Association of neuroticism with incident dementia, neuroimaging outcomes, and cognitive function.

INTRODUCTION: Higher neuroticism might be associated with dementia risk. Here we investigated modification by genetic predisposition to dementia, mediation by mental health and vascular conditions, neuroimaging outcomes, and cognitive function. METHODS: Cox proportional-hazards models were used to assess the association between neuroticism score and incident dementia over up to 15 years in 1,74,164 participants. Cross-sectional analyses on dementia-related neuroimaging outcomes and cognitive function were conducted in 39,459 dementia-free participants. RESULTS: Higher neuroticism was associated with an 11% higher risk of incident dementia, especially vascular dementia (15% higher risk), regardless of genetic predisposition to dementia. Mental and vascular conditions mediated the association of neuroticism with all-cause dementia and vascular dementia. Neuroticism was associated with higher cerebrovascular pathology, lower gray matter volume, and worse function across multiple cognitive domains. DISCUSSION: Neuroticism could represent a risk factor for dementia, and vascular and mental health might drive these associations. HIGHLIGHTS: Neuroticism was associated with an increased risk of incident all-cause dementia, particularly vascular dementia. Associations were not modified by genetic predisposition to dementia. Associations were largely mediated by mental and vascular conditions. Neuroticism was associated with increased cerebrovascular pathology and lower gray matter volume. Neuroticism was associated with worse function across multiple cognitive domains.

Brain Care Score and Neuroimaging Markers of Brain Health in Asymptomatic Middle-Age Persons.

OBJECTIVES: To investigate associations between health-related behaviors as measured using the Brain Care Score (BCS) and neuroimaging markers of white matter injury. METHODS: This prospective cohort study in the UK Biobank assessed the BCS, a novel tool designed to empower patients to address 12 dementia and stroke risk factors. The BCS ranges from 0 to 21, with higher scores suggesting better brain care. Outcomes included white matter hyperintensities (WMH) volume, fractional anisotropy (FA), and mean diffusivity (MD) obtained during 2 imaging assessments, as well as their progression between assessments, using multivariable linear regression adjusted for age and sex. RESULTS: We included 34,509 participants (average age 55 years, 53% female) with no stroke or dementia history. At first and repeat imaging assessments, every 5-point increase in baseline BCS was linked to significantly lower WMH volumes (25% 95% CI [23%-27%] first, 33% [27%-39%] repeat) and higher FA (18% [16%-20%] first, 22% [15%-28%] repeat), with a decrease in MD (9% [7%-11%] first, 10% [4%-16%] repeat). In addition, a higher baseline BCS was associated with a 10% [3%-17%] reduction in WMH progression and FA decline over time. DISCUSSION: This study extends the impact of the BCS to neuroimaging markers of clinically silent cerebrovascular disease. Our results suggest that improving one's BCS could be a valuable intervention to prevent early brain health decline.

Association of Metabolic Syndrome With Neuroimaging and Cognitive Outcomes in the UK Biobank.

OBJECTIVE: Metabolic syndrome (MetS) has been linked to dementia. In this study, we examined the association of MetS with neuroimaging and cognition in dementia-free adults, offering insight into the impact of MetS on brain health prior to dementia onset. RESEARCH DESIGN AND METHODS: We included 37,395 dementia-free adults from the UK Biobank database. MetS was defined as having at least three of the following components: larger waist circumference; elevated levels of triglycerides, blood pressure, HbA1c; or reduced HDL cholesterol levels. Multivariable-adjusted linear regression was used to assess associations of MetS with structural neuroimaging and cognitive domains. RESULTS: MetS was associated with lower total brain (standardized ß: -0.06; 95% CI -0.08, -0.04), gray matter (ß: -0.10; 95% CI -0.12, -0.08) and hippocampal (for left side, ß: -0.03, 95% CI -0.05, -0.01; for right side, ß: -0.04, 95% CI -0.07, -0.02) volumes, and greater white matter hyperintensity (WMH) volume (ß: 0.08; 95% CI 0.06, 0.11). Study participants with MetS performed poorer on cognitive tests of working memory (ß: -0.10; 95% CI -0.13, -0.07), verbal declarative memory (ß: -0.08; 95% CI -0.11, -0.05), processing speed (ß: -0.06; 95% CI -0.09, -0.04), verbal and numerical reasoning (ß: -0.07; 95% CI -0.09, -0.04), nonverbal reasoning (ß: -0.03; 95% CI -0.05, -0.01), and on tests of executive function, where higher scores indicated poorer performance (ß: 0.05; 95% CI 0.03, 0.08). More MetS components were also associated with less brain volume, greater WMH, and poorer cognition across all domains. CONCLUSIONS: MetS was associated poorer brain health in dementia-free adults, characterized by less brain volume, greater vascular pathology, and poorer cognition. Further research is necessary to understand whether reversal or improvement of MetS can improve brain health.

