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Background We aimed to investigate the association between OA and treatment with dementia risk and structural brain abnormalities. Methods We recruited a total of 466,460 individuals from the UK Biobank to investigate the impact of OA on the incidence of dementia. Among the total population, there were 63,081 participants diagnosed with OA. We subsequently categorised the OA patients into medication and surgery groups based on treatment routes. Cox regression models explored the associations between OA/OA treatment and dementia risk, with the results represented as hazard ratios (HRs) and 95% confidence intervals (95% CI). Linear regression models assessed the associations of OA/OA therapy with alterations in cortical structure. Results During an average of 11.90 (± 1.01) years of follow-up, 5,627 individuals were diagnosed with all-cause dementia (ACD), including 2,438 AD (Alzheimer's disease), and 1,312 VaD (vascular dementia) cases. Results revealed that OA was associated with the elevated risk of ACD (HR: 1.116; 95% CI: 1.039–1.199) and AD (HR: 1.127; 95% CI: 1.013–1.254). OA therapy lowered the risk of dementia in both medication group (HR: 0.746; 95% CI: 0.652–0.854) and surgery group (HR: 0.841; 95% CI: 0.736–0.960). OA was negatively associated with cortical area, especially precentral, postcentral and temporal regions. Conclusions Osteoarthritis increased the likelihood of developing dementia, and had an association with regional brain atrophy. OA treatment lowered the dementia risk. OA is a promising modifiable risk factor for dementia. [ABSTRACT FROM AUTHOR]

Background: Varicose veins (VV) are one of the common human diseases, but the role of genetics in its development is not fully understood. Methods: We conducted an exome-wide association study of VV using whole-exome sequencing data from the UK Biobank, and focused on common and rare variants using single-variant association analysis and gene-level collapsing analysis. Findings: A total of 13,823,269 autosomal genetic variants were obtained after quality control. We identified 36 VV-related independent common variants mapping to 34 genes by single-variant analysis and three rare variant genes (PIEZO1, ECE1, FBLN7) by collapsing analysis, and most associations between genes and VV were replicated in FinnGen. PIEZO1 was the closest gene associated with VV (P = 5.05 × 10−31), and it was found to reach exome-wide significance in both single-variant and collapsing analyses. Two novel rare variant genes (ECE1 and METTL21A) associated with VV were identified, of which METTL21A was associated only with females. The pleiotropic effects of VV-related genes suggested that body size, inflammation, and pulmonary function are strongly associated with the development of VV. Conclusions: Our findings highlight the importance of causal genes for VV and provide new directions for treatment. Author summary: In this study, whole-exome sequencing data from the UK Biobank were used to explore the effect of genetic variants on varicose veins (VV) and search for new VV-related genes. In contrast to traditional association studies, large-scale whole-exome sequencing analysis is more capable of identifying rare genetic variants (MAF < 1%) in diseases. The current study identified 34 VV-associated common variant genes by single-variant analysis and three rare variant genes (PIEZO1, ECE1, FBLN7) by collapsing analysis, and most associations were validated in FinnGen. In addition to replicating several genes reported in previous genome-wide association studies, we identified 17 novel genes that may be associated with VV. Through subsequent phenome-wide association analyses of identified genes, we found that these genes are also strongly associated with body size, inflammation, and pulmonary function. These findings contribute to understanding the underlying mechanisms of pathogenesis and developing novel therapeutic strategies for VV. [ABSTRACT FROM AUTHOR]

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]

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]

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]

Background: Alzheimer's disease (AD) patients rank among the highest levels of comorbidities compared to persons with other diseases. However, it is unclear whether the conditions are caused by shared pathophysiology due to the genetic pleiotropy for AD risk genes.Objective: To figure out the genetic pleiotropy for AD risk genes in a wide range of diseases.Methods: We estimated the polygenic risk score (PRS) for AD and tested the association between PRS and 16 ICD10 main chapters, 136 ICD10 level-1 chapters, and 377 diseases with cases more than 1,000 in 312,305 individuals without AD diagnosis from the UK Biobank.Results: After correction for multiple testing, AD PRS was associated with two main ICD10 chapters: Chapter IV (endocrine, nutritional and metabolic diseases) and Chapter VII (eye and adnexa disorders). When narrowing the definition of the phenotypes, positive associations were observed between AD PRS and other types of dementia (OR = 1.39, 95% CI [1.34, 1.45], p = 1.96E-59) and other degenerative diseases of the nervous system (OR = 1.18, 95% CI [1.13, 1.24], p = 7.74E-10). In contrast, we detected negative associations between AD PRS and diabetes mellitus, obesity, chronic bronchitis, other retinal disorders, pancreas diseases, and cholecystitis without cholelithiasis (ORs range from 0.94 to 0.97, FDR <  0.05).Conclusion: Our study confirms several associations reported previously and finds some novel results, which extends the knowledge of genetic pleiotropy for AD in a range of diseases. Further mechanistic studies are necessary to illustrate the molecular mechanisms behind these associations. [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]

