Alzheimer’s disease (AD), the most common neurodegenerative disorder among the elderly, is characterized by progressive and irreversible loss of memory, cognitive skills, and ultimately leads to death. Despite significant efforts and advances in understanding the underlying causes and mechanisms over the past two decades, the etiology of AD remains elusive. Recently, we discovered that Caudatin, an active constituent of the Chinese medicinal herb Cynanchum otophyllum, can bind to and activate PPARα, thereby transcriptionally regulating TFEB and enhancing lysosomal degradation of Aβ and pTau aggregates in both cellular and animal models of AD. Furthermore, we identified Caudatin as a promising autophagy inducer that inhibits GSK3β activity through phosphorylation at Ser9, but not at Ser21. Molecular docking studies further predict that Caudatin enhances the interaction between GSK3β and ULK1, promoting phosphorylation at Ser405 rather than Ser415. Notably, Caudatin increases and activates both GSK3β and ULK1 by inducing phosphorylation at S405, which initiates autophagy and augments lysosomal clearance of Aβ and pTau aggregates in AD models. This research offers new insights into the molecular mechanisms underlying the targeted delivery of Caudatin, which demonstrates high brain permeability and promising efficacy for AD therapeutics, and holds great potential for improving the healthcare of the aging population worldwide.