Benzodiazepine use in relation to long-term dementia risk and imaging markers of neurodegeneration: a population-based study.

BACKGROUND: Benzodiazepine use is common, particularly in older adults. Benzodiazepines have well-established acute adverse effects on cognition, but long-term effects on neurodegeneration and dementia risk remain uncertain. METHODS: We included 5443 cognitively healthy (MMSE ≥ 26) participants from the population-based Rotterdam Study (57.4% women, mean age 70.6 years). Benzodiazepine use from 1991 until baseline (2005-2008) was derived from pharmacy dispensing records, from which we determined drug type and cumulative dose. Benzodiazepine use was defined as prescription of anxiolytics (ATC-code: N05BA) or sedative-hypnotics (ATC-code: N05CD) between inception of pharmacy records and study baseline. Cumulative dose was calculated as the sum of the defined daily doses for all prescriptions. We determined the association with dementia risk until 2020 using Cox regression. Among 4836 participants with repeated brain MRI, we further determined the association of benzodiazepine use with changes in neuroimaging markers using linear mixed models. RESULTS: Of all 5443 participants, 2697 (49.5%) had used benzodiazepines at any time in the 15 years preceding baseline, of whom 1263 (46.8%) used anxiolytics, 530 (19.7%) sedative-hypnotics, and 904 (33.5%) used both; 345 (12.8%) participants were still using at baseline assessment. During a mean follow-up of 11.2 years, 726 participants (13.3%) developed dementia. Overall, use of benzodiazepines was not associated with dementia risk compared to never use (HR [95% CI]: 1.06 [0.90-1.25]), irrespective of cumulative dose. Risk estimates were somewhat higher for any use of anxiolytics than for sedative-hypnotics (HR 1.17 [0.96-1.41] vs 0.92 [0.70-1.21]), with strongest associations for high cumulative dose of anxiolytics (HR [95% CI] 1.33 [1.04-1.71]). In imaging analyses, current use of benzodiazepine was associated cross-sectionally with lower brain volumes of the hippocampus, amygdala, and thalamus and longitudinally with accelerated volume loss of the hippocampus and to a lesser extent amygdala. However, imaging findings did not differ by type of benzodiazepines or cumulative dose. CONCLUSIONS: In this population-based sample of cognitively healthy adults, overall use of benzodiazepines was not associated with increased dementia risk, but potential class-dependent adverse effects and associations with subclinical markers of neurodegeneration may warrant further investigation.

Trends in population attributable fraction of modifiable risk factors for cardiovascular diseases across three decades.

AIM: To evaluate temporal trends, across three decades, in the population attributable fractions (PAFs) of modifiable risk factors for 5-year risk of cardiovascular diseases (CVDs). METHODS: Within population-based Rotterdam Study, we defined three time-groups of individuals without established CVD at 'baseline' with a mean age of 70 years, and followed for five years: Epoch 1990s (1989-1993, N=6195), Epoch 2000s (1997-2001, N=5572) and Epoch 2010s (2009-2014, N=5135). The prevalence of risk factors and related relative risks were combined to quantify PAFs. RESULTS: The PAF of the six risk factors combined for global CVD was 0.57 (95% confidence interval [CI] 0.47 to 0.65), 0.52 (0.39 to 0.62) and 0.39 (0.18 to 0.54) in three respective epochs. Hypertension contributed the highest PAF to global CVD in Epoch 1990s (0.37, 95% CI: 0.28 to 0.44) and 2000s (0.34, 95% CI: 0.22 to 0.43), while smoking was the largest contributor in Epoch 2010s (0.20, 95% CI: 0.06 to 0.32). Dyslipidemia changed population-level coronary heart disease risk over time. For stroke, hypertension became a less significant contributor over time, but smoking became a larger contributor. For heart failure, all risk factors showed non-significant PAFs in Epoch 2010s. PAFs related to individual risk factor varied among women and men. CONCLUSION: Six modifiable risk factors to population-level global CVD risk decreased over time, but still explained 39% of total CVD in the latest decade. PAFs changed considerably for hypertension, dyslipidemia, and smoking. Risk factors had different PAFs for different CVDs with pronounced sex differences.

The contribution of the individual cardiovascular risk factors to population CVD risk considerably changed over the past 3 decades, especially for hypertension, dyslipidemia, and smoking. Traditional modifiable risk factors exerted declining contributions to population burden of total CVD over the past three decades, suggesting good progress in CVD prevention. Nonetheless, in the latest decade, unfavorable risk factors accounted for 39% of total CVD burden. Sex differences in the contributions of abdominal obesity, diabetes and smoking to cardiovascular outcomes were observed.

