Genetic predisposition to high circulating levels of interleukin 6 and risk for Alzheimer's disease. Discovery and replication.

Importance: Aging is accompanied by immune dysregulation, which has been implicated in Alzheimer's disease (AD) pathogenesis. Individuals who are genetically predisposed to elevated levels of proinflammatory mediators might be at increased risk for AD.

Objective: To investigate whether genetic propensity for higher circulating levels of interleukin 6 (IL-6) is associated with AD risk.

The genomic architecture of circulating cytokine levels points to drug targets for immune-related diseases.

Circulating cytokines orchestrate immune reactions and are promising drug targets for immune-mediated and inflammatory diseases. Exploring the genetic architecture of circulating cytokine levels could yield key insights into causal mediators of human disease. Here, we performed genome-wide association studies (GWAS) for 40 circulating cytokines in meta-analyses of 74,783 individuals.

Deep Learning-Based Detection of Carotid Plaques Informs Cardiovascular Risk Prediction and Reveals Genetic Drivers of Atherosclerosis.

Atherosclerotic cardiovascular disease, the leading cause of global mortality, is driven by lipid accumulation and plaque formation within arterial walls. Carotid plaques, detectable via ultrasound, are a well-established marker of subclinical atherosclerosis. In this study, we trained a deep learning model to detect plaques in 177,757 carotid ultrasound images from 19,499 UK Biobank (UKB) participants (aged 47-83 years) to assess the prevalence, risk factors, prognostic significance, and genetic architecture of carotid atherosclerosis in a large population-based cohort.

Risk factors and clinical significance of post-stroke incident ischemic lesions.

Introduction: While incident ischemic lesions (IILs) are not unusual on follow-up magnetic resonance imaging (MRI) following stroke, their risk factors and prognostic significance remain unknown.

Methods: In a prospective multicenter study of 503 acute stroke patients, we assessed IILs on registered MRI images at baseline and 6 months, analyzing risk factors and clinical outcomes across 36 months.

Results: At 6 months, 78 patients (15.

Genetically proxied IL-6 signaling and risk of Alzheimer's disease and lobar intracerebral hemorrhage: A drug target Mendelian randomization study.

Introduction: Evidence suggests that higher C-reactive protein (CRP) is associated with lower risk of Alzheimer's disease (AD) and lobar intracerebral hemorrhage (ICH). Whether interleukin (IL)-6 signaling, an active pharmacological target upstream of CRP, is associated with these amyloid-related pathologies remains unknown.

Methods: We used 26 CRP-lowering variants near the IL-6 receptor gene to perform Mendelian randomization analyses for AD (111,326 cases, 677,663 controls) and ICH (1545 cases, 1481 controls).

Genetically proxied HTRA1 protease activity and circulating levels independently predict risk of ischemic stroke and coronary artery disease.

Genetic variants in HTRA1 are associated with stroke risk. However, the mechanisms mediating this remain largely unknown, as does the full spectrum of phenotypes associated with genetic variation in HTRA1. Here we show that rare HTRA1 variants are linked to ischemic stroke in the UK Biobank and BioBank Japan.

The role of the gluteofemoral adipose tissue in cerebrovascular disease risk: evidence from a mendelian randomization and mediation analysis.

Objective: To explore causal associations between BMI-independent body fat distribution profiles and cerebrovascular disease risk, and to investigate potential mediators underlying these associations.

Methods: Leveraging data from genome wide association studies of BMI-independent gluteofemoral (GFAT), abdominal subcutaneous (ASAT), and visceral (VAT) adipose tissue volumes in UK Biobank, we selected variants associated with each trait, and performed univariable and multivariable mendelian randomization (MR) analyses on ischemic stroke and subtypes (large artery (LAS), cardioembolic (CES), small vessel (SVS)). We used coronary artery disease (CAD), carotid intima media thickness (cIMT), and an MRI-confirmed lacunar stroke as positive controls.

Translating Anti-Inflammatory Strategies for Atherosclerosis: Deep Phenotyping, Next-Generation Drug Targets, and Precision Medicine.

Atherosclerosis is the main pathology underlying cardiovascular disease (CVD), including myocardial infarction and ischemic stroke [...

Human genetics implicate thromboembolism in the pathogenesis of long COVID in individuals of European ancestry.

SARS-CoV-2 infection can result in long COVID, characterized by post-acute symptoms from multiple organs. Current hypotheses on mechanisms underlying long COVID include persistent inflammation and thromboembolism; however, compelling evidence from humans is limited and causal associations remain unclear. Here, we tested the association of thromboembolism-related genetic variants with long COVID in the Long COVID Host Genetics Initiative ( =3,018; =994,582).

High-Sensitivity Cardiac Troponin T and Cognitive Function Over 12 Months After Stroke-Results of the DEMDAS Study.

Background: Subclinical myocardial injury in form of hs-cTn (high-sensitivity cardiac troponin)  levels has been associated with cognitive impairment and imaging markers of cerebral small vessel disease (SVD) in population-based and cardiovascular cohorts. Whether hs-cTn is associated with domain-specific cognitive decline and SVD burden in patients with stroke remains unknown.

Methods And Results: We analyzed patients with acute stroke without premorbid dementia from the prospective multicenter DEMDAS (DZNE [German Center for Neurodegenerative Disease]-Mechanisms of Dementia after Stroke) study.

