miRNA-seq identifies shared regulatory changes in PSEN1-associated familial Alzheimer’s disease

Pathogenic variants in PSEN1 are the leading cause of familial early-onset Alzheimer’s disease (fAD); however, their impact on miRNA-mediated regulatory networks in human neurons remains poorly defined. We performed small RNA sequencing in human iPSC-derived cortical neurons at day 70 of differentiation from six lines: three carrying distinct PSEN1 variants (M146L, A246E, and T119I, a novel variant identified in an Argentinian fAD pedigree) and three wild-type controls. Differential expression analysis (edgeR, FDR < 0.05, |log₂FC| ≥ 1.5) identified 154 dysregulated miRNAs in fAD versus controls (70 up, 84 down). Among the shared changes, miR-4707-3p showed the strongest increase (log₂FC +6.3 across variants), while miR-219a-2-3p and members of the miR-34 family were consistently downregulated. miR-219a-2-3p has been implicated in tau regulation, whereas the miR-34 family is linked to p53 signaling and neuronal stress responses. miR-100-5p was also reduced, potentially affecting mTOR-related regulation of autophagy and proteostasis. Target enrichment highlighted neuronal apoptosis, PI3K-AKT/FoxO signaling, and senescence as major affected processes. Together, these findings reveal coordinated miRNA dysregulation across distinct PSEN1 variants, converging on pathways relevant to neuronal survival, stress responses, and proteostasis in fAD.