Search

Iron plays a fundamental role in multiple brain disorders. However, the genetic underpinnings of brain iron and its implications for these disorders are still lacking. Here, we conduct an exome-wide association analysis of brain iron, measured by quantitative susceptibility mapping technique, across 26 brain regions among 26,789 UK Biobank participants. We find 36 genes linked to brain iron, with 29 not being previously reported, and 16 of them can be replicated in an independent dataset with 3,039 subjects. Many of these genes are involved in iron transport and homeostasis, such as FTH1 and MLX. Several genes, while not previously connected to brain iron, are associated with iron-related brain disorders like Parkinson's (STAB1, KCNA10), Alzheimer's (SHANK1), and depression (GFAP). Mendelian randomization analysis reveals six causal relationships from regional brain iron to brain disorders, such as from the hippocampus to depression and from the substantia nigra to Parkinson's. These insights advance our understanding of the genetic architecture of brain iron and offer potential therapeutic targets for brain disorders. Brain iron accumulation has been associated with multiple brain disorders, but the mechanism is not well understood. Here, the authors investigate the genetic determinants of brain iron accumulation and their implications for neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

Background: Muscle weakness is a prominent feature of Parkinson's disease, but whether the occurrence of this deficit in healthy adults is associated with subsequent PD diagnosis remains unclear. Objective: This study sought to examine the relationship between muscle strength, represented by grip strength and walking pace, and the risk of incident PD. Methods: A total of 422,531 participants from the UK biobank were included in this study. Longitudinal associations of grip strength and walking pace with the risk of incident PD were investigated by Cox proportional hazard models adjusting for several well-established risk factors. Subgroup and sensitivity analyses were also conducted for further validation. Results: After a median follow-up of 9.23 years, 2,118 (0.5%) individuals developed incident PD. For per 5 kg increment of absolute grip strength, there was a significant 10.2% reduction in the risk of incident PD (HR = 0.898, 95% CI [0.872–0.924], P < 0.001). Similarly, per 0.05 kg/kg increment of relative grip strength was related to a 9.2% reduced risk of incident PD (HR = 0.908, 95% CI [0.887–0.929], P < 0.001). Notably, the associations remained consistent when grip strength was calculated as quintiles. Moreover, participants with a slower walking pace demonstrated an elevated risk of incident PD (HR = 1.231, 95%CI [1.075–1.409], P = 0.003). Subgroup and sensitivity analyses further validated the robustness of the observed associations. Conclusion: Our findings showed a negative association of grip strength and walking pace with the risk of incident PD independent of important confounding factors. These results hold potential implications for the early screening of people at high-risk of PD. [ABSTRACT FROM AUTHOR]

Healthy lifestyle might alleviate the socioeconomic inequities in health, but the extent of the joint and interactive effects of these two factors on dementia are unclear. This study aimed to detect the joint and interactive associations of socioeconomic status (SES) and lifestyle factors with incident dementia risk, and the underlying brain imaging alterations. Cox proportional hazards analysis was performed to test the joint and interactive associations. Partial correlation analysis was performed to reflect the brain imaging alterations. A total of 276,730 participants with a mean age of 55.9 (±8.0) years old from UK biobank were included. Over 8.5 (±2.6) years of follow-up, 3013 participants were diagnosed with dementia. Participants with high SES and most healthy lifestyle had a significantly lower risk of incident dementia (HR=0.19, 95% CI=0.14 to 0.26, P<2×10−16), Alzheimer's disease (AD, HR=0.19, 95% CI=0.13 to 0.29, P=8.94×10−15), and vascular dementia (HR=0.24, 95% CI=0.12 to 0.48, P=7.57×10−05) compared with participants with low SES and an unhealthy lifestyle. Significant interactions were found between SES and lifestyle on dementia (P=0.002) and AD (P=0.001) risks; the association between lifestyle and dementia was stronger among those of high SES. The combination of high SES and healthy lifestyle was positively associated with higher volumes in brain regions vulnerable to dementia-related atrophy. These findings suggest that SES and lifestyle significantly interact and influence dementia with its related brain structure phenotypes. [ABSTRACT FROM AUTHOR]