Plasma Extracellular MicroRNAs Associated With Cardiovascular Disease Risk Factors in Middle-Aged and Older Adults.

BACKGROUND: Extracellular microRNAs (miRNAs) are a class of noncoding RNAs that remain stable in the extracellular milieu, where they contribute to various physiological and pathological processes by facilitating intercellular signaling. Previous studies have reported associations between miRNAs and cardiovascular diseases (CVDs); however, the plasma miRNA signatures of CVD and its risk factors have not been fully elucidated at the population level. METHODS AND RESULTS: Plasma miRNA levels were measured in 4440 FHS (Framingham Heart Study) participants. Linear regression analyses were conducted to test the cross-sectional associations of each miRNA with 8 CVD risk factors. Prospective analyses of the associations of miRNAs with new-onset obesity, hypertension, type 2 diabetes, CVD, and all-cause mortality were conducted using proportional hazards regression. Replication was carried out in 1999 RS (Rotterdam Study) participants. Pathway enrichment analyses were conducted and target genes were predicted for miRNAs associated with ≥5 risk factors in the FHS. In the FHS, 6 miRNAs (miR-193b-3p, miR-122-5p, miR-365a-3p, miR-194-5p, miR-192-5p, and miR-193a-5p) were associated with ≥5 risk factors. This miRNA signature was enriched for pathways associated with CVD and several genes annotated to these pathways were predicted targets of the identified miRNAs. Furthermore, miR-193b-3p, miR-194-5p, and miR-193a-5p were each associated with ≥2 risk factors in the RS. Prospective analysis revealed 8 miRNAs associated with all-cause mortality in the FHS. CONCLUSIONS: These findings highlight associations between miRNAs and CVD risk factors that may provide valuable insights into the underlying pathogenesis of CVD.

Unraveling interindividual variation of trimethylamine N-oxide and its precursors at the population level.

Trimethylamine N-oxide (TMAO) is a circulating microbiome-derived metabolite implicated in the development of atherosclerosis and cardiovascular disease (CVD). We investigated whether plasma levels of TMAO, its precursors (betaine, carnitine, deoxycarnitine, choline), and TMAO-to-precursor ratios are associated with clinical outcomes, including CVD and mortality. This was followed by an in-depth analysis of their genetic, gut microbial, and dietary determinants. The analyses were conducted in five Dutch prospective cohort studies including 7834 individuals. To further investigate association results, Mendelian Randomization (MR) was also explored. We found only plasma choline levels (hazard ratio [HR] 1.17, [95% CI 1.07; 1.28]) and not TMAO to be associated with CVD risk. Our association analyses uncovered 10 genome-wide significant loci, including novel genomic regions for betaine (6p21.1, 6q25.3), choline (2q34, 5q31.1), and deoxycarnitine (10q21.2, 11p14.2) comprising several metabolic gene associations, for example, CPS1 or PEMT. Furthermore, our analyses uncovered 68 gut microbiota associations, mainly related to TMAO-to-precursors ratios and the Ruminococcaceae family, and 16 associations of food groups and metabolites including fish-TMAO, meat-carnitine, and plant-based food-betaine associations. No significant association was identified by the MR approach. Our analyses provide novel insights into the TMAO pathway, its determinants, and pathophysiological impact on the general population.

Sharing brain imaging data in the Open Science era: how and why?

The sharing of human neuroimaging data has great potential to accelerate the development of imaging biomarkers in neurological and psychiatric disorders; however, major obstacles remain in terms of how and why to share data in the Open Science context. In this Health Policy by the European Cluster for Imaging Biomarkers, we outline the current main opportunities and challenges based on the results of an online survey disseminated among senior scientists in the field. Although the scientific community fully recognises the importance of data sharing, technical, legal, and motivational aspects often prevent active adoption. Therefore, we provide practical advice on how to overcome the technical barriers. We also call for a harmonised application of the General Data Protection Regulation across EU countries. Finally, we suggest the development of a system that makes data count by recognising the generation and sharing of data as a highly valuable contribution to the community.

The NOS1AP gene rs10494366 common genetic variant does not modify the risk of sudden cardiac death in users of digoxin.