Frailty trajectories preceding dementia: an individual-level analysis of four cohort studies in the United States and United Kingdom.

Frailty may represent a modifiable risk factor for dementia, but the direction of that association remains uncertain. We investigated frailty trajectories in the years preceding dementia onset using data from 23,672 participants (242,760 person-years of follow-up, 2,906 cases of incident dementia) across four cohort studies in the United States and United Kingdom. Bayesian non-linear models revealed accelerations in frailty trajectories 4-9 years before incident dementia. Among participants whose time between frailty measurement and incident dementia exceeded that prodromal period, frailty remained positively associated with dementia risk (adjusted hazard ratios ranged from 1.20 [95% confidence interval, CI = 1.15-1.26] to 1.43 [95% CI = 1.14-1.81]). This observational evidence suggests that frailty increases dementia risk independently of any reverse causality. These findings indicate that frailty measurements can be used to identify high-risk population groups for preferential enrolment into clinical trials for dementia prevention and treatment. Frailty itself may represent a useful upstream target for behavioural and societal approaches to dementia prevention.

Assessing the Value of Incorporating a Polygenic Risk Score with Nongenetic Factors for Predicting Breast Cancer Diagnosis in the UK Biobank.

BACKGROUND: Previous studies have demonstrated that incorporating a polygenic risk score (PRS) to existing risk prediction models for breast cancer improves model fit, but to determine its clinical utility the impact on risk categorization needs to be established. We add a PRS to two well-established models and quantify the difference in classification using the net reclassification improvement (NRI). METHODS: We analyzed data from 126,490 post-menopausal women of "White British" ancestry, aged 40 to 69 years at baseline from the UK Biobank prospective cohort. The breast cancer outcome was derived from linked registry data and hospital records. We combined a PRS for breast cancer with 10-year risk scores from the Tyrer-Cuzick and Gail models, and compared these to the risk scores from the models using phenotypic variables alone. We report metrics of discrimination and classification, and consider the importance of the risk threshold selected. RESULTS: The Harrell's C statistic of the 10-year risk from the Tyrer-Cuzick and Gail models was 0.57 and 0.54, respectively, increasing to 0.67 when the PRS was included. Inclusion of the PRS gave a positive NRI for cases in both models [0.080 (95% confidence interval (CI), 0.053-0.104) and 0.051 (95% CI, 0.030-0.073), respectively], with negligible impact on controls. CONCLUSIONS: The addition of a PRS for breast cancer to the well-established Tyrer-Cuzick and Gail models provides a substantial improvement in the prediction accuracy and risk stratification. IMPACT: These findings could have important implications for the ongoing discussion about the value of PRS in risk prediction models and screening.

Incorporating polygenic risk into the Leicester Risk Assessment score for 10-year risk prediction of type 2 diabetes.

AIMS: We evaluated whether incorporating information on ethnic background and polygenic risk enhanced the Leicester Risk Assessment (LRA) score for predicting 10-year risk of type 2 diabetes. METHODS: The sample included 202,529 UK Biobank participants aged 40-69 years. We computed the LRA score, and developed two new risk scores using training data (80% sample): LRArev, which incorporated additional information on ethnic background, and LRAprs, which incorporated polygenic risk for type 2 diabetes. We assessed discriminative and reclassification performance in a test set (20% sample). Type 2 diabetes was ascertained using primary care, hospital inpatient and death registry records. RESULTS: Over 10 years, 7,476 participants developed type 2 diabetes. The Harrell's C indexes were 0.796 (95% Confidence Interval [CI] 0.785, 0.806), 0.802 (95% CI 0.792, 0.813), and 0.829 (95% CI 0.820, 0.839) for the LRA, LRArev and LRAprs scores, respectively. The LRAprs score significantly improved the overall reclassification compared to the LRA (net reclassification index [NRI] = 0.033, 95% CI 0.015, 0.049) and LRArev (NRI = 0.040, 95% CI 0.024, 0.055) scores. CONCLUSIONS: Polygenic risk moderately improved the performance of the existing LRA score for 10-year risk prediction of type 2 diabetes.