Background: Previous studies found that cancer survivors had a reduced risk of dementia compared with the general population. However, these findings were uncertain because of survivor bias and a lack of stratification by cancer types. This current cohort study used data from the UK Biobank to explore these associations. Methods: Multivariable Cox regression analyses were used to examine the association of cancer status and the risk of dementia with its subtypes after adjusting for age and sex. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated as a measure of relative risk by comparing observed dementia incidence among cancer patients. Results: We included 263,151 participants in the observational analysis. During a median follow-up of 9.18 years, dementia was diagnosed in 472 individuals with cancer and 3685 individuals without cancer, respectively. Cancer patients had lower risks of dementia (hazard ratio: 0.89, confidence interval: 0.81–0.98) and its subtypes (Alzheimer's disease [AD]: 0.85 [0.74–0.98]; vascular dementia [VD]: 0.81 [0.66–0.99]) in the Cox regression adjusted for age and sex. Individuals with cancers in the male genital system had substantially reduced risks of dementia (0.66 [0.46–0.93]) and AD (0.53 [0.29–0.97]) than those with cancers in other systems. Moreover, non-melanoma skin cancer and prostate cancer were associated with a reduced risk of dementia (0.79 [0.62–0.99]; 0.69 [0.49–0.97]), but not with AD or VD (P>0.05). Conclusions: The current study supported a negative association between cancer and dementia risk, and encourages further exploration of the mechanistic basis of this inverse relationship to improve understanding. [ABSTRACT FROM AUTHOR]

Background/Aims: The storage amount of liver glycogen could affect the liver fibrosis assessment made by MRI-based methods. However, it remained unclear whether glycogen amount could bias the estimation of liver fat content by proton density fat fraction. In this study, we aimed to investigate whether glycogen metabolism gene variants could contribute to the bias of PDFF by genetic association. Methods: We conducted an association study of the glycogen metabolism genes based on the PDFF data of 11,129 participants in the UK Biobank. The effect of the SNPs in these genes on non-alcoholic fatty liver disease was estimated by a meta-analysis of the available NAFLD case-control studies. Results: We identified significant associations of the SNPs near the genes encoding glycogen phosphorylase (PYGM and PYGL) and synthase (GYS2) with PDFF (FDR-corrected p value < 0.05). The genes encoding the regulatory proteins of glycogenolysis (PHKB , CALM2/3), glucose transporter (SLC2A1), and glucose kinase (GCK) were also associated with PDFF. The SNP rs5402 of SLC2A2 and rs547066 of PYGM were associated with NAFLD (p < 0.05) with others being insignificant. Except for the PYGM gene, the PDFF-associated SNPs showed no associations with NAFLD. In addition, the burden tests of rare variants in these genes were not significant after FDR correction. Conclusion: Liver glycogen metabolism genes associated with PDFF were not associated with NAFLD, which implicated a potential bias effect of glycogen storage on the quantification of liver fat content by PDFF. [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]

Dementia is a major public health issue and a heavy economic burden. It is urgently necessary to understand the underlying biological processes and to identify biomarkers predicting risk of dementia in the preclinical stage for prevention and treatment. By using the data of the 367,093 white British individuals from UK Biobank, we investigated the relationship between 56 laboratory measures and 5-year dementia incidence using logistic regression. Adjusted odds ratios for dementia incidence with values below or above the 95 % confidence interval (<2.5th or > 97.5th percentile) on each of clinical laboratory tests were computed. We observed that markers of endocrine dysregulation: elevated hemoglobin A1C (AOR = 2.01 [1.35, 2.88]) was associated with increased dementia incidence. Indicators of liver dysfunction: elevated gamma glutamyltransferase (AOR = 2.28 [1.49, 3.32]), and albumin (AOR = 2.01 [1.15, 3.25]), indicators of renal impairment: high urea (AOR = 1.69 [1.15, 2.40]), and cystatin C (AOR = 1.89 [1.30, 2.67]), and some immune markers, like elevated neutrophill count, low lymphocyte count, and indicators of anemia were also observed to be associated with increased dementia incidence. Both low and high concentrations of insulin-like growth factor 1 were found to be risk factors for dementia. This is an observational study. Several systemic biomarkers were associated with dementia incidence. These results implicate a contributory role of diverse biological processes to dementia onset, and enrich our understanding of potential dementia prevention strategy. • We examined associations of serum lab tests with dementia incidence longitudinally. • Endocrine, liver, renal dysfunction, immunity, and anemia markers are linked to dementia. • Our findings suggest diverse biological processes contribute to dementia onset. [ABSTRACT FROM AUTHOR]