AIMS: Common genetic variations in the nitric oxide synthase-1 adaptor protein (NOS1AP) gene are associated with QT-interval prolongation. In a previous study, we observed an association between the rs10494366 variant of this gene and an increased QT-interval shortening in digoxin users. As QT-interval shortening is a risk factor for sudden cardiac death (SCD), in this study, we investigated whether the association between digoxin use and risk of SCD differs in participants with different NOS1AP rs10494366 genotypes. METHODS: We included 11 377 individuals from the prospective population-based cohort of the Rotterdam Study. We used Cox proportional hazard regression analysis with digoxin as time-dependent exposure to estimate the associations between current digoxin use and the risk of SCD among different rs10494366 genotype groups in the adjusted models. We also studied whether such an association was dose-dependent, comparing high dosage (≥ 0.250 mg), moderate dosage (0.125 mg ≤ dose< 0.250 mg) and low dosage (< 0.125 mg) digoxin users with non-users. RESULTS: The median baseline age of the total study population was 62 (interquartile range [IQR] 58-71) years. The cumulative incidence of SCD was 4.1% (469 cases), and among them, 74 (15.7%) individuals were current digoxin users at the time of death, during a median follow-up of 11.5 (IQR 6.5-17) years. Current digoxin users had an increased risk of SCD (multivariable adjusted model hazard ratio [HR]: 3.07; 95% confidence interval [CI]: 2.38-3.98), with no significant differences between the three genotype groups. The adjusted HRs were 4.03 [95% CI: 1.98-8.21] in the minor homozygous GG, 3.46 [95% CI: 2.37-5.04] in the heterozygous TG and 2.56 [95%CI: 1.70-3.86] in the homozygous TT genotype groups. Compared to low- and moderate-dose, high-dose digoxin users with GG genotype had the highest risk of SCD (HR: 5.61 [95% CI: 1.34-23.47]). CONCLUSIONS: Current use of digoxin is associated with a significantly increased risk of SCD. The NOS1AP gene rs10494366 variant did not modify the digoxin-associated risk of SCD in a population of European ancestry.

Sex-differences in the association of social health and marital status with blood-based immune and neurodegeneration markers in a cohort of community-dwelling older adults.

BACKGROUND: The immune system has been proposed to play a role in the link between social health and all-cause dementia risk. We explored cross-sectional and longitudinal associations between social health, immune system balance and plasma neurodegeneration markers in community-dwelling older adults, and explored whether the balance between innate and adaptive immunity mediates associations between social health and both cognition and total brain volume. METHODS: Social health markers (social support, marital status, loneliness) were measured in the Rotterdam Study between 2002-2008. Immune system cell counts and balance were assessed repeatedly from 2002 to 2016 using white blood-cell-based indices and individual counts (granulocyte-to-lymphocyte ratio (GLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII)). Plasma neurodegeneration biomarkers (amyloid-ß40, amyloid-ß42, total tau and neurofilament light chain) were measured once from blood samples collected between 2002-2008. Global cognitive function and total brain volume (MRI) were measured at the follow-up visit between 2009-2014. We used linear mixed models to study longitudinal associations and performed causal mediation analyses. RESULTS: In 8374 adults (mean age 65.7, 57 % female), never married participants (n = 394) had higher GLR, PLR and SII compared to married peers at baseline and during follow-up, indicating imbalance towards innate immunity. Being never married was associated with higher plasma amyloid-ß40, and being widowed or divorced with higher plasma total tau levels at baseline. Widowed or divorced males, but not females, had higher GLR, PLR and SII at baseline. Higher social support was associated with lower PLR in females, but higher PLR in males. Loneliness was not associated with any of the immune system balance ratios. Never married males had higher levels of all plasma neurodegeneration markers at baseline. Immune system balance did not mediate associations between social health and cognition or total brain volume, but does interact with marital status. CONCLUSION: This study indicates that marital status is associated with blood-based immune system markers toward innate immunity and higher levels of plasma neurodegeneration markers. This is particularly evident for never married or previously married male older adults compared to married or female peers.

Plasma trimethylamine N-oxide (TMAO): associations with cognition, neuroimaging, and dementia.

