Polygenic Hazard Score for Predicting Age-associated Risk of Alzheimer's Disease in European Populations: Development and Validation.

Objectives: Polygenic hazard score (PHS) models can be used to predict the age-associated risk for complex diseases, including Alzheimer's disease (AD). In this study, we present an improved PHS model for AD that incorporates a large number of genetic variants and demonstrates enhanced predictive accuracy for age of onset in European populations compared to alternative models.

Methods: We used the genotyped European Alzheimer & Dementia Biobank (EADB) sample (n=42,120) to develop and evaluate the performance of the PHS model.

Vitamin D and lipopolysaccharide jointly induce a distinct epigenetic and transcriptional program in human monocytes.

Pathogen-associated molecular patterns such as lipopolysaccharide (LPS) mimic immune responses triggered by bacterial infections. The hormonally active form of vitamin D, 1α,25-dihydroxyvitamin D [1,25(OH)D], supports innate immunity, but its molecular mechanisms remain incompletely understood. We investigated epigenomic and transcriptomic changes in THP-1 monocytes that were either unprimed or primed for 24 h with 1,25(OH)D or LPS, followed by a second 24-hour stimulation with 1,25(OH)D, LPS, or their combination.

Machine learning in Alzheimer's disease genetics.

Traditional statistical approaches have advanced our understanding of the genetics of complex diseases, yet are limited to linear additive models. Here we applied machine learning (ML) to genome-wide data from 41,686 individuals in the largest European consortium on Alzheimer's disease (AD) to investigate the effectiveness of various ML algorithms in replicating known findings, discovering novel loci, and predicting individuals at risk. We utilised Gradient Boosting Machines (GBMs), biological pathway-informed Neural Networks (NNs), and Model-based Multifactor Dimensionality Reduction (MB-MDR) models.

Multi-ancestry genome-wide association analyses incorporating SNP-by-psychosocial interactions identify novel loci for serum lipids.

Serum lipid levels, which are influenced by both genetic and environmental factors, are key determinants of cardiometabolic health and are influenced by both genetic and environmental factors. Improving our understanding of their underlying biological mechanisms can have important public health and therapeutic implications. Although psychosocial factors, including depression, anxiety, and perceived social support, are associated with serum lipid levels, it is unknown if they modify the effect of genetic loci that influence lipids.

Transferability of European-derived Alzheimer's disease polygenic risk scores across multiancestry populations.

A polygenic score (PGS) for Alzheimer's disease (AD) was derived recently from data on genome-wide significant loci in European ancestry populations. We applied this PGS to populations in 17 European countries and observed a consistent association with the AD risk, age at onset and cerebrospinal fluid levels of AD biomarkers, independently of apolipoprotein E locus (APOE). This PGS was also associated with the AD risk in many other populations of diverse ancestries.

GWAS meta-analysis of CSF Alzheimer's disease biomarkers 18,948 individuals reveal novel loci and genes regulating lipid metabolism, brain volume and autophagy.

Cerebrospinal fluid (CSF) amyloid beta (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau181) are well accepted markers of Alzheimer's disease. We performed a GWAS meta-analysis including 18,948 individuals of European and 416 non-European ancestry. We identified 12 genome-wide significant loci across all three biomarkers, eight of them novel.

Prevalence of Epilepsy in Frontotemporal Dementia and Timing of Dementia Diagnosis.

Importance: Previous studies have described a potential association between epilepsy and frontotemporal dementia (FTD), but no systematic data are available.

Objective: To determine whether epilepsy is more prevalent in patients with FTD than in healthy controls (HCs) or patients with Alzheimer disease (AD).

Design, Setting, And Participants: In this case-control study, we compared the prevalence of epilepsy and purchases of antiseizure medicines (ASMs) among patients with FTD, matched HCs, and patients with AD from 2 early-onset dementia diagnostics centers in the same geographic regions of Finland.

stratified genome-wide association studies provide novel insights into the genetic etiology of Alzheimers's disease.

Among the more than 90 identified genetic risk loci for late-onset Alzheimer's disease (AD) and related dementias, the apolipoprotein E gene () ε2/ε3/ε4 polymorphism remains the longstanding benchmark for genetic disease risk with a consistently large effect across studies. Despite this massive signal, the exact mechanisms for how ε4 increases and for how ε2 decreases dementia risk is not well-understood. Importantly, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in s4 carriers, hampering the treatment of those with the highest unmet need.

Monoallelic TYROBP deletion is a novel risk factor for Alzheimer's disease.

Biallelic loss-of-function variants in TYROBP and TREM2 cause autosomal recessive presenile dementia with bone cysts known as Nasu-Hakola disease (NHD, alternatively polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL). Some other TREM2 variants contribute to the risk of Alzheimer's disease (AD) and frontotemporal dementia, while deleterious TYROBP variants are globally extremely rare and their role in neurodegenerative diseases remains unclear. The population history of Finns has favored the enrichment of deleterious founder mutations, including a 5.

High expression of miR-7974 predicts poor prognosis and is associated with autophagy in estrogen receptor-positive breast cancer.

Estrogen receptor-positive (ER+) breast cancers (BC) cause death despite well-established treatments. MicroRNAs (miRNAs) have potential as biomarkers specific to cancer subtypes and tissues, therefore miRNA-based biomarkers could help improve patient survival. In this study, we investigated a relatively unknown miRNA, miR-7974.

