Brain microRNAs differentially expressed in age-related cerebral pathologies

Multiple brain pathologies accumulate with age, but their underlying biology remains unclear. We investigated the role of microRNAs (miRNAs) in ten age-related cerebral pathologies. Using miRNA sequencing profiles from the dorsolateral prefrontal cortex of 617 brain donors, we identified miRNAs associated with Alzheimer's disease (AD) pathology, Lewy body pathology, arteriolosclerosis, cerebral amyloid angiopathy, and LATE-NC after adjusting for age, sex, and education. After additionally adjusting for co-existing cerebral pathologies, we found miRNAs specifically associated with AD pathology (n = 75), Lewy body pathology (n = 45), arteriolosclerosis (n = 3), cerebral amyloid angiopathy (n = 1), and LATE-NC (n = 4). While some miRNAs were pathology-specific, 14 miRNAs (including those in the miR-132/212 cluster) were associated with both AD pathology and Lewy body pathology, and one (miR-193a-5p) was associated with both AD pathology and cerebral amyloid angiopathy. Gene set enrichment analysis showed that miRNAs associated with arteriolosclerosis target genes involved in glutathione metabolism, synaptic functions, cellular transport, and innate immune response. These findings highlight the role of miRNAs in age-related cerebral pathologies and provide a foundation for future mechanistic studies.