Identifying circulating metabolites associated with dementia, cognition, and brain volume may improve the understanding of dementia pathogenesis and provide novel insights for preventive and therapeutic interventions. This cohort study included a total of 87 885 participants (median follow‐up of 9.1 years, 54% female) without dementia at baseline from the UK Biobank. A total of 249 plasma metabolites were measured using nuclear magnetic resonance spectroscopy at baseline. Cox proportional regression was used to examine the associations of each metabolite with incident dementia (cases = 1134), Alzheimer's disease (AD; cases = 488), and vascular dementia (VD; cases = 257) during follow‐up. Dementia‐associated metabolites were further analyzed for association with cognitive deficits (N = 87 885) and brain volume (N = 7756) using logistic regression and linear regression. We identified 26 metabolites associated with incident dementia, of which 6 were associated with incident AD and 5 were associated with incident VD. These 26 dementia‐related metabolites were subfractions of intermediate‐density lipoprotein, large low‐density lipoprotein (L‐LDL), small high‐density lipoprotein (S‐HDL), very‐low‐density lipoprotein, fatty acids, ketone bodies, citrate, glucose, and valine. Among them, the cholesterol percentage in L‐LDL (L‐LDL‐C%) was associated with lower risk of AD (HR [95% CI] = 0.92 [0.87–0.97], p = 0.002), higher brain cortical (β = 0.047, p = 3.91 × 10−6), and hippocampal (β = 0.043, p = 1.93 × 10−4) volume. Cholesteryl ester–to–total lipid ratio in L‐LDL (L‐LDL‐CE%) was associated with lower risk of AD (HR [95% CI] = 0.93 [0.90–0.96], p = 1.48 × 10−4), cognitive deficits (odds ratio = 0.98, p = 0.009), and higher hippocampal volume (β = 0.027, p = 0.009). Cholesteryl esters in S‐HDL (S‐HDL‐CE) were associated with lower risk of VD (HR [95% CI] = 0.81 [0.71–0.93], p = 0.002), but not AD. Taken together, circulating levels of L‐LDL‐CE% and L‐LDL‐C% were robustly associated with risk of AD and AD phenotypes, but not with VD. S‐HDL‐CE was associated with lower risk of VD, but not with AD or AD phenotypes. These metabolites may play a role in the advancement of future intervention trials. Additional research is necessary to gain a complete comprehension of the molecular mechanisms behind these associations. [ABSTRACT FROM AUTHOR]

Background: The correlations between genetic risk for Alzheimer's disease (AD) with comprehensive brain regions at a regional scale are still not well understood. We aim to explore whether these associations vary across different age stages. Methods: This study used large existing genome-wide association datasets to calculate polygenic risk score (PRS) for AD in two populations from the UK Biobank (N ~ 23 000) and Adolescent Brain Cognitive Development Study (N ~ 4660) who had multimodal macrostructural and microstructural magnetic resonance imaging (MRI) metrics. We used linear mixed-effect models to assess the strength of the association between AD PRS and multiple MRI metrics of regional brain structures at different stages of life. Results: Compared to those with lower PRSs, adolescents with higher PRSs had thinner cortex in the caudal anterior cingulate and supramarginal. In the middle-aged and elderly population, AD PRS had correlations with regional structure shrink primarily located in the cingulate, prefrontal cortex, hippocampus, thalamus, amygdala, and striatum, whereas the brain expansion was concentrated near the occipital lobe. Furthermore, both adults and adolescents with higher PRSs exhibited widespread white matter microstructural changes, indicated by decreased fractional anisotropy (FA) or increased mean diffusivity (MD). Conclusions: In conclusion, our results suggest genetic loading for AD may influence brain structures in a highly dynamic manner, with dramatically different patterns at different ages. This age-specific change is consistent with the classical pattern of brain impairment observed in AD patients. [ABSTRACT FROM AUTHOR]

Cohort studies report inconsistent associations between omega-3 polyunsaturated fatty acids (n-3 PUFA) or fish oil and dementia risk. Furthermore, evidence relating omega-6 polyunsaturated fatty acids (n-6 PUFA) with dementia is scarce. Here, we included 440,750 dementia-free participants from UK Biobank to comprehensively investigate the associations between plasma levels of different types of PUFA, fish oil supplementation, and dementia risk. During a median follow-up of 9.25 years, 7768 incident dementia events occurred. Higher plasma levels of five PUFA measures showed consistent associations with lower dementia risk (hazard ratios [95% confidence intervals] for per standard deviation increment of plasma concentrations 0.85 [0.81–0.89] for total PUFAs; 0.90 [0.86–0.95] for omega-3 PUFAs; 0.92 [0.87–0.96] for docosahexaenoic acid (DHA); 0.86 [0.82–0.90] for omega-6 PUFAs; 0.86 [0.82–0.90] for linoleic acid (LA); all p < 0.001). Compared with non-users, fish oil supplement users had a 7% decreased risk of developing all-cause dementia (0.93 [0.89–0.97], p = 0.002), and the relationship was partially mediated by plasma n-3 PUFA levels (omega-3 PUFAs: proportion of mediation = 57.99%; DHA: proportion of mediation = 56.95%). Furthermore, we observed significant associations of plasma n-3 PUFA levels and fish oil supplementation with peripheral immune markers that were related to dementia risk, as well as the positive associations of plasma PUFA levels with brain gray matter volumes and white matter microstructural integrity, suggesting they may affect dementia risk by affecting peripheral immunity and brain structure. Taken together, higher plasma PUFA levels and fish oil supplementation were associated with lower risk of incident dementia. This study may support the value of interventions to target PUFAs (specifically n-3 PUFAs) to prevent dementia. [ABSTRACT FROM AUTHOR]