BACKGROUND: The gut-derived metabolite Trimethylamine N-oxide (TMAO) and its precursors - betaine, carnitine, choline, and deoxycarnitine - have been associated with an increased risk of cardiovascular disease, but their relation to cognition, neuroimaging markers, and dementia remains uncertain. METHODS: In the population-based Rotterdam Study, we used multivariable regression models to study the associations between plasma TMAO, its precursors, and cognition in 3,143 participants. Subsequently, we examined their link to structural brain MRI markers in 2,047 participants, with a partial validation in the Leiden Longevity Study (n = 318). Among 2,517 participants, we assessed the risk of incident dementia using multivariable Cox proportional hazard models. Following this, we stratified the longitudinal associations by medication use and sex, after which we conducted a sensitivity analysis for individuals with impaired renal function. RESULTS: Overall, plasma TMAO was not associated with cognition, neuroimaging markers or incident dementia. Instead, higher plasma choline was significantly associated with poor cognition (adjusted mean difference: -0.170 [95% confidence interval (CI) -0.297;-0.043]), brain atrophy and more markers of cerebral small vessel disease, such as white matter hyperintensity volume (0.237 [95% CI: 0.076;0.397]). By contrast, higher carnitine concurred with lower white matter hyperintensity volume (-0.177 [95% CI: -0.343;-0.010]). Only among individuals with impaired renal function, TMAO appeared to increase risk of dementia (hazard ratio (HR): 1.73 [95% CI: 1.16;2.60]). No notable differences were observed in stratified analyses. CONCLUSIONS: Plasma choline, as opposed to TMAO, was found to be associated with cognitive decline, brain atrophy, and markers of cerebral small vessel disease. These findings illustrate the complexity of relationships between TMAO and its precursors, and emphasize the need for concurrent study to elucidate gut-brain mechanisms.

Healthcare avoidance during the early stages of the COVID-19 pandemic and all-cause mortality: a longitudinal community-based study.

Background During the COVID-19 pandemic, global trends of reduced healthcare-seeking behaviour were observed. This raises concerns about the consequences of healthcare avoidance for population health. Aim To determine the association between healthcare avoidance during the early stages of the COVID-19 pandemic and all-cause mortality. Design and setting 32-month follow-up within the population-based Rotterdam Study, after sending a COVID-19 questionnaire at the onset of the pandemic in April 2020 to all non-institutionalised participants (response rate 73%). Method Cox proportional hazards models assessed the risk of all-cause mortality among respondents who avoided healthcare because of the COVID-19 pandemic. Mortality status was collected through municipality registries and medical records. Results Of 5656 respondents, one-fifth avoided healthcare due to the COVID-19 pandemic (N=1143). Compared to non-avoiders, those who avoided healthcare more often reported symptoms of depression (31.2% versus 12.3%) and anxiety (29.7% versus 12.2%), and more often valued their health as poor to fair (29.4% versus 10.1%). Healthcare avoiders had an increased adjusted risk of all-cause mortality (HR: 1.30; 95%CI 1.01-1.67), which remained nearly identical after adjustment for history of any non-communicable disease (1.20;0.93-1.54). However, this association attenuated after additional adjustment for mental and self-appreciated health factors (0.96;0.74-1.24). Conclusion We found an increased risk of all-cause mortality among individuals who avoided healthcare during COVID-19. These individuals were characterised by poor mental and physical self-appreciated health. Therefore, interventions should be targeted to these vulnerable individuals to safeguard their access to primary and specialist care in order to limit health disparities, inside and beyond healthcare crises.

Revisiting the Clinical Interpretation of CT-Measured Pulmonary Artery-to-Aorta Ratio-The Rotterdam Study.

RATIONALE: The pulmonary artery (PA) diameter-to-aorta ratio (PA:A) ratio is a novel marker in cardiovascular imaging for detecting pulmonary hypertension. However, we question the effect of the varying aorta diameter on the ratio, which complicates the interpretation of the PA:A ratio. OBJECTIVE: Investigate the variability of the PA:A ratio by examining the correlation between PA:A ratio and aorta diameter and by comparing the associations of the PA diameter, aorta diameters, and PA:A ratio. METHODS: We included 2197 participants from the Rotterdam Study who underwent non-contrast multidetector computed tomography to measure the PA and aorta diameters. Pearson correlation coefficient was calculated between the PA:A ratio and aorta diameter. Multiple linear regression analyses were performed to compare the determinants of the individual diameters and PA:A ratio. RESULTS: We found a statistically significant correlation between the PA:A ratio and aorta diameter (r = -0.38, p < 0.001). The PA diameter was statistically significantly associated with, height, weight, diastolic blood pressure, blood pressure medication, prevalence of atrial fibrillation, prevalence of heart failure, and prevalence of stroke (p < 0.05). Except for blood pressure medication, the PA:A ratio had similar determinants compared to the PA diameter but was also statistically significantly associated with sex, and systolic blood pressure (p < 0.05), which were statistically significantly associated with the aorta diameter (p < 0.05). CONCLUSION: The PA:A ratio should not be interpreted without taking into account the variability of the individual components (PA and aorta diameter) according to the anthropomorphic and clinical characteristics.