A common NFKB1 variant detected through antibody analysis in UK Biobank predicts risk of infection and allergy.

Infectious agents contribute significantly to the global burden of diseases through both acute infection and their chronic sequelae. We leveraged the UK Biobank to identify genetic loci that influence humoral immune response to multiple infections. From 45 genome-wide association studies in 9,611 participants from UK Biobank, we identified NFKB1 as a locus associated with quantitative antibody responses to multiple pathogens, including those from the herpes, retro-, and polyoma-virus families. An insertion-deletion variant thought to affect NFKB1 expression (rs28362491), was mapped as the likely causal variant and could play a key role in regulation of the immune response. Using 121 infection- and inflammation-related traits in 487,297 UK Biobank participants, we show that the deletion allele was associated with an increased risk of infection from diverse pathogens but had a protective effect against allergic disease. We propose that altered expression of NFKB1, as a result of the deletion, modulates hematopoietic pathways and likely impacts cell survival, antibody production, and inflammation. Taken together, we show that disruptions to the tightly regulated immune processes may tip the balance between exacerbated immune responses and allergy, or increased risk of infection and impaired resolution of inflammation.

Assessing the importance of primary care diagnoses in the UK Biobank.

The UK Biobank has made general practitioner (GP) data (censoring date 2016-2017) available for approximately 45% of the cohort, whilst hospital inpatient and death registry (referred to as "HES/Death") data are available cohort-wide through 2018-2022 depending on whether the data comes from England, Wales or Scotland. We assessed the importance of case ascertainment via different data sources in UKB for three diseases that are usually first diagnosed in primary care: Parkinson's disease (PD), type 2 diabetes (T2D), and all-cause dementia. Including GP data at least doubled the number of incident cases in the subset of the cohort with primary care data (e.g. from 619 to 1390 for dementia). Among the 786 dementia cases that were only captured in the GP data before the GP censoring date, only 421 (54%) were subsequently recorded in HES. Therefore, estimates of the absolute incidence or risk-stratified incidence are misleadingly low when based only on the HES/Death data. For incident cases present in both HES/Death and GP data during the full follow-up period (i.e. until the HES censoring date), the median time difference between an incident diagnosis of dementia being recorded in GP and HES/Death was 2.25 years (i.e. recorded 2.25 years earlier in the GP records). Similar lag periods were also observed for PD (median 2.31 years earlier) and T2D (median 2.82 years earlier). For participants with an incident GP diagnosis, only 65.6% of dementia cases, 69.0% of PD cases, and 58.5% of T2D cases had their diagnosis recorded in HES/Death within 7 years since GP diagnosis. The effect estimates (hazard ratios, HR) of established risk factors for the three health outcomes mostly remain in the same direction and with a similar strength of association when cases are ascertained either using HES only or further adding GP data. The confidence intervals of the HR became narrower when adding GP data, due to the increased statistical power from the additional cases. In conclusion, it is desirable to extend both the coverage and follow-up period of GP data to allow researchers to maximise case ascertainment of chronic health conditions in the UK.

Associations of inner retinal layers with risk of incident dementia: An individual participant data analysis of four prospective cohort studies.

INTRODUCTION: Our main objective was to investigate whether retinal neurodegeneration, estimated from lower thickness of inner retinal layers, was associated with incident all-cause dementia and Alzheimer's disease (AD). METHODS: We performed an individual participant data meta-analysis using unpublished data from four prospective cohort studies with a total of 69,955 participants (n = 1087 cases of incident all-cause dementia; n = 520 cases incident AD; follow-up time median [interquartile range] 11.3 [8.8-11.5] years). RESULTS: General baseline characteristics of the study population were mean (standard deviation) age, 58.1 (8.8) years; 47% women. After adjustment, lower baseline macular retinal nerve fiber layer thickness was significantly associated with a 10% and 11% higher incidence of all-cause dementia and AD, respectively. Lower baseline macular ganglion cell-inner plexiform layer thickness was not significantly associated with these outcomes. DISCUSSION: These findings suggest that retinal neurodegeneration precedes the onset of clinical dementia. Retinal imaging tools may be informative biomarkers for the study of the early pathophysiology of dementia.