KCNA2 IgG autoimmunity in neuropsychiatric diseases.

Background: Autoantibodies against the potassium voltage-gated channel subfamily A member 2 (KCNA2) have been described in a few cases of neuropsychiatric disorders, but their diagnostic and pathophysiological role is currently unknown, imposing challenges to medical practice.

Design / Methods: We retrospectively collected comprehensive clinical and paraclinical data of 35 patients with KCNA2 IgG autoantibodies detected in cell-based and tissue-based assays. Patients' sera and cerebrospinal fluid (CSF) were used for characterization of the antigen, clinical-serological correlations, and determination of IgG subclasses.

Mendelian Randomization Applied to Neurology: Promises and Challenges.

The Mendelian randomization (MR) paradigm allows for causal inferences to be drawn using genetic data. In recent years, the expansion of well-powered publicly available genetic association data related to phenotypes such as brain tissue gene expression, brain imaging, and neurologic diseases offers exciting opportunities for the application of MR in the field of neurology. In this review, we discuss the basic principles of MR, its myriad applications to research in neurology, and potential pitfalls of injudicious applications.

Proteogenomic Data Integration Reveals CXCL10 as a Potentially Downstream Causal Mediator for IL-6 Signaling on Atherosclerosis.

Background: Genetic and experimental studies support a causal involvement of IL-6 (interleukin-6) signaling in atheroprogression. Although trials targeting IL-6 signaling are underway, any benefits must be balanced against an impaired host immune response. Dissecting the mechanisms that mediate the effects of IL-6 signaling on atherosclerosis could offer insights about novel drug targets with more specific effects.

Risk factors for cognitive impairment and dementia after stroke: a systematic review and meta-analysis.

Background: Cognitive impairment and dementia are highly prevalent among stroke survivors and represent a major burden for patients, carers, and health-care systems. We studied the risk factors for post-stroke cognitive impairment (PSCI) and dementia (PSD) beyond the well established risk factors of age and stroke severity.

Methods: In this systematic review and meta-analysis we conducted a systematic literature search from database inception until Sept 15, 2023.

Genetically proxied HTRA1 protease activity and circulating levels independently predict risk of ischemic stroke and coronary artery disease.

has emerged as a major risk gene for stroke and cerebral small vessel disease with both rare and common variants contributing to disease risk. However, the precise mechanisms mediating this risk remain largely unknown as does the full spectrum of phenotypes associated with genetic variation in in the general population. Using a family-history informed approach, we first show that rare variants in are linked to ischemic stroke in 425,338 European individuals from the UK Biobank with replication in 143,149 individuals from the Biobank Japan.

Genetic and Nongenetic Components of Stroke Family History: A Population Study of Adopted and Nonadopted Individuals.

Background Genetic and nongenetic factors account for the association of family history with disease risk. Comparing adopted and nonadopted individuals provides an opportunity to disentangle those factors. Methods and Results We examined associations between family history of stroke and heart disease with incident stroke and myocardial infarction (MI) in 495 640 UK Biobank participants (mean age, 56.

Deep Resequencing of the 1q22 Locus in Non-Lobar Intracerebral Hemorrhage.

Objective: Genome-wide association studies have identified 1q22 as a susceptibility locus for cerebral small vessel diseases, including non-lobar intracerebral hemorrhage (ICH) and lacunar stroke. In the present study, we performed targeted high-depth sequencing of 1q22 in ICH cases and controls to further characterize this locus and prioritize potential causal mechanisms, which remain unknown.

Methods: A total of 95,000 base pairs spanning 1q22, including SEMA4A, SLC25A44, and PMF1/PMF1-BGLAP were sequenced in 1,055 spontaneous ICH cases (534 lobar and 521 non-lobar) and 1,078 controls.

Interplay Between Chronic Kidney Disease, Hypertension, and Stroke: Insights From a Multivariable Mendelian Randomization Analysis.

Background And Objectives: Chronic kidney disease (CKD) increases the risk of stroke, but the extent through which this association is mediated by hypertension is unknown. We leveraged large-scale genetic data to explore causal relationships between CKD, hypertension, and cerebrovascular disease phenotypes.

Methods: We used data from genome-wide association studies of European ancestry to identify genetic proxies for kidney function (CKD diagnosis, estimated glomerular filtration rate [eGFR], and urinary albumin-to-creatinine ratio [UACR]), systolic blood pressure (SBP), and cerebrovascular disease (ischemic stroke and its subtypes and intracerebral hemorrhage).

Genetic variation supports a causal role for valproate in prevention of ischemic stroke.

Background: Valproate is a candidate for ischemic stroke prevention due to its anti-atherosclerotic effects in vivo. Although valproate use is associated with decreased ischemic stroke risk in observational studies, confounding by indication precludes causal conclusions.

Aims: We applied Mendelian randomization to determine whether genetic variants that influence seizure response among valproate users associate with ischemic stroke.

Genetic and non-genetic components of family history of stroke and heart disease: a population-based study among adopted and non-adopted individuals.

Background: It is increasingly clear that genetic and non-genetic factors account for the association of family history with disease risk in offspring. We sought to distinguish the genetic and non-genetic contributions of family history of stroke and heart disease on incident events by examining adopted and non-adopted individuals.

Methods: We examined associations between family history of stroke and heart disease with incident stroke and myocardial infarction (MI) in 495,640 participants of the UK Biobank (mean age 56.