Background: Previous studies have reported inconsistent associations between chronic kidney disease (CKD) and dementia.Objective: To evaluate whether CKD is a risk factor for dementia and compare the performance of different measures of calculating estimated glomerular filtration rate (eGFR).Methods: 275,167 participants from UK Biobank were included and eGFR at baseline was calculated using serum creatinine (eGFRcr), cystatin C (eGFRcys), and creatinine-cystatin C equations (eGFRcr-cys). Restricted cubic splines and Cox regression models were performed to assess the relationship of eGFR with all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD).Results: We observed a U-shaped relationship between each eGFR and risk of all-cause dementia and VaD, with eGFRcys and eGFRcr-cys showing a closer linkage (peGFRcys <0.0001, peGFRcrhboxcys<0.0001 and peGFRcr = 0.0001). Lower and supranormal eGFR were related to increased risk of all-cause dementia. Compared to the reference category of 90-104 ml/min/1.73 m2, adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of all-cause dementia for eGFRcr-cys 30-59, <30, and ≥105 ml/min/1.73 m2 were 1.26 (95% CI [1.05-1.50], p = 0.012), 2.62 (95% CI [1.54-4.47], p < 0.001), and 1.41 (95% CI [1.17-1.70], p < 0.001). No statistically significant association was observed between eGFR with risk of AD.Conclusion: This prospective study identified impaired kidney function as a critical risk factor for dementia and noted the application of cystatin C strengthened the relationship between CKD and dementia, underlining the significant value of preserving kidney function to reduce the risk of dementia and considering cystatin C measurement as part of clinical practice. [ABSTRACT FROM AUTHOR]

Background: Resting heart rate (RHR) has been linked with an increased risk of dementia. However, evidence characterizing the associations of RHR with different dementia subtypes and their underlying mechanisms remains scarce. This study aims to investigate the relationships of RHR with different dementia types, cognitive function, and brain structural abnormalities. Methods: Three hundred thirty-nine thousand nine hundred one participants with no prior diagnosis of dementia from the UK biobank were analyzed. Cox regression and restricted cubic spline models examined the associations between RHR with all-cause dementia (ACD) and its major subtypes—Alzheimer's disease (AD) and vascular dementia (VaD). Logistic regression models assessed the associations of RHR with cognitive function, and linear regression models estimated the associations with hippocampal subfield volume and white matter tract integrity indexed by magnetic resonance imaging data. Results: During an average of 3148 (± 941.08) days of follow-up, 4177 individuals were diagnosed with dementia, including 2354 AD and 989 VaD cases. RHR ≥ 80bpm was associated with ACD (HR: 1.18, 95% CI: 1.08–1.28, P < 0.001) and VaD (HR: 1.29, 95% CI: 1.08–1.54, P = 0.005) but not AD in multi-adjusted models. A 10-bpm increment of RHR demonstrated non-linear effects in VaD, consisting of J-shape relationships. Several heterogeneities were indicated in stratified analysis, in which RHR measures only showed associations with dementia incidents in relatively younger populations (age ≤ 65) and females. Apart from dementia analysis, elevated RHR was associated with worsening performance in fluid intelligence and reaction time of cognitive tasks, decreased hippocampal subfields volume, and poor white matter tract integrity. Conclusions: RHR is associated with increased risks of ACD and VaD but also presented with few heterogeneities across different sex and age groups. Elevated RHR also appears to have deleterious effects on cognitive function and is distinctively associated with volume reduction in hippocampal subfields and impaired white matter tract integrity. [ABSTRACT FROM AUTHOR]

The relevance between circulating metabolites and vascular events remains controversial and comprehensive studies are lacking. We sought to investigate the prospective associations of plasma metabolomics with risks of incident stroke, ischemic stroke (IS), hemorrhagic stroke (HS), and myocardial infarction (MI). Within the UK Biobank cohort, 249 circulating metabolites were measured in 90 438 participants without baseline vascular diseases. Cox proportional hazards regressions were applied to estimate adjusted hazard ratios (HRs) for per 1 standard deviation increment in metabolites. The least absolute shrinkage and selection operator algorithm was used for selecting metabolite subsets. During a median of 9.0 years of follow‐up, we documented 833 incident stroke and 1256 MI cases. Lipid constituents, comprising cholesterol, cholesteryl esters, free cholesterol, phospholipids, and total lipids, in very low‐ (VLDL), intermediate‐ (IDL), and low‐density lipoprotein (LDL) particles were positively associated with MI risk (HR = 1.12 to 1.36; 95% CI = 1.06 to 1.44), while in high‐density lipoprotein (HDL) particles showed inverse associations (HR = 0.68 to 0.81; 95% CI = 0.63 to 0.87). Similar association pattern with MI was also observed for VLDL, IDL, LDL, and HDL particles themselves. In contrast, triglycerides within all lipoproteins, including most HDL particles, were positively associated with MI risk (HR = 1.14 to 1.28; 95% CI = 1.08 to 1.35) and, to a slightly lesser extent, with stroke and IS. Unsaturation of fatty acids and albumin were inversely associated with risks of stroke, IS, and MI. In contrast, the linear association for HS is absent. When combining multiple metabolites, the metabolite risk score captured a drastically elevated risk of all vascular events, about twice that of any single metabolite. Taken together, circulating metabolites showed remarkably widespread associations with incident MI, but substantially weakened associations with risks of stroke and its subtypes. Exhaustive metabolomics profiling may shed light on vascular risk prediction and, in turn, guide pertinent strategies of intervention and treatment. [ABSTRACT FROM AUTHOR]

