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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\u2032-UTR activity, mRNA, protein, and enzymatic activity, while increasing tau mRNA and protein. Neprilysin diminution impairs A\u03b2 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.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Teaser<\/jats:title>\n                  <jats:p>MiRNA-181 is a key regulator of Alzheimer\u2019s risk through its effects on neprilysin and tau proteins, a novel potential target.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.11.731747","type":"posted-content","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T18:45:19Z","timestamp":1781635519000},"source":"Crossref","is-referenced-by-count":0,"title":["MicroRNA-181 influences Alzheimer\u2019s risk by regulating neprilysin and microtubule-associated tau pathways, offering a novel target"],"prefix":"10.64898","author":[{"given":"Ruizhi","family":"Wang","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Neurogenetics, Departments of Psychiatry, Stark Neuroscience Research Institute, Indiana Alzheimer\u2019s 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S.","family":"Beck","sequence":"additional","affiliation":[{"name":"Departments of Translational Neuroscience and Family Medicine, Michigan State University, Grand Rapids, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2851-9763","authenticated-orcid":false,"given":"Scott E.","family":"Counts","sequence":"additional","affiliation":[{"name":"Departments of Translational Neuroscience and Family Medicine, Michigan State University, Grand Rapids, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1664-5933","authenticated-orcid":false,"given":"Debomoy K.","family":"Lahiri","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neurogenetics, Departments of Psychiatry, Stark Neuroscience Research Institute, Indiana Alzheimer\u2019s Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, USA"},{"name":"Deaprtment of Medical & Molecular 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