Antidepressant use in relation to dementia risk, cognitive decline, and brain atrophy.

INTRODUCTION: We aimed to assess the effect of antidepressant use on dementia risk, cognitive decline, and brain atrophy. METHODS: In this prospective cohort study, we included 5511 dementia-free participants (Mini-Mental State Examination [MMSE] > 25) of the Rotterdam study (57.5% women, mean age 70.6 years). Antidepressant use was extracted from pharmacy records from 1991 until baseline (2002-2008). Incident dementia was monitored from baseline until 2018, with repeated cognitive assessment and magnetic resonance imaging (MRI) every 4 years. RESULTS: Compared to never use, any antidepressant use was not associated with dementia risk (hazard ratio [HR] 1.14, 95% confidence interval [CI] 0.92-1.41), or with accelerated cognitive decline or atrophy of white and gray matter. Compared to never use, dementia risk was somewhat higher with tricyclic antidepressants (HR 1.36, 95% CI 1.01-1.83) than with selective serotonin reuptake inhibitors (HR 1.12, 95% CI 0.81-1.54), but without dose-response relationships, accelerated cognitive decline, or atrophy in either group. DISCUSSION: Antidepressant medication in adults without indication of cognitive impairment was not consistently associated with long-term adverse cognitive effects. HIGHLIGHTS: Antidepressant medications are frequently prescribed, especially among older adults. In this study, antidepressant use was not associated with long-term dementia risk. Antidepressant use was not associated with cognitive decline or brain atrophy. Our results support safe prescription in an older, cognitively healthy population.

Towards a Clearer Causal Question Underlying the Association Between Cancer and Dementia.

BACKGROUND: Several observational studies have described an inverse association between cancer diagnosis and subsequent dementia risk. Multiple biologic mechanisms and potential biases have been proposed in attempts to explain this association. One proposed explanation is the opposite expression of Pin1 in cancer and dementia, and we use this explanation and potential drug target to illustrate the required assumptions and potential sources of bias for inferring an effect of Pin1 on dementia risk from analyses measuring cancer diagnosis as a proxy for Pin1 expression. METHODS: We used data from the Rotterdam Study, a population-based cohort. We estimate the association between cancer diagnosis (as a proxy for Pin1) and subsequent dementia diagnosis using two different proxy methods and with confounding and censoring for death addressed with inverse probability weights. We estimate and compare the complements of a weighted Kaplan-Meier survival estimator at 20 years of follow-up. RESULTS: Out of 3634 participants, 899 (25%) were diagnosed with cancer, of whom 53 (6%) had dementia, and 567 (63%) died. Among those without cancer, 15% (411) were diagnosed with dementia, and 667 (24%) died over follow-up. Depending on the confounding and selection bias control, and the way in which cancer was used as a time-varying proxy exposure, the risk ratio for dementia diagnosis ranged from 0.71 (95% confidence interval [CI] = 0.49, 0.95) to 1.1 (95% CI = 0.79, 1.3). CONCLUSION: Being explicit about the underlying mechanism of interest is key to maximizing what we can learn from this cancer-dementia association given available or readily collected data, and to defining, detecting, and preventing potential biases.

Lifetime prevalence and associated factors of itch with skin conditions: Atopic dermatitis, psoriasis and dry skin in individuals aged over 50.

BACKGROUND: Itch, common in dermatological conditions, is often accompanied by psychological distress and reduced quality of life. However, research on the prevalence and associated factors of itch with skin conditions in general populations is limited. OBJECTIVES: This cross-sectional study aimed to determine the lifetime prevalence of itch with skin conditions and identify its associated factors in middle-aged and elderly individuals. METHODS: Participants from the Rotterdam Study, a population-based cohort, were interviewed to assess whether they had ever had an itchy skin condition, defining lifetime itch with skin conditions. Over 20 demographic, lifestyle, dermatological, and non-dermatological factors were collected. Multivariable logistic regression analysis explored associations between these factors and itch with skin conditions, reported as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: 5,246 eligible participants (age range: 51-100, median age: 67, female: 56.0%) revealed a lifetime prevalence of 33.7% for itch with skin conditions. Female sex (OR (95% CI): 1.26 (1.11-1.43)), body mass index (1.02 (1.01-1.03)), self-reported and presence of atopic dermatitis (4.29 (3.74-4.92), and 1.97 (1.60-2.43)), self-reported and presence of psoriasis (2.31 (1.77-3.01), and 2.11 (1.55-2.87)), self-reported dry skin (1.95 (1.73-2.29)), self-reported asthma (1.40 (1.08-1.83)), renal impairment (1.45 (1.17-1.79)), and clinically relevant depressive and anxiety symptoms (1.85 (1.52-2.25), and 1.36 (1.11-1.66)) were significantly associated with it. CONCLUSIONS: This study reveals a substantial one-third lifetime prevalence of itch with skin conditions in individuals aged over 50. Significant associations with diverse lifestyle, demographic, dermatological and, intriguingly, non-dermatological factors including renal impairment, imply additional contributors to itch induction or persistence in individuals with skin conditions.