Association between metabolic syndrome and risk of incident dementia in UK Biobank.

INTRODUCTION: The association between metabolic syndrome (MetS) and incident dementia remains inconclusive. METHODS: In 176,249 dementia-free UK Biobank participants aged ≥60 years at baseline, Cox proportional-hazards models were used to investigate the association between MetS and incident dementia. MetS was defined as the presence of ≥3 of the following: elevated waist circumference, triglycerides, blood pressure, blood glucose, and reduced high-density lipoprotein cholesterol. RESULTS: Over 15 years of follow-up (median = 12.3), 5255 participants developed dementia. MetS was associated with an increased risk of incident dementia (hazard ratio [HR]: 1.12, 95% confidence interval [CI]: 1.06, 1.18). The association remained consistent when restricting to longer follow-up intervals: >5 to 10 years (HR: 1.17, 95% CI: 1.07, 1.27) and >10 years (HR: 1.22, 95% CI: 1.12, 1.32). Stronger associations were observed in those with ≥4 MetS components and in apolipoprotein-E (APOE)-ε4 non-carriers. DISCUSSION: In this large population-based prospective cohort, MetS was associated with an increased risk of dementia. HIGHLIGHTS: MetS was associated with a 12% increased risk of incident all-cause dementia. Associations remained similar after restricting the analysis to those with longer follow-up. The presence of four or five MetS components was significantly associated with dementia. Stronger associations were observed in those with a low genetic risk for dementia.

Frailty and Other Factors Associated With Early Outcomes in Middle-to Older Age Trauma Patients: A Prospective Cohort Study.

OBJECTIVES: To prospectively investigate associations of frailty and other predictor variables with functional recovery and health outcomes in middle-aged and older patients with trauma. DESIGN: Single-center prospective cohort study. SETTING: Emergency department of Wan Fang Hospital in Taiwan. PARTICIPANTS: Trauma patients aged 45 and older. MEASUREMENTS: Frailty was assessed with the Clinical Frailty Scale (CFS). Injury mechanisms, pre-existing diseases, and fracture locations were recorded at baseline. The primary outcome was functional recovery assessed using the Barthel Index (BI). Secondary outcomes were new care needs, unscheduled return visits, and falls 3 months postinjury. RESULTS: A total of 588 participants were included in the final analysis. For every one-point increase in the CFS, the multivariable-adjusted odds ratio (OR, 95% confidence interval [CI]) of failure to retain the preinjury BI was 1.34 (1.16-1.55); associations were consistent across levels of age and injury severities. Significant joint associations of frailty and age with poor functional recovery were observed. CFS was also associated with new care needs (OR for every one-point increase, 1.36, 95% CI, 1.17-1.58), unscheduled return visits (OR 1.26, 95% CI, 1.04-1.51), and falls (OR 1.23, 95% CI, 1.01-1.51). Other variables associated with failure to retain preinjury BI included road traffic accident and presence of hip fracture. CONCLUSION: Frailty was significantly associated with poor functional and health outcomes regardless of injury severity in middle-aged and older patients with trauma. Injury mechanisms and fracture locations were also significant predictors of functional recovery postinjury.

The predictive validity of a Brain Care Score for dementia and stroke: data from the UK Biobank cohort.

Introduction: The 21-point Brain Care Score (BCS) was developed through a modified Delphi process in partnership with practitioners and patients to promote behavior changes and lifestyle choices in order to sustainably reduce the risk of dementia and stroke. We aimed to assess the associations of the BCS with risk of incident dementia and stroke. Methods: The BCS was derived from the United Kingdom Biobank (UKB) baseline evaluation for participants aged 40-69 years, recruited between 2006-2010. Associations of BCS and risk of subsequent incident dementia and stroke were estimated using Cox proportional hazard regressions, adjusted for sex assigned at birth and stratified by age groups at baseline. Results: The BCS (median: 12; IQR:11-14) was derived for 398,990 UKB participants (mean age: 57; females: 54%). There were 5,354 incident cases of dementia and 7,259 incident cases of stroke recorded during a median follow-up of 12.5 years. A five-point higher BCS at baseline was associated with a 59% (95%CI: 40-72%) lower risk of dementia among participants aged <50. Among those aged 50-59, the figure was 32% (95%CI: 20-42%) and 8% (95%CI: 2-14%) for those aged >59 years. A five-point higher BCS was associated with a 48% (95%CI: 39-56%) lower risk of stroke among participants aged <50, 52% (95%CI, 47-56%) among those aged 50-59, and 33% (95%CI, 29-37%) among those aged >59. Discussion: The BCS has clinically relevant and statistically significant associations with risk of dementia and stroke in approximately 0.4 million UK people. Future research includes investigating the feasibility, adaptability and implementation of the BCS for patients and providers worldwide.

