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

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 Ca²⁺/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.