MicroRNA-181 influences Alzheimer’s risk by regulating neprilysin and microtubule-associated tau pathways, offering a novel target

Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) peptide plaques and neurofibrillary tangles from hyperphosphorylated tau, though factors linking amyloid and tau pathology remain unclear. We investigated whether microRNA-181d-5p (miR-181d) associates with AD-related brain changes and regulates neprilysin and tau. Modeling miR-181d across individuals with no cognitive impairment, mild cognitive impairment, and AD revealed region- and sex-specific associations. Higher miR-181d levels associated with greater AD probability in the temporal lobe and cerebellum, and lower probability in the posterior cingulate cortex of males; miR-181c attenuated these probabilities. SNPs near MIR181 associated with altered entorhinal cortical thickness. In cellular models, miR-181 reduced neprilysin 3′-UTR activity, mRNA, protein, and enzymatic activity, while increasing tau mRNA and protein. Neprilysin diminution impairs Aβ clearance and elevates tau, contributing to AD. RNA sequencing identified miR-181d-responsive neurodegenerative pathways. These findings identify miR-181 as a regulator of AD-relevant amyloid and tau pathways, providing novel targets.