Central Adiposity Increases Risk of Kidney Stone Disease through Effects on Serum Calcium Concentrations.

SIGNIFICANCE STATEMENT: Kidney stone disease is a common disorder with poorly understood pathophysiology. Observational and genetic studies indicate that adiposity is associated with an increased risk of kidney stone disease. However, the relative contribution of general and central adipose depots and the mechanisms by which effects of adiposity on kidney stone disease are mediated have not been defined. Using conventional and genetic epidemiological techniques, we demonstrate that general and central adiposity are independently associated with kidney stone disease. In addition, one mechanism by which central adiposity increases risk of kidney stone disease is by increasing serum calcium concentration. Therapies targeting adipose depots may affect calcium homeostasis and help to prevent kidney stone disease. BACKGROUND: Kidney stone disease affects approximately 10% of individuals in their lifetime and is frequently recurrent. The disease is linked to obesity, but the mechanisms mediating this association are uncertain. METHODS: Associations of adiposity and incident kidney stone disease were assessed in the UK Biobank over a mean of 11.6 years/person. Genome-wide association studies and Mendelian randomization (MR) analyses were undertaken in the UK Biobank, FinnGen, and in meta-analyzed cohorts to identify factors that affect kidney stone disease risk. RESULTS: Observational analyses on UK Biobank data demonstrated that increasing central and general adiposity is independently associated with incident kidney stone formation. Multivariable MR, using meta-analyzed UK Biobank and FinnGen data, established that risk of kidney stone disease increases by approximately 21% per one standard deviation increase in body mass index (BMI, a marker of general adiposity) independent of waist-to-hip ratio (WHR, a marker of central adiposity) and approximately 24% per one standard deviation increase of WHR independent of BMI. Genetic analyses indicate that higher WHR, but not higher BMI, increases risk of kidney stone disease by elevating adjusted serum calcium concentrations (ß=0.12 mmol/L); WHR mediates 12%-15% of its effect on kidney stone risk in this way. CONCLUSIONS: Our study indicates that visceral adipose depots elevate serum calcium concentrations, resulting in increased risk of kidney stone disease. These findings highlight the importance of weight loss in individuals with recurrent kidney stones and suggest that therapies targeting adipose depots may affect calcium homeostasis and contribute to prevention of kidney stone disease.

Kidney function, albuminuria, and their modification by genetic factors and risk of incident dementia in UK Biobank.