Background: Observational studies have suggested that herpesvirus infection increased the risk of Alzheimer's disease (AD), but it is unclear whether the association is causal. The aim of the present study is to evaluate the causal relationship between four herpesvirus infections and AD. Methods: We performed a two-sample Mendelian randomization analysis to investigate association of four active herpesvirus infections with AD using summary statistics from genome-wide association studies. The four herpesvirus infections (i.e., chickenpox, shingles, cold sores, mononucleosis) are caused by varicella-zoster virus, herpes simplex virus type 1, and Epstein-Barr virus (EBV), respectively. A large summary statistics data from International Genomics of Alzheimer's Project was used in primary analysis, including 21,982 AD cases and 41,944 controls. Validation was further performed using family history of AD data from UK Biobank (27,696 cases of maternal AD, 14,338 cases of paternal AD and 272,244 controls). Results: We found evidence of a significant association between mononucleosis (caused by EBV) and risk of AD after false discovery rates (FDR) correction (odds ratio [OR] = 1.634, 95% confidence interval [CI] = 1.092–2.446, P = 0.017, FDR-corrected P = 0.034). It has been verified in validation analysis that mononucleosis is also associated with family history of AD (OR [95% CI] = 1.392 [1.061, 1.826], P = 0.017). Genetically predicted shingles were associated with AD risk (OR [95% CI] = 0.867 [0.784, 0.958], P = 0.005, FDR-corrected P = 0.020), while genetically predicted chickenpox was suggestively associated with increased family history of AD (OR [95% CI] = 1.147 [1.007, 1.307], P = 0.039). Conclusions: Our findings provided evidence supporting a positive relationship between mononucleosis and AD, indicating a causal link between EBV infection and AD. Further elucidations of this association and underlying mechanisms are likely to identify feasible interventions to promote AD prevention. [ABSTRACT FROM AUTHOR]

Background: Environmental factors are associated with human longevity, but their specificity and causality remain mostly unclear. By integrating the innovative "exposome" concept developed in the field of environmental epidemiology, this study aims to determine the components of exposome causally linked to longevity using Mendelian randomization (MR) approach.Methods: A total of 4587 environmental exposures extracting from 361,194 individuals from the UK biobank, in exogenous and endogenous domains of exposome were assessed. We examined the relationship between each environmental factor and two longevity outcomes (i.e., surviving to the 90th or 99th percentile age) from various cohorts of European ancestry. Significant results after false discovery rates correction underwent validation using an independent exposure dataset.Results: Out of all the environmental exposures, eight age-related diseases and pathological conditions were causally associated with lower odds of longevity, including coronary atherosclerosis (odds ratio = 0.77, 95% confidence interval [0.70, 0.84], P = 4.2 × 10-8), ischemic heart disease (0.66, [0.51, 0.87], P = 0.0029), angina (0.73, [0.65, 0.83], P = 5.4 × 10-7), Alzheimer's disease (0.80, [0.72, 0.89], P = 3.0 × 10-5), hypertension (0.70, [0.64, 0.77], P = 4.5 × 10-14), type 2 diabetes (0.88 [0.80, 0.96], P = 0.004), high cholesterol (0.81, [0.72, 0.91], P = 0.0003), and venous thromboembolism (0.92, [0.87, 0.97], P = 0.0028). After adjusting for genetic correlation between different types of blood lipids, higher levels of low-density lipoprotein cholesterol (0.72 [0.64, 0.80], P = 2.3 × 10-9) was associated with lower odds of longevity, while high-density lipoprotein cholesterol (1.36 [1.13, 1.62], P = 0.001) showed the opposite. Genetically predicted sitting/standing height was unrelated to longevity, while higher comparative height size at 10 was negatively associated with longevity. Greater body fat, especially the trunk fat mass, and never eat sugar or foods/drinks containing sugar were adversely associated with longevity, while education attainment showed the opposite.Conclusions: The present study supports that some age-related diseases as well as education are causally related to longevity and highlights several new targets for achieving longevity, including management of venous thromboembolism, appropriate intake of sugar, and control of body fat. Our results warrant further studies to elucidate the underlying mechanisms of these reported causal associations. [ABSTRACT FROM AUTHOR]

