Authors
Melas K, Talevi V, Aslam Imtiaz M, Krueger DM, Pena-Centeno T, Fischer A, Aziz NA, Breteler MMB
Journal
MedRxiv
Citation
medRxiv 2025.05.09.25327286
Abstract
MicroRNAs have been linked to brain disorders, but their relations with hippocampal structure and atrophy remain unexplored. As the hippocampus is pivotal for cognition and dementia, understanding these relations and their specificity for the hippocampus would elucidate microRNA involvement in brain health and neurodegeneration. Here, using population-based data, we cross-sectionally and longitudinally examined the associations of blood-derived microRNAs with left and right hippocampal volume, hippocampal asymmetry, and total brain volume. Expression of microRNAs and their putative target genes was measured at study baseline in whole blood using RNA sequencing. Brain imaging measures were examined at baseline and re-examined 4.60 to 8.02 years later using 3T MRI. We investigated microRNA associations with imaging measures cross-sectionally using linear regression and longitudinally using linear mixed-effect models. Cross-sectionally, six microRNAs (miR-199a-3p, miR-199b-3p, miR-155-5p, miR-146a-5p, miR-6859-5p, miR-505-5p) were associated exclusively with left hippocampal volume. Longitudinally, another five microRNAs (miR-361-3p, miR-4473, miR-381-3p, miR-543, miR-370-3p) were associated with left hippocampal, right hippocampal, and total brain atrophy rates. Twenty-one microRNAs were exclusively associated with total brain atrophy rate. MicroRNAs identified in the cross-sectional analysis regulated target genes involved in brain development, memory, and synapse assembly. MicroRNAs from the longitudinal analysis regulated genes related to axonal and dendritic growth. Our findings suggest an asymmetric and specialized role of the cross-sectional microRNA signature during left hippocampal early-life development and a more universal role of the longitudinal signature during whole-brain aging or neurodegeneration. Importantly, some identified microRNAs have been previously linked to dementia and could be investigated as presymptomatic blood-based biomarkers.