BACKGROUND: Associations between kidney function and dementia risk are inconclusive. Chronic kidney disease (CKD) severity is determined by levels of both estimated glomerular filtration rate (eGFR) and the urine albumin to creatinine ratio (ACR). However, whether there is a graded increase in dementia risk for worse eGFR in each ACR category is unclear. Also, whether genetic risk for dementia impacts the associations is unknown. The current study aims to investigate the associations between eGFR and albuminuria with dementia risk both individually and jointly, whether the associations vary by different follow-up periods, and whether genetic factors modified the associations. METHODS: In 202,702 participants aged ≥ 60 years from the UK Biobank, Cox proportional-hazards models were used to examine the associations between eGFR and urine albumin creatinine ratio (ACR) with risk of incident dementia. GFR was estimated based on serum creatinine, cystatin C, or both. The models were restricted to different follow-up periods (< 5 years, 5-10 years, and ≥ 10 years) to investigate potential reverse causation. RESULTS: Over 15 years of follow-up, 6,042 participants developed dementia. Decreased kidney function (eGFR < 60 ml/min/1.73m2) was associated with an increased risk of dementia (Hazard Ratio [HR] = 1.42, 95% Confidence Interval [CI] 1.28-1.58), compared to normal kidney function (≥ 90 ml/min/1.73m2). The strength of the association remained consistent when the models were restricted to different periods of follow-up. The HRs for incident dementia were 1.16 (95% CI 1.07-1.26) and 2.24 (95% CI 1.79-2.80) for moderate (3-30 mg/mmol) and severely increased ACR (≥ 30 mg/mmol) compared to normal ACR (< 3 mg/mmol). Dose-response associations were observed when combining eGFR and ACR, with those in the severest eGFR and ACR group having the greatest risk of dementia (HR = 4.70, 95% CI 2.34-9.43). APOE status significantly modified the association (p = 0.04), with stronger associations observed among participants with a lower genetic risk of dementia. There was no evidence of an interaction between kidney function and non-APOE polygenic risk of dementia with dementia risk (p = 0.42). CONCLUSIONS: Kidney dysfunction and albuminuria were individually and jointly associated with higher dementia risk. The associations were greater amongst participants with a lower genetic risk of dementia based on APOE, but not non-APOE polygenic risk.

Association Between Retinal Nerve Fiber Layer Thickness and Incident Dementia in the European Prospective Investigation into Cancer in Norfolk Cohort.

BACKGROUND: Retinal nerve fiber layer (RNFL) thickness may reflect cerebral status. OBJECTIVE: This study assessed the relationship between RNFL thickness and incident all-cause dementia in the European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) Eye Study. METHODS: Glaucoma detection with variable corneal compensation (GDx-VCC) and Heidelberg Retinal Tomograph II (HRT II) derived global mean RNFL thickness from dementia-free participants at baseline within the EPIC-Norfolk Eye Study were analyzed. Incident dementia was identified through linkage to electronic medical records. Cox proportional hazard mixed-effects regression models adjusted for key confounders were used to examine the associations between RNFL thickness and incident dementia in four separate models. RESULTS: 6,239 participants were included with 322 cases of incident dementia and mean age of 67.5-years old, with 49.7% women (median follow-up 13.2-years, interquartile range (11.7 to 14.6 years). Greater RNFL thickness (GDx-VCC) was not significantly associated with a lower risk of incident dementia in the full adjusted model [HR per quartile increase 0.95; 95% CI 0.82-1.10]. Similarly, RNFL thickness assessed with HRT II was also not associated with incident dementia in any model (full adjusted model; HR per quartile increase: 1.06; [95% CI 0.93-1.19]. Gender did not modify any associations under study. CONCLUSION: GDx-VCC and HRT II derived RNFL thickness are unlikely to be useful predictors of incident dementia. Higher resolution optical imaging technologies may clarify whether there are useful relationships between neuro-retinal morphology and brain measures.

Combining machine learning with Cox models to identify predictors for incident post-menopausal breast cancer in the UK Biobank.

We aimed to identify potential novel predictors for breast cancer among post-menopausal women, with pre-specified interest in the role of polygenic risk scores (PRS) for risk prediction. We utilised an analysis pipeline where machine learning was used for feature selection, prior to risk prediction by classical statistical models. An "extreme gradient boosting" (XGBoost) machine with Shapley feature-importance measures were used for feature selection among [Formula: see text] 1.7 k features in 104,313 post-menopausal women from the UK Biobank. We constructed and compared the "augmented" Cox model (incorporating the two PRS, known and novel predictors) with a "baseline" Cox model (incorporating the two PRS and known predictors) for risk prediction. Both of the two PRS were significant in the augmented Cox model ([Formula: see text]). XGBoost identified 10 novel features, among which five showed significant associations with post-menopausal breast cancer: plasma urea (HR = 0.95, 95% CI 0.92-0.98, [Formula: see text]), plasma phosphate (HR = 0.68, 95% CI 0.53-0.88, [Formula: see text]), basal metabolic rate (HR = 1.17, 95% CI 1.11-1.24, [Formula: see text]), red blood cell count (HR = 1.21, 95% CI 1.08-1.35, [Formula: see text]), and creatinine in urine (HR = 1.05, 95% CI 1.01-1.09, [Formula: see text]). Risk discrimination was maintained in the augmented Cox model, yielding C-index 0.673 vs 0.667 (baseline Cox model) with the training data and 0.665 vs 0.664 with the test data. We identified blood/urine biomarkers as potential novel predictors for post-menopausal breast cancer. Our findings provide new insights to breast cancer risk. Future research should validate novel predictors, investigate using multiple PRS and more precise anthropometry measures for better breast cancer risk prediction.