Background: Environmental factors are associated with human longevity, but their specificity and causality remain mostly unclear. By integrating the innovative "exposome" concept developed in the field of environmental epidemiology, this study aims to determine the components of exposome causally linked to longevity using Mendelian randomization (MR) approach. Methods: A total of 4587 environmental exposures extracting from 361,194 individuals from the UK biobank, in exogenous and endogenous domains of exposome were assessed. We examined the relationship between each environmental factor and two longevity outcomes (i.e., surviving to the 90th or 99th percentile age) from various cohorts of European ancestry. Significant results after false discovery rates correction underwent validation using an independent exposure dataset. Results: Out of all the environmental exposures, eight age-related diseases and pathological conditions were causally associated with lower odds of longevity, including coronary atherosclerosis (odds ratio = 0.77, 95% confidence interval [0.70, 0.84], P = 4.2 × 10−8), ischemic heart disease (0.66, [0.51, 0.87], P = 0.0029), angina (0.73, [0.65, 0.83], P = 5.4 × 10−7), Alzheimer's disease (0.80, [0.72, 0.89], P = 3.0 × 10−5), hypertension (0.70, [0.64, 0.77], P = 4.5 × 10−14), type 2 diabetes (0.88 [0.80, 0.96], P = 0.004), high cholesterol (0.81, [0.72, 0.91], P = 0.0003), and venous thromboembolism (0.92, [0.87, 0.97], P = 0.0028). After adjusting for genetic correlation between different types of blood lipids, higher levels of low-density lipoprotein cholesterol (0.72 [0.64, 0.80], P = 2.3 × 10−9) was associated with lower odds of longevity, while high-density lipoprotein cholesterol (1.36 [1.13, 1.62], P = 0.001) showed the opposite. Genetically predicted sitting/standing height was unrelated to longevity, while higher comparative height size at 10 was negatively associated with longevity. Greater body fat, especially the trunk fat mass, and never eat sugar or foods/drinks containing sugar were adversely associated with longevity, while education attainment showed the opposite. Conclusions: The present study supports that some age-related diseases as well as education are causally related to longevity and highlights several new targets for achieving longevity, including management of venous thromboembolism, appropriate intake of sugar, and control of body fat. Our results warrant further studies to elucidate the underlying mechanisms of these reported causal associations. [ABSTRACT FROM AUTHOR]

Variability exists in the trajectories of Alzheimer's disease (AD). We aimed to identify genetic modulators of clinical progression in AD. We conducted the first genome-wide survival study on AD using a two-stage approach. The discovery and replication stage separately included 1158 and 211,817 individuals without dementia from the Alzheimer's Disease Neuroimaging Initiative and the UK Biobank, respectively (325 and 1103 progressed in average follow-up of 4.33 and 8.63 years, respectively). Cox proportional hazards models were applied with time to AD dementia as the phenotype of clinical progression. A series of bioinformatic analyses and functional experiments was performed to validate the novel findings. We found that APOE and PARL , a novel locus tagged by rs6795172 (hazard ratio = 1.66, p = 1.45 × 10−9), were significantly associated with AD clinical progression and were successfully replicated. The novel locus was linked to accelerated cognitive changes, higher tau levels, and faster atrophy of AD-specific brain structures, which were also verified in UK Biobank neuroimaging follow-up. Gene analysis and summary data–based Mendelian randomization indicated PARL as the most functionally relevant gene in the locus. Expression quantitative trait locus analyses and dual-luciferase reporter assays confirmed that PARL expression could be regulated by rs6795172. Three different AD mouse models consistently showed decreased PARL expression accompanied by elevated tau levels, and in vitro experiments revealed that knockdown/overexpression of PARL inversely changed tau levels. Collectively, genetic, bioinformatic, and functional evidence suggests that PARL modulates clinical progression and neurodegeneration in AD. Targeting PARL may potentially modify AD progression and have implications for disease-modifying therapies. [ABSTRACT FROM AUTHOR]

The corpus callosum (CC) is the main structure transferring information between the cerebral hemispheres. Although previous large-scale genome-wide association study (GWAS) has illustrated the genetic architecture of white matter integrity of CC, CC volume is less stressed. Using MRI data from 33,861 individuals in UK Biobank, we conducted univariate and multivariate GWAS for CC fractional anisotropy (FA) and volume with PLINK 2.0 and MOSTest. All discovered SNPs in the multivariate framework were functionally annotated in FUMA v1.3.8. In the meanwhile, a series of gene property analyses was conducted simultaneously. In addition, we estimated genetic relationship between CC metrics and other neuropsychiatric traits and diseases. We identified a total of 36 and 82 significant genomic loci for CC FA and volume (P < 5 × 10−8). And 53 and 27 genes were respectively mapped by four mapping strategies. For CC volume, gene-set analysis revealed pathways mainly relating to cell migration; cell-type analysis found the top enrichment in neuroglia while for CC FA in GABAergic neurons. Furthermore, we found a lot of genetic overlap and shared loci between CC FA and volume and common neuropsychiatric diseases. Collectively, this study helps to better understand the genetic architecture of whole CC and CC subregions. However, the way to divide CC FA and volume in our study restricts the interpretations of our results. Future work will be needed to pay attention to the genetic structure of white matter volume, and an appropriate division of CC may help to better understand CC structure. • The genetic architecture of microstructure and macrostructure of corpus callosum (CC). • Genetic correlations between CC metrics and other brain measures derived from MRI. • Genetic overlap between CC metrics and common neuropsychiatric diseases. [ABSTRACT FROM AUTHOR]

