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Dual-specificity tyrosine-phosphorylation-regulated kinase 1a (Dyrk1a) phosphorylates tau and amyloid precursor protein and regulates inflammatory signaling, positioning it as a convergence point across pathogenic pathways. We show that brain Dyrk1a protein levels are consistently elevated across ADRDs, replicating findings in AD, confirming prior observations in Pick\u2019s disease, and demonstrating dysregulation in corticobasal degeneration and progressive supranuclear palsy. We developed DYR533, a selective, orally bioavailable, brain-penetrant Type 1 Dyrk1a kinase inhibitor that also inhibits autophosphorylation and reduces kinase abundance. Across three mouse models (3xTg-AD, PS19, Ts65Dn), DYR533 reduced pathological tau hyperphosphorylation, attenuated neuroinflammation, ameliorated amyloidosis, and improved anxiety-like behavior and spatial memory, collectively supporting Dyrk1a inhibition and DYR533 as a therapeutic strategy for ADRD.<\/jats:p>","DOI":"10.64898\/2026.01.20.700091","type":"posted-content","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T20:50:15Z","timestamp":1769201415000},"source":"Crossref","is-referenced-by-count":1,"title":["Dyrk1a inhibition with the Novel Compound DYR533: A Cross-Disease Therapeutic Strategy Targeting Amyloidosis, Tau Pathogenesis, and Neuroinflammation"],"prefix":"10.64898","author":[{"given":"SK","family":"Bartholomew","sequence":"first","affiliation":[{"name":"Arizona State University-Banner Neurodegenerative Disease Research Center at the Biodesign Institute, Arizona State University, Tempe, AZ"},{"name":"School of Life Sciences, Arizona State University, Tempe, 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