Association between coeliac disease and cardiovascular disease: prospective analysis of UK Biobank data.

Objectives: To investigate whether people with coeliac disease are at increased risk of cardiovascular disease, including ischaemic heart disease, myocardial infarction, and stroke. Design: Prospective analysis of a large cohort study. Setting: UK Biobank database. Participants: 469 095 adults, of which 2083 had coeliac disease, aged 40-69 years from England, Scotland, and Wales between 2006 and 2010 without cardiovascular disease at baseline. Main outcome measure: A composite primary outcome was relative risk of cardiovascular disease, ischaemic heart disease, myocardial infarction, and stroke in people with coeliac disease compared with people who do not have coeliac disease, assessed using Cox proportional hazard models. Results: 40 687 incident cardiovascular disease events occurred over a median follow-up of 12.4 years (interquartile range 11.5-13.1), with 218 events among people with coeliac disease. Participants with coeliac disease were more likely to have a lower body mass index and systolic blood pressure, less likely to smoke, and more likely to have an ideal cardiovascular risk score than people who do not have coeliac disease. Despite this, participants with coeliac disease had an incidence rate of 9.0 cardiovascular disease cases per 1000 person years (95% confidence interval 7.9 to 10.3) compared with 7.4 per 1000 person years (7.3 to 7.4) in people with no coeliac disease. Coeliac disease was associated with an increased risk of cardiovascular disease (hazard ratio 1.27 (95% confidence interval 1.11 to 1.45)), which was not influenced by adjusting for lifestyle factors (1.27 (1.11 to 1.45)), but was strengthened by further adjusting for other cardiovascular risk factors (1.44 (1.26 to 1.65)). Similar associations were identified for ischaemic heart disease and myocardial infarction but fewer stroke events were reported and no evidence of an association between coeliac disease and risk of stroke. Conclusions: Individuals with coeliac disease had a lower prevalence of traditional cardiovascular risk factors but had a higher risk of developing cardiovascular disease than did people with no coeliac disease. Cardiovascular risk scores used in clinical practice might therefore not adequately capture the excess risk of cardiovascular disease in people with coeliac disease, and clinicians should be aware of the need to optimise cardiovascular health in this population.

Polygenic Risk of Prediabetes, Undiagnosed Diabetes, and Incident Type 2 Diabetes Stratified by Diabetes Risk Factors.

Context: Early diagnosis of type 2 diabetes is crucial to reduce severe comorbidities and complications. Current screening recommendations for type 2 diabetes include traditional risk factors, primarily body mass index (BMI) and family history, however genetics also plays a key role in type 2 diabetes risk. It is important to understand whether genetic predisposition to type 2 diabetes modifies the effect of these traditional factors on type 2 diabetes risk. Objective: This work aimed to investigate whether genetic risk of type 2 diabetes modifies associations between BMI and first-degree family history of diabetes with 1) prevalent prediabetes or undiagnosed diabetes; and 2) incident confirmed type 2 diabetes. Methods: We included 431 658 individuals aged 40 to 69 years at baseline of multiethnic ancestry from the UK Biobank. We used a multiethnic polygenic risk score for type 2 diabetes (PRST2D) developed by Genomics PLC. Prediabetes or undiagnosed diabetes was defined as baseline glycated hemoglobin greater than or equal to 42 mmol/mol (6.0%), and incident type 2 diabetes was derived from medical records. Results: At baseline, 43 472 participants had prediabetes or undiagnosed diabetes, and 17 259 developed type 2 diabetes over 15 years follow-up. Dose-response associations were observed for PRST2D with each outcome in each category of BMI or first-degree family history of diabetes. Those in the highest quintile of PRST2D with a normal BMI were at a similar risk as those in the middle quintile who were overweight. Participants who were in the highest quintile of PRST2D and did not have a first-degree family history of diabetes were at a similar risk as those with a family history who were in the middle category of PRST2D. Conclusion: Genetic risk of type 2 diabetes remains strongly associated with risk of prediabetes, undiagnosed diabetes, and future type 2 diabetes within categories of nongenetic risk factors. This could have important implications for identifying individuals at risk of type 2 diabetes for prevention and early diagnosis programs.

