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In this study, we re\u2010evaluated abemaciclib, a clinically approved CDK4\/6 inhibitor for breast cancer and uncovered its previously unrecognized therapeutic potential in AD via CDK4\/6\u2010independent mechanisms. Using the APP\n                    <jats:sup>NL\u2212F<\/jats:sup>\n                    \/MAPT double knock\u2010in mouse model (dKI) and AD patient\u2010derived brain organoids, we found that abemaciclib robustly ameliorates cognitive deficits and reduces neurodegeneration without altering amyloid burden or glial activation. Mechanistically, abemaciclib selectively inhibited key tau kinases, particularly Ca\n                    <jats:sup>2<\/jats:sup>\n                    \u207a\/calmodulin\u2010dependent protein kinase II (CaMKII) and glycogen synthase kinase 3\u03b2 (GSK3\u03b2), independent of CDK4\/6 inhibition, as confirmed by lentiviral knockdown experiments. Furthermore, abemaciclib enhanced autophagic flux and lysosomal activity, promoting clearance of pathological tau proteins. This dual modulation\u2014suppression of tau phosphorylation and facilitation of degradation\u2014highlights abemaciclib as a promising repurposed therapeutic for AD. Our findings establish a novel pharmacological profile for abemaciclib beyond its canonical role in cell cycle control, offering immediate translational potential for tau\u2010targeted AD therapy.\n                  <\/jats:p>","DOI":"10.1002\/advs.202513135","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T13:30:11Z","timestamp":1768397411000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Dual Targeting of Tau Kinases and Autophagy by Abemaciclib Independent of CDK4\/6 Inhibition"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6108-8235","authenticated-orcid":false,"given":"Jihui","family":"Han","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, College of Medicine Seoul National University Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"June\u2010Hyun","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Medicine Seoul National University Seoul Republic of Korea"},{"name":"Convergence Dementia Research Center, Medical Research Center Seoul National University Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongjoon","family":"Lee","sequence":"additional","affiliation":[{"name":"Convergence Dementia Research Center, Medical Research Center Seoul National University Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0322-4611","authenticated-orcid":false,"given":"Yujin","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Medicine Seoul National University Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7682-2707","authenticated-orcid":false,"given":"Yujin","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Medicine Seoul National University Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun Sun","family":"Jung","sequence":"additional","affiliation":[{"name":"Convergence Dementia Research Center, Medical Research Center Seoul National University Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haeng Jun","family":"Kim","sequence":"additional","affiliation":[{"name":"Convergence Dementia Research Center, Medical Research Center Seoul National University Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Woo Youn","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Chemistry KAIST  Daejeon Republic of Korea"},{"name":"HITS Inc.  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