Antipsychotics (APs) are among the most widely prescribed medications, and have been shown to cause cognitive decline. But previous studies on their effects on dementia risk are controversial and scarce. We aimed to examine the relationships of APs exposure with the risk of dementia. Data were obtained from a prospective cohort of 415,100 UK Biobank (UKB) participants. We investigated the effects of APs exposure and their various classes on dementia risk by using multivariable Cox proportional hazard models and further the dose-response effects of oral APs. After a mean follow-up of 8.64 years, 5235 (1.3 %) participants developed all-cause dementia (ACD), among whom 2313 (0.6 %) developed Alzheimer's disease (AD), and 1213 (0.3 %) developed vascular dementia (VaD). Exposure to any APs conferred increased risks of ACD (HR: 1.33, 95 % CI = 1.17–1.51, P < 0.001) and VaD (HR: 1.90, 95 % CI = 1.51–2.40, P < 0.001), but not AD (HR: 1.22, 95 % CI = 1.00–1.48, P = 0.051). Cumulative dose-response relationships of oral APs with the risks of ACD and VaD were observed (P for trend, P < 0.05). Our study is observational and does not show evidence of causality. Since there are relatively few cases of dementia in the UKB, APs exposure may be higher than estimated in our study. APs exposure increased the risk of developing dementia. Dose-response relationships were found between oral APs and dementia risk. Efforts to raise awareness of doctors and patients about this potential drug-related risk are critical to reducing APs use. • Exposure to any antipsychotics (APs) conferred increased risks of dementia. • Cumulative dose-response relationships between oral APs and dementia risk existed. • Both typical and atypical APs increased dementia risk with different effect sizes. • The results were robust across a range of sensitivity analyses. [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]

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]

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.)

Alcohol consumption is a heritable behavior seriously endangers human health. However, genetic studies on alcohol consumption primarily focuses on common variants, while insights from rare coding variants are lacking. Here we leverage whole exome sequencing data across 304,119 white British individuals from UK Biobank to identify protein-coding variants associated with alcohol consumption. Twenty-five variants are associated with alcohol consumption through single variant analysis and thirteen genes through gene-based analysis, ten of which have not been reported previously. Notably, the two unreported alcohol consumption-related genes GIGYF1 and ANKRD12 show enrichment in brain function-related pathways including glial cell differentiation and are strongly expressed in the cerebellum. Phenome-wide association analyses reveal that alcohol consumption-related genes are associated with brain white matter integrity and risk of digestive and neuropsychiatric diseases. In summary, this study enhances the comprehension of the genetic architecture of alcohol consumption and implies biological mechanisms underlying alcohol-related adverse outcomes., (© 2024. The Author(s).)

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.)

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.)

Previous hypothesis-driven research has identified many risk factors linked to dementia. However, the multiplicity and co-occurrence of risk factors have been underestimated. Here we analysed data of 344,324 participants from the UK Biobank with 15 yr of follow-up data for 210 modifiable risk factors. We first conducted an exposure-wide association study and then combined factors associated with dementia to generate composite scores for different domains. We then evaluated their joint associations with dementia in a multivariate Cox model. We estimated the potential impact of eliminating the unfavourable profiles of risk domains on dementia using population attributable fraction. The associations varied by domain, with lifestyle (16.6%), medical history (14.0%) and socioeconomic status (13.5%) contributing to the majority of dementia cases. Overall, we estimated that up to 47.0%-72.6% of dementia cases could be prevented., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background Although the association between shift work and individual cardiometabolic diseases has been well studied, its role in the progression to cardiometabolic multimorbidity (CMM) remains unclear. In this study, we investigate the association between shift work and the incidence of CMM in patients with hypertension. Methods and Results This study is a population-based and prospective cohort study on 36 939 UK Biobank participants. We used competing risk models to examine the association between shift work and the risk of CMM, which was defined as coexistence of hypertension and diabetes, coronary heart disease, or stroke in our study. We also investigated the association between the frequency and duration of shift work and CMM risks. In addition, we conducted a cross-classification analysis with the combination of frequency and duration of shift work, chronotype and sleep duration as the exposure metrics. During a median follow-up of 11.6 years, a total of 5935 participants developed CMM. We found that usually/always night shift workers were associated with a 16% higher risk of CMM compared with day workers (hazard ratio [HR], 1.16 [95% CI, 1.02-1.31]). We also found that a higher frequency of night shifts (>10/month) was associated with increased risk of CMM (HR, 1.19 [95% CI, 1.06-1.34]) that was more pronounced for >10/month in combination with a morning chronotype or <7 hours or >8 hours of sleep duration (HR, 1.26 [95% CI, 1.02-1.56]; HR, 1.43 [95% CI, 1.19-1.72], respectively). Conclusions We find that night shift work is associated with higher CMM risk in patients with hypertension.