Burden of intracranial artery calcification in white patients with ischemic stroke.

INTRODUCTION: The diagnostic workup of stroke doesn't identify an underlying cause in two-fifths of ischemic strokes. Intracranial arteriosclerosis is acknowledged as a cause of stroke in Asian and Black populations, but is underappreciated as such in whites. We explored the burden of Intracranial Artery Calcification (IAC), a marker of intracranial arteriosclerosis, as a potential cause of stroke among white patients with recent ischemic stroke or TIA. PATIENTS AND METHODS: Between December 2005 and October 2010, 943 patients (mean age 63.8 (SD ± 14.0) years, 47.9% female) were recruited, of whom 561 had ischemic stroke and 382 a TIA. CT-angiography was conducted according to stroke analysis protocols. The burden of IAC was quantified on these images, whereafter we assessed the presence of IAC per TOAST etiology underlying the stroke and assessed associations between IAC burden, symptom severity, and short-term functional outcome. RESULTS: IAC was present in 62.4% of patients. Furthermore, IAC was seen in 84.8% of atherosclerotic strokes, and also in the majority of strokes with an undetermined etiology (58.5%). Additionally, patients with larger IAC burden presented with heavier symptoms (adjusted OR 1.56 (95% CI [1.06-2.29]), but there was no difference in short-term functional outcome (1.14 [0.80-1.61]). CONCLUSION: IAC is seen in the majority of white ischemic stroke patients, aligning with findings from patient studies in other ethnicities. Furthermore, over half of patients with a stroke of undetermined etiology presented with IAC. Assessing IAC burden may help identify the cause in ischemic stroke of undetermined etiology, and could offer important prognostic information.

Depressive Symptoms and Plasma Markers of Alzheimer's Disease and Neurodegeneration: A Coordinated Meta-Analysis of 8 Cohort Studies.

BACKGROUND: Depressive symptoms are associated with an increased risk of Alzheimer's disease (AD). There has been a recent emergence in plasma biomarkers for AD pathophysiology, such as amyloid-beta (Aß) and phosphorylated tau (p-tau), as well as for axonal damage (neurofilament light, NfL) and astrocytic activation (glial fibrillary acidic protein, GFAP). Hypothesizing that depressive symptoms may occur along the AD process, we investigated associations between plasma biomarkers of AD with depressive symptoms in individuals without dementia. METHODS: A two-stage meta-analysis was performed on 2 clinic-based and 6 population-based cohorts (N = 7210) as part of the Netherlands Consortium of Dementia Cohorts. Plasma markers (Aß42/40, p-tau181, NfL, and GFAP) were measured using Single Molecular Array (Simoa; Quanterix) assays. Depressive symptoms were measured with validated questionnaires. We estimated the cross-sectional association of each standardized plasma marker (determinants) with standardized depressive symptoms (outcome) using linear regressions, correcting for age, sex, education, and APOE ε4 allele presence, as well as subgrouping by sex and APOE ε4 allele. Effect estimates were entered into a random-effects meta-analysis. RESULTS: Mean age of participants was 71 years. The prevalence of clinically relevant depressive symptoms ranged from 1% to 22%. None of the plasma markers were associated with depressive symptoms in the meta-analyses. However, NfL was associated with depressive symptoms only in APOE ε4 carriers (ß 0.11; 95% CI: 0.05-0.17). CONCLUSIONS: Late-life depressive symptoms did not show an association to plasma biomarkers of AD pathology. However, in APOE ε4 allele carriers, a more profound role of neurodegeneration was suggested with depressive symptoms.

Genome-wide characterization of circulating metabolic biomarkers.

Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1-7. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases8-11. Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases.

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.

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.