixed-effects meta-analyses. RESULTS: During 4,900,181 person-years of follow-up, we documented 19,475 incident type 2 diabetes cases. In multivariable-adjusted meta-analyses, participants in the highest quintiles of total vitamin B2 and B6 intakes had lower risk of diabetes compared with those in the lowest quintiles (HR 0.93 [95% CI 0.89, 0.98] for B2 and 0.93 [0.89, 0.97] for B6). With stratification by source, significant associations remained for B2 from food but not from supplements. Neither association for B6 from food nor association for B6 from supplements attained significance. No association was observed between total B12 intake and diabetes. However, B12 from food was marginally associated with higher diabetes risk (1.05 [1.00-1.11]) but not after additional adjustment for red meat intake (1.04 [0.99-1.10]). No evidence of association was observed between intakes of folate and diabetes. CONCLUSIONS: The results of our study suggest that higher intake of vitamin B2 and B6, especially B2 from food sources, may be associated with a modestly lower type 2 diabetes risk.