This study aimed to analyze the impact of a wide spectrum of occupational characteristics on the incidence of anxiety and depression, and to determine the features affecting adaptation to specific characteristics. Participants in paid employment or self-employed at baseline in UKB were included, with occupational characteristics extracted from O*NET. Cox-proportional-hazard models were conducted in the main analyses and subgroup analyses. Direct work with the public and exposure to disease/infections were first time demonstrated to be risk factors for both anxiety and depression, along with occupations involving more physical activities and dealing with unpleasant/physically aggressive people. Protective factors for both: time spent sitting, communication, decision making, creativity and reasoning, and responsibility in work. Protective factors for anxiety only: Coordinating/leading, fluency of ideas, originality, problem sensitivity, decision latitude, and time pressure. Risk factor for depression only: Exposure to contaminants. Females were found more sensitive to dealing with unpleasant/physically aggressive people. The impact of exposure to disease/infections was more significant among those with lower education levels. Those with BMI over 24 were more sensitive to the risk factors. The short-term effect of the above exposures remained unclear. The scores of occupational characteristics were based on self-reported questionnaires. There was the potential for undiagnosed anxiety or depression events. The participants included only those aged from 40 to 69. Participants included in this cohort were mainly White British. Our findings advocate closer monitoring of the mental health of workers with risk work-related factors. Guideline of the study. Left, UK Biobank data used in the study. Top right, association between occupational characteristics and the incidence of anxiety and depression. Bottom right, subgroup analyses. [Display omitted] • Risk factors for both anxiety and depression included direct work with the public and exposure to disease or infections occupations involving more physical activities, and dealing with unpleasant and physically aggressive people. And protective factors for anxiety and depression included time spent sitting, communication, decision making, creativity and reasoning, and responsibility in work. • Protective factors for anxiety only included coordinating/leading, fluency of ideas, originality, problem sensitivity, decision latitude, and time pressure, while exposure to contaminants was a risk factor for depression only. • Females were found more sensitive to dealing with unpleasant and physically aggressive people. • The impact of exposure to disease/infections was more significant among those with lower education level. • Risk factors except for physical activities were found significant impact only among those with BMI over 24. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the associations between courses of depression, the application of depression treatment, and the risk of incident dementia. In this prospective cohort study, 354,313 participants ages 50–70 years were recruited from the UK Biobank between 2006 and 2010 and were followed until 2020, with a total of 4,212,929 person-years. We initially studied the effect of depression on dementia incidence across 4 subgroups characterized by courses of depressive symptoms. Then, 46,820 participants with a diagnosis of depression were further categorized into treated and untreated groups. We compared the risk of dementia among different depression treatment groups in all participants who were depressed as well as 4 courses of depressive symptoms by performing survival analyses. Depression was associated with a 51% higher risk of dementia, among which the increasing, chronically high, and chronically low courses were associated with increased dementia risk, while no association was found in the decreasing course. Compared to those who were depressed but untreated, receiving depression treatments corresponded to a hazard ratio of 0.7 (95% CI, 0.62–0.77). Among the 3 detrimental courses, treatments for increasing and chronically low symptoms of depression were associated with a 32% and 28% lower risk of dementia, respectively, while the reduction effect for chronically high symptoms was insignificant. The negative association between depression treatment and incident dementia was significant in the increasing and chronically low courses, highlighting the necessity of timely interventional strategies before depression progresses to a chronically severe state. [ABSTRACT FROM AUTHOR]

Considerable uncertainty remains regarding associations of multiple risk factors with Alzheimer's disease (AD). We aimed to systematically screen and validate a wide range of potential risk factors for AD. Among 502,493 participants from the UK Biobank, baseline data were extracted for 4171 factors spanning 10 different categories. Phenome-wide association analyses and time-to-event analyses were conducted to identify factors associated with both polygenic risk scores for AD and AD diagnosis at follow-up. We performed two-sample Mendelian randomization analysis to further assess their potential causal relationships with AD and imaging association analysis to discover underlying mechanisms. We identified 39 factors significantly associated with both AD polygenic risk scores and risk of incident AD, where higher levels of education, body size, basal metabolic rate, fat-free mass, computer use, and cognitive functions were associated with a decreased risk of developing AD, and selective food intake and more outdoor exposures were associated with an increased risk of developing AD. The identified factors were also associated with AD-related brain structures, including the hippocampus, entorhinal cortex, and inferior/middle temporal cortex, and 21 of these factors were further supported by Mendelian randomization evidence. To our knowledge, this is the first study to comprehensively and rigorously assess the effects of wide-ranging risk factors on AD. Strong evidence was found for fat-free body mass, basal metabolic rate, computer use, selective food intake, and outdoor exposures as new risk factors for AD. Integration of genetic, clinical, and neuroimaging information may help prioritize risk factors and prevention targets for AD. [ABSTRACT FROM AUTHOR]

