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Amyloid-\u03b2 peptide (A\u03b2) contributes to the etiology and progression of the disease. A\u03b2 is derived from the amyloid-\u03b2 precursor protein (APP). Multiple microRNA (miRNA) species are also implicated in AD. We report that human hsa-miR20b-5p (miR-20b), produced from the MIR20B gene on Chromosome X, may play complex roles in AD pathogenesis, including A\u03b2 regulation. Specifically, miR-20b-5p miRNA levels were altered in association with disease progression in three regions of the human brain: temporal neocortex, cerebellum, and posterior cingulate cortex. In cultured human neuronal cells, miR-20b-5p treatment interfered with calcium homeostasis, neurite outgrowth, and branchpoints. A single-nucleotide polymorphism (SNP) upstream of the <jats:italic>MIR20B<\/jats:italic> gene (rs13897515) associated with differences in levels of cerebrospinal fluid (CSF) A\u03b2<jats:sub>1-42<\/jats:sub> and thickness of the entorhinal cortex. We located a miR-20b-5p binding site in the APP mRNA 3\u2032-untranslated region (UTR), and treatment with miR-20b-5p reduced APP mRNA and protein levels. Network analysis of protein-protein interactions and gene coexpression revealed other important potential miR-20b-5p targets among AD-related proteins\/genes. MiR-20b-5p, a miRNA that <jats:italic>downregulated<\/jats:italic> APP, was paradoxically associated with an <jats:italic>increased<\/jats:italic> risk for AD. However, miR-20b-5p also reduced, and the blockade of APP by siRNA likewise reduced calcium influx. As APP plays vital roles in neuronal health and does not exist solely to be the source of \u201cpathogenic\u201d A\u03b2, the molecular etiology of AD is likely to not just be a disease of \u201cexcess\u201d but a disruption of delicate homeostasis.<\/jats:p>","DOI":"10.1038\/s41380-021-01351-3","type":"journal-article","created":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T10:02:56Z","timestamp":1643277776000},"page":"1256-1273","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":67,"title":["Human microRNA (miR-20b-5p) modulates Alzheimer\u2019s disease pathways and neuronal function, and a specific polymorphism close to the MIR20B gene influences Alzheimer\u2019s biomarkers"],"prefix":"10.1038","volume":"27","author":[{"given":"Ruizhi","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nipun","family":"Chopra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwangsik","family":"Nho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2364-9649","authenticated-orcid":false,"given":"Bryan","family":"Maloney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander G.","family":"Obukhov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter T.","family":"Nelson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott E.","family":"Counts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1664-5933","authenticated-orcid":false,"given":"Debomoy K.","family":"Lahiri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,1,27]]},"reference":[{"key":"1351_CR1","doi-asserted-by":"publisher","unstructured":"Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. 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