Circulating microRNAs are related to cognitive domains in the general population

INTRODUCTION Circulating microRNAs have been suggested as candidates for detecting and preventing subclinical cognitive dysfunction. However, replication of previous findings and identification of novel microRNAs associated with cognitive domains, including their relation to brain structure and the pathways they regulate, are still lacking. METHODS We examined circulating microRNAs and microRNA co-expression clusters in relation to cognitive domains, structural MRI measures, and target gene expression in 2869 participants of a population-based cohort. RESULTS Five previously identified and 10 novel microRNAs were associated with cognitive domains. Importantly, seven of these microRNAs were also associated with cortical thickness and two with hippocampal volume. Functional genomics analysis showed that the identified microRNAs regulated genes in pathways like neurogenesis, axon guidance, and synapse assembly. DISCUSSION We identified microRNAs 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the Federal Ministry of Education and Research grant [FKZ: 01KX2230] with the title "PreBeDem - Mit Praevention und Behandlung gegen Demenz" and the Helmholtz Association under the 2023 Innovation Pool. The Rhineland Study is funded by the German Center for Neurodegenerative Diseases (DZNE). Andre Fischer received funding from the DFG priority program 1738, SFB1286, SFB 1002, by Germany's Excellence Strategy - EXC 2067/1 390729940, the ERA-Net Neuron project EPINEURODEVO and the JPND project EPI-3E. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of the University of Bonn, Medical Faculty gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Access to data can be provided to scientists in accordance with the Rhineland Study's Data Use and Access Policy. Requests for additional information or to access to the Rhineland Study's datasets can be send to RS-DUAC(at)dzne.de. * AD : Alzheimer’s Disease ROIs : Regions Of Interest eTIV : estimated Total Intracranial Volume DKT : Desikan–Killiany–Tourville SD : Standard Deviation WGCNA : Weighted Gene Co-Expression Analysis fdr : false discovery rate GWAS : Genome-Wide Association Study MCI : Mild Cognitive Impairment CI : Confidence Interval HCV : Hippocampal Volume TGF-β : transforming growth factor beta