The Spatial Transcriptional Activity of Hepatic TCF7L2 Regulates Zonated Metabolic Pathways that Contribute to Liver Fibrosis.

The molecular mechanisms regulating the zonal distribution of metabolism in liver are incompletely understood. Here we use single nuclei genomics techniques to examine the spatial transcriptional function of transcription factor 7-like 2 (TCF7L2) in mouse liver, and determine the consequences of TCF7L2 transcriptional inactivation on the metabolic architecture of the liver and the function of zonated metabolic pathways. We report that while Tcf7l2 mRNA expression is ubiquitous across the liver lobule, accessibility of the consensus TCF/LEF DNA binding motif is restricted to pericentral (PC) hepatocytes in zone 3.

Criminal Behavior in Early Onset Neurodegenerative Diseases.

Introduction: Literature on criminal behavior preceding a neurodegenerative disease diagnosis is insufficient. Some studies suggest increased crime rates among patients with frontotemporal dementia (FTD).

Methods: Patients with neurodegenerative diseases were gathered from Kuopio and Oulu University Hospitals and compared with nonselective general population data from Statistics Finland (N = 24,144).

A large-scale genome-wide study of gene-sleep duration interactions for blood pressure in 811,405 individuals from diverse populations.

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discovered 22 novel gene-sleep duration interaction loci for blood pressure, mapped to 23 genes.

The protective PLCγ2-P522R variant mitigates Alzheimer's disease-associated pathologies by enhancing beneficial microglial functions.

Background: Phospholipase C gamma 2, proline 522 to arginine (PLCγ2-P522R) is a protective variant that reduces the risk of Alzheimer's disease (AD). Recently, it was shown to mitigate β-amyloid pathology in a 5XFAD mouse model of AD. Here, we investigated the protective functions of the PLCγ2-P522R variant in a less aggressive APP/PS1 mouse model of AD and assessed the underlying cellular mechanisms using mouse and human microglial models.

Overlap in the diagnostic criteria of frontotemporal dementia syndromes with parkinsonism.

BackgroundDifferentiating neurodegenerative diseases can be difficult in the clinical setting. This study examines the overlap of diagnostic criteria between frontotemporal dementia (FTD) syndromes with parkinsonism [e.g.

Low prevalence of CWH43 variants among Finnish and Norwegian idiopathic normal pressure hydrocephalus patients: a cohort-based observational study.

Background: Heterozygous CWH43 loss-of-function (LOF) variants have been identified as iNPH risk factors, with 10-15% of iNPH patients carrying these variants in cohorts from the US. Mouse model harboring CWH43 LOF variants display a hydrocephalic phenotype with ventricular cilia alterations. Our aim was to study the effect of CWH43 variants on disease risk and clinical phenotype in Finnish and Norwegian iNPH cohorts.

Pseudo-3D HSQC, a method to create a true 2D HSQC-plane. Application to softwood extract analysis.

Pseudo-3D HSQC provides an alternative and easy way to record and analyze quantitative HSQC-data. In the original time-zero extrapolated H-C HSQC (HSQC), three separate 2D constant-time (CT) HSQC-experiments (HSQC, i = 1-3) are acquired, where either 1,2 or 3 consecutive CT-HSQC-propagators are repeated in each pulse sequence, and the 2D integral data from the three 2D experiments is analyzed via linear regression. In the presented pseudo-3D HSQC, HSQC is one of the dimensions and all data is contained within one dataset, which is recorded in interleaved manner by acquiring the same t-value for each HSQC-point before t-incrementation.

Convection compensation in 3D iDOSY-HMBC H-C-correlation experiments.

3D iDOSY-HMBC (3D incorporated Diffusion Ordered SpectroscopY-Heteronuclear Multiple Bond Correlation) pulse sequences were modified to incorporate convection compensation element. No additional delays were required, and convection compensation was directly constructed within the existing delay periods in 3D iDOSY-HMBC pulse sequence. Convection compensation was achieved by pulsed field gradient double echo, thus avoiding the intensity loss normally related to stimulated echo methods.

Risk Variants Associated With Normal Pressure Hydrocephalus: Genome-Wide Association Study in the FinnGen Cohort.

Background And Objectives: Large-scale genome-wide studies of chronic hydrocephalus have been lacking. We conducted a genome-wide association study (GWAS) in normal pressure hydrocephalus (NPH).

Methods: We used a case-control study design implementing FinnGen data containing 473,691 Finns with genotypes and nationwide health records.

A Large-Scale Genome-Wide Study of Gene-Sleep Duration Interactions for Blood Pressure in 811,405 Individuals from Diverse Populations.

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discover 22 novel gene-sleep duration interaction loci for blood pressure, mapped to 23 genes.

On the mechanism of sp C-H borylation using -substituted pyridinium cations.

-Substituted pyridinium cations with the weakly coordinating anion [B(CF)] have been studied and crucial structural features in the sp C-H borylation catalysis of 3-methylthiophene have been identified. The electron-deficiency of the aromatic core of the cation is essential for activity together with accessible protons. The spectroscopic yield of the borylation of 3-methylthiophene with catecholborane (CatBH) was optimized up to 86% and the method was further applied to other substrates such as -alkylbenzenes.