Visual impairment and interventions to preserve vision may impact dementia risk. Thus, we aimed to explore the associations of cataract and cataract surgery with the risk of dementia. Prospective data from 300,823 individuals in the UK Biobank were used. We used multivariate Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals for associations, with healthy control subjects as a reference. The same method was used to explore the effects of surgery on dementia outcomes of patients with cataract. One-way analysis of variance was performed to examine the associations between cataract and brain morphometric measures. After a mean follow-up of 8.4 years, 3226 individuals were diagnosed with dementia. The nonsurgical cataract group had increased risk of all-cause dementia (HR, 1.214; 95% CI, 1.012–1.456; p =.037) and Alzheimer's disease (HR, 1.479; 95% CI, 1.105–1.981; p =.009). However, there was no difference in dementia risk between the cataract surgery group and the healthy control group. Cataract surgery was associated with decreased risk of all-cause dementia (HR, 0.632; 95% CI, 0.421–0.947; p =.026) and Alzheimer's disease (HR, 0.399; 95% CI, 0.196–0.812; p =.011) compared with the nonsurgical group. Additionally, cataract was negatively associated with cortical volumes, aging-related subcortical volumes, and fractional anisotropy of white matter fibers. Cataract patients who did not receive surgical treatment had an increased risk of dementia. However, cataract surgery could reverse the risk of dementia. Our findings on brain structures and pathways in patients with cataract also provided evidence for the mechanism. Reversible visual impairment, such as cataract, is a promising modifiable risk factor for dementia. [ABSTRACT FROM AUTHOR]

• Life-course risk for incident dementia was modulated by lung function. • Immunity, oxygen-carrying indices and specific metabolites are critical mediators. • Brain structures were substantially changed with poor lung function. • Monitoring lung function is of great significance for cognitive brain health. Whether lung function prospectively affects cognitive brain health independent of their overlapping factors remains largely unknown. This study aimed to investigate the longitudinal association between decreased lung function and cognitive brain health and to explore underlying biological and brain structural mechanisms. This population-based cohort included 43,1834 non-demented participants with spirometry from the UK Biobank. Cox proportional hazard models were fitted to estimate the risk of incident dementia for individuals with low lung function. Mediation models were regressed to explore the underlying mechanisms driven by inflammatory markers, oxygen-carrying indices, metabolites, and brain structures. During a follow-up of 3,736,181 person-years (mean follow-up 8.65 years), 5,622 participants (1.30 %) developed all-cause dementia, which consisted of 2,511 Alzheimer's dementia (AD) and 1,308 Vascular Dementia (VD) cases. Per unit decrease in lung function measure was each associated with increased risk for all-cause dementia (forced expiratory volume in 1 s [liter]: hazard ratio [HR, 95 %CI], 1.24 [1.14–1.34], P = 1.10 × 10-07; forced vital capacity [liter]: 1.16 [1.08–1.24], P = 2.04 × 10-05; peak expiratory flow [liter/min]: 1.0013 [1.0010–1.0017], P = 2.73 × 10-13). Low lung function generated similar hazard estimates for AD and VD risks. As underlying biological mechanisms, systematic inflammatory markers, oxygen-carrying indices, and specific metabolites mediated the effects of lung function on dementia risks. Besides, brain grey and white matter patterns mostly affected in dementia were substantially changed with lung function. Life-course risk for incident dementia was modulated by individual lung function. Maintaining optimal lung function is useful for healthy aging and dementia prevention. [ABSTRACT FROM AUTHOR]

