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INTRODUCTION: Blood‐derived microRNAs (miRNAs) are potential candidates for detecting and preventing subclinical cognitive dysfunction. However, replication of previous findings and identification of novel miRNAs associated with cognitive domains, including their relation to brain structure and the pathways they regulate, are still lacking. METHODS: We examined blood‐derived miRNAs and miRNA co‐expression clusters in relation to cognitive domains, structural magnetic resonance imaging measures, target gene expression, and genetic variants in 2869 participants of a population‐based cohort. RESULTS: Five previously identified and 14 novel miRNAs were associated with cognitive domains. Eleven of these were also associated with cortical thickness and two with hippocampal volume. Multi‐omics analysis showed that certain identified miRNAs were genetically influenced and regulated genes in pathways like neurogenesis and synapse assembly. DISCUSSION: We identified miRNAs associated with cognitive domains, brain regions, and neuronal processes affected by aging and neurodegeneration, making them promising candidate blood‐based biomarkers or therapeutic targets of subclinical cognitive dysfunction. Highlights: We investigated the association of blood‐derived microRNAs with cognitive domains.Five previously identified and 14 novel microRNAs were associated with cognition.Eleven cognition‐related microRNAs were also associated with cortical thickness.Identified microRNAs were linked to genes associated with neuronal functions.Results provide putative biomarkers or therapeutic targets of cognitive aging. [ABSTRACT FROM AUTHOR]

Background: Neurofilament light chain (NfL) levels in circulation have been established as a sensitive biomarker of neuro‐axonal damage across a range of neurodegenerative disorders. Elucidation of the genetic architecture of blood NfL levels and its genetic correlation with neurological traits could therefore provide new insights into shared molecular mechanisms underlying neurodegenerative disorders. Method: To identify the genetic variations underlying blood NfL levels, we conducted an ancestry‐specific meta‐analyses of genome‐wide association studies (GWAS) based on 18,532 participants from 11 cohorts of European and 1142 participants (3 cohorts) of African‐American ancestry. In the post‐GWAS analyses, we performed expression quantitative trait loci (eQTL) analysis, LD‐regression, and genetic risk score (GRS) association analysis with neurological traits. Result: In the European ancestry GWAS meta‐analysis, we identified two genome‐wide significant (P< 5×10−8) loci at 16p12 (UMOD), and 17q24 (SLC39A11). In the African‐American ancestry GWAS meta‐analysis, we identified three novel loci at 1q43 (FMN2), 12q14, and 12q21. Genetic correlation based on the European ancestry meta‐analysis with neurological traits showed a strong genetic correlation of NfL with Alzheimer's disease (AD) (rg = 0.32, P = 1.74×10−6), total‐tau (rg = 2.01, P = 1.03×10−6), amyloid‐beta (Aβ)‐40 (rg = 0.80, P = 6.92×10−6),and Aβ‐42 (rg = 1.03, P = 4.39×10−5). A higher genetic risk score based on NfL‐associated genetic variants was also related to increased plasma levels of total‐tau (P = 1.97×10−4), Aβ‐ 40 (P = 2.24×10−5), Aβ‐42 (P = 2.92×10−4) in the Rotterdam Study. Conclusion: This large‐scale GWAS meta‐analysis revealed multiple novel genetic loci of NfL levels in blood in participants from European and African‐American ancestry. Significant genetic correlation of genes underlying NfL with AD, Aβ‐42, and total‐tau may indicate a common underlying pathway of neurodegeneration. [ABSTRACT FROM AUTHOR]

Background: Many neurodegenerative disorders are characterised by changes in specific eye movement (EM) outcomes. Individuals with Alzheimer's disease (AD) make more antisaccade errors and correct a lower proportion of those errors compared to controls. EM impairments occur at an early stage of neuropathological changes and have, therefore, been discussed as a potential biomarker. Despite high test‐retest correlations for measures of EM performance and an estimated heritability of >40% for antisaccade performance, genetic association studies identified only a few single‐nucleotide polymorphisms (SNPs) related to EM performance. Polygenic risk scores (PRSs) are advantageous as they summarize the effects of many SNPs into a single score. Therefore, we assessed whether higher genetic risk for AD in healthy participants was associated with higher antisaccade error rate and lower correction rate of antisaccade errors. Method: The analyses were based on data of the first 2,000 participants (aged 30‐95) of the Rhineland Study, a community‐based prospective cohort study in Bonn, Germany. Genotyping was performed on Omni 2.5 exome arrays. We created PRS for AD by including all SNPs that reached genome‐wide significance at a threshold of p=5x10‐7in stage one of the GWAS of the "IGAP consortium". Missing SNPs were imputed using the 1000 Genomes reference panel. We examined the association between genetic risk for AD and antisaccade error rate using multivariable regression with PRS as predictor and antisaccade error rate as outcome variables. For antisaccade correction rate we used a one‐inflated beta regression model as the residuals were severely skewed. Ancestry, age, age2, sex, visual acuity and education were added as covariates in both regression models. Result: Polygenic risk for AD was associated with neither antisaccade error rate nor the proportion of uncorrected errors in those who did not correct all of their errors. However, a higher PRS for AD was associated with a lower odds of correcting all mistakes (odds ratio=0.85 (95%‐CI:0.73‐1.00) per one standard deviation increase in PRS). Conclusion: Polygenic risk for AD was associated with error correction rate in healthy individuals. Our findings suggest that eye movement performance may be a potential biomarker for early‐stage AD‐related neuropathological changes in the general population. [ABSTRACT FROM AUTHOR]