Dual Targeting of Tau Kinases and Autophagy by Abemaciclib Independent of CDK4/6 Inhibition

ABSTRACT Alzheimer's disease (AD) is marked by progressive cognitive decline driven largely by tau pathology, yet disease‐modifying therapies targeting tau remain limited. In this study, we re‐evaluated abemaciclib, a clinically approved CDK4/6 inhibitor for breast cancer and uncovered its previously unrecognized therapeutic potential in AD via CDK4/6‐independent mechanisms. Using the APP NL−F /MAPT double knock‐in mouse model (dKI) and AD patient‐derived 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 2 ⁺/calmodulin‐dependent protein kinase II (CaMKII) and glycogen synthase kinase 3β (GSK3β), 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—suppression of tau phosphorylation and facilitation of degradation—highlights 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‐targeted AD therapy.