Background: Shift work is associated with susceptibility to several neuropsychiatric disorders. This study aims to investigate the effect of shift work on the incidence of neuropsychiatric disorders, and highlighting how individual variability may influence the association., Methods: UK Biobank participants with employment information were included. Cox survival was conducted in main and subgroup analyses. Correlation analyses explored the impact of shift work on brain structures, and mediation analyses were performed to elucidate the shared underlying mechanisms. Shift work tolerance was evaluated through survival analyses contrasting the risks associated with five neuropsychiatric disorders in shift versus non-shift workers across different demographic or occupational strata., Results: The analysis encompassed 254,646 participants. Shift work was associated with higher risk of dementia (HR 1.29, 95 % CI 1.10-1.52), anxiety (1.08, 1.01-1.15), depression (1.29, 1.22-1.36), and sleep disorders (1.18, 1.09-1.28), but not stroke (p = 0.20). Shift work was correlated with decreasing volume of various brain regions, particularly in thalamus, lateral orbitofrontal, and middle temporal. Mediation analysis revealed that increased immune response and glucose levels are common pathways linking shift work to these disorders. We observed diversity in shift work tolerance across different individual characteristics, among which socioeconomic status and length of working hours were the most essential., Limitations: Self-reported employment information may cause misclassification and recall bias. And since we focused on the middle-aged population, the conclusions may not be representative of younger or older populations., Conclusions: Our findings indicated the need to monitor shift worker health and provide personalized management to help adapt to shift work., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Evidence supporting cardiovascular diseases could increase the risk of dementia remains fragmented. A comprehensive study to illuminate the distinctive associations across different dementia types is still lacking. This study is sought to: (1) determine the clinical validity of Framingham General Cardiovascular Risk Score (FGCRS) for dementia assessment and (2) examine the associations between cardiovascular diseases and the risk of dementia., Methods: A total of 432 079 dementia-free individuals at baseline from UK Biobank were included. Multivariable Cox proportional hazard models were used to investigate the prospective associations for FGCRS and a series of cardiovascular diseases with all-cause dementia (ACD) and its major components, Alzheimer's disease (AD) and vascular dementia (VaD)., Results: During a median follow-up of 110.1 months, 4711 individuals were diagnosed with dementia. FGCRS was associated with increased risks across the dementia spectrum. In stratification analysis, high-risk groups have demonstrated the greatest dementia burdens, particularly to VaD. Over 74 traits, 9 adverse associations, such as chronic ischaemic heart disease (ACD: HR=1.354; AD: HR=1.269; VaD: HR=1.768), atrioventricular block (ACD: HR=1.562; AD: HR=1.556; VaD: HR=2.069), heart failure (ACD: HR=1.639; AD: HR=1.543; VaD: HR=2.141) and hypotension (ACD: HR=2.912; AD: HR=2.361; VaD: HR=3.315) were observed. Several distinctions were also found, with atrial fibrillation, cerebral infarction, and haemorrhage only associated with greater risks of ACD and VaD., Discussion: By identifying distinctive associations between cardiovascular diseases and dementia, this study has established a comprehensive 'mapping' that may untangle the long-standing discrepancy. FGCRS has demonstrated its predictivity beyond cardiovascular diseases burdens, suggesting potential opportunities for implantation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

While numerous genomic loci have been identified for neuropsychiatric conditions, the contribution of protein-coding variants has yet to be determined. Here we conducted a large-scale whole-exome-sequencing study to interrogate the impact of protein-coding variants on 46 neuropsychiatric diseases and 23 traits in 350,770 adults from the UK Biobank. Twenty new genes were associated with neuropsychiatric diseases through coding variants, among which 16 genes had impacts on the longitudinal risks of diseases. Thirty new genes were associated with neuropsychiatric traits, with SYNGAP1 showing pleiotropic effects across cognitive function domains. Pairwise estimation of genetic correlations at the coding-variant level highlighted shared genetic associations among pairs of neurodegenerative diseases and mental disorders. Lastly, a comprehensive multi-omics analysis suggested that alterations in brain structures, blood proteins and inflammation potentially contribute to the gene-phenotype linkages. Overall, our findings characterized a compendium of protein-coding variants for future research on the biology and therapeutics of neuropsychiatric phenotypes., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Although sleep, physical activity and sedentary behavior have been found to be associated with dementia risk, findings are inconsistent and their joint relationship remains unclear. This study aimed to investigate independent and joint associations of these three modifiable behaviors with dementia risks. A total of 431,924 participants (median follow-up 9.0 years) without dementia from UK Biobank were included. Multiple Cox regressions were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Models fitted with restricted cubic spline were conducted to test for linear and nonlinear shapes of each association. Sleep duration, leisure-time physical activity (LTPA), and screen-based sedentary behavior individually associated with dementia risks in different non-linear patterns. Sleep duration associated with dementia in a U-shape with a nadir at 7 h/day. LTPA revealed a curvilinear relationship with dementia in diminishing tendency, while sedentary behavior revealed a J-shaped relationship. The dementia risk was 17% lower in the high LTPA group (HR[95%CI]: 0.83[0.76-0.91]) and 22% higher in the high sedentary behavior group (1.22[1.10-1.35]) compared to the corresponding low-level group, respectively. A combination of seven-hour/day sleep, moderate-to-high LTPA, and low-to-moderate sedentary behavior showed the lowest dementia risk (0.59[0.50-0.69]) compared to the referent group (longer or shorter sleep/low LTPA/high sedentary behavior). Notably, each behavior was non-linearly associated with brain structures in a pattern similar to its association with dementia, suggesting they may affect dementia risk by affecting brain structures. Our findings highlight the potential to change these three daily behaviors individually and simultaneously to reduce the risk of dementia., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)