Blood-derived microRNA signatures associated with hippocampal structure and atrophy rate: findings from the Rhineland Study.

MicroRNAs (miRNAs) 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 miRNA involvement in brain health and neurodegeneration. Here, using population-based data, we cross-sectionally and longitudinally examined the associations of blood-derived miRNAs with left and right hippocampal volume, hippocampal asymmetry, and total brain volume. Expression of miRNAs 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 4.60-8.02 years later using 3 T MRI. We investigated miRNA associations with imaging measures cross-sectionally using linear regression and longitudinally using linear mixed-effect models. Cross-sectionally, six miRNAs (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 miRNAs (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 miRNAs were exclusively associated with total brain atrophy rate. In whole blood, miRNAs identified in the cross-sectional analysis targeted genes related to brain development, memory, and synapse assembly. MiRNAs from the longitudinal analysis targeted genes related to axonal and dendritic growth. Several identified miRNAs were previously linked to neurodegeneration. Especially miR-146a-5p and miR-370-3p have been consistently linked to dementia and could be investigated as presymptomatic blood-based biomarkers. The brain-specific functions and interactions with target genes of identified miRNAs could be further investigated to develop therapeutic strategies against neurodegeneration.