Hypertension, a dementia polygenic risk score, APOE genotype, and incident dementia.

INTRODUCTION: There is inconsistent evidence on whether genetic risk for dementia modifies the association between hypertension and dementia. METHODS: In 198,965 dementia-free participants aged ≥60 years, Cox proportional-hazards models were used to investigate the association between hypertension and incident dementia. A polygenic risk score (PRS) based on 38 non-apolipoprotein E (APOE) single nucleotide polymorphisms and APOE ε4 status were used to determine genetic risk for dementia. RESULTS: Over 15 years follow-up, 6270 participants developed dementia. Hypertension was associated with a 19% increased risk of dementia (hazard ratio = 1.19, 95% confidence interval 1.11-1.27). The associations remained similar when stratifying by genetic risk, with no evidence for multiplicative interaction by dementia PRS (P = 0.20) or APOE ε4 status (P = 0.16). However, the risk difference between those with and without hypertension was larger among those at higher genetic risk. DISCUSSION: Hypertension was associated with an increased risk of dementia regardless of genetic risk for dementia.

Association of Multimorbidity, Disease Clusters, and Modification by Genetic Factors With Risk of Dementia.

Importance: Individual conditions have been identified as risk factors for dementia; however, it is important to consider the role of multimorbidity, as conditions often co-occur. Objective: To investigate whether multimorbidity is associated with incident dementia and whether associations vary by different clusters of disease and genetic risk for dementia. Design, Setting, and Participants: This population-based prospective cohort study used data from the UK Biobank cohort, with baseline data collected between 2006 and 2010 and with up to 15 years of follow-up. Participants included women and men without dementia and aged at least 60 years at baseline. Medical conditions were captured as part of nurse-led verbal interviews conducted at baseline assessment centers. Data were analyzed from October 2020 to July 2022. Exposures: The presence of at least 2 long-term conditions from a preselected list of 42 conditions was used to define multimorbidity. High genetic risk for dementia was based on presence of 1 or 2 apolipoprotein (APOE) ε4 alleles. Main Outcomes and Measures: The main outcome, incident dementia, was derived from hospital inpatient and death registry records. Associations of multimorbidity with dementia were assessed with Cox proportional hazards models. Results: A total of 206 960 participants (mean [SD] age, 64.1 [2.9] years, 108 982 [52.7%] women) were included in the final sample, of whom 89 201 participants (43.1%) had multimorbidity. Over a mean (SD) of 11.8 (2.2) years of follow-up, 6182 participants (3.0%) developed dementia. The incidence rate was 1.87 (95% CI, 1.80-1.94) per 1000 person-years for those without multimorbidity and 3.41 (95% CI, 3.30-3.53) per 1000 person-years for those with multimorbidity. In Cox proportional hazards models adjusted for age, sex, ethnicity, education, socioeconomic status, and APOE-ε4 carrier status, multimorbidity was associated with an increased risk of incident dementia (hazard ratio [HR], 1.63 [95% CI, 1.55-1.71]). The highest dementia risk was observed for the hypertension, diabetes, and coronary heart disease cluster (HR, 2.20 [95% CI, 1.98-2.46]) and pain, osteoporosis, and dyspepsia cluster (HR, 2.00 [95% CI, 1.68-2.37]) in women and in the diabetes and hypertension cluster (HR, 2.24 [95% CI, 1.97-2.55]) and coronary heart disease, hypertension, and stroke cluster (HR, 1.94 [95% CI, 1.71-2.20]) in men, compared with no multimorbidity. The associations between multimorbidity and dementia were greater in those with a lower genetic risk of dementia (HR, 1.96 [95% CI, 1.81-2.11]) than in those with a higher genetic risk of dementia (HR, 1.39 [95% CI, 1.30-1.49]). Similar findings were observed when stratifying diseases clusters by genetic risk for dementia. Conclusions and Relevance: These findings suggest that multimorbidity was associated with an increased risk of dementia. The associations varied by clusters of disease and genetic risk for dementia. These findings could help with the identification of individuals at high risk of dementia as well as the development of targeted interventions to reduce or delay dementia incidence.