The GSK3 hypothesis of Alzheimer's disease proposes that glycogen synthase kinase 3 (GSK3) plays a central role in the pathogenesis of both sporadic and familial forms of Alzheimer's disease (AD). GSK3 is a constitutively active kinase involved in various physiological processes, including glycogen metabolism, gene transcription, and apoptosis. It is implicated in the hyper-phosphorylation of tau, increased production of β-amyloid (Aβ), and inflammatory responses in AD. The hypothesis suggests that over-activity of GSK3 contributes to memory impairment, neurofibrillary tangles (NFTs), and Aβ plaques, which are hallmarks of AD. GSK3 is regulated by insulin and Wnt signaling pathways. Insulin signaling leads to the activation of Akt, which phosphorylates GSK3, reducing its activity. Wnt signaling displaces GSK3 from regulatory complexes, preventing the degradation of β-catenin and promoting its nuclear translocation, which is essential for Wnt target gene expression. GSK3 also plays a role in the hyper-phosphorylation of tau, a key event in the formation of NFTs. GSK3 is involved in the production of Aβ from the amyloid precursor protein (APP) and contributes to the inflammatory response in AD. GSK3 is up-regulated in various brain regions in AD patients, and its activity is associated with memory impairment and neurodegeneration. Inhibitors of GSK3 may offer a novel therapeutic approach for AD. The GSK3 hypothesis integrates and extends the amyloid cascade hypothesis by linking GSK3 activity to key pathological features of AD, including tau hyper-phosphorylation, Aβ production, and inflammation. If validated, GSK3 inhibitors could provide a promising treatment strategy for AD.The GSK3 hypothesis of Alzheimer's disease proposes that glycogen synthase kinase 3 (GSK3) plays a central role in the pathogenesis of both sporadic and familial forms of Alzheimer's disease (AD). GSK3 is a constitutively active kinase involved in various physiological processes, including glycogen metabolism, gene transcription, and apoptosis. It is implicated in the hyper-phosphorylation of tau, increased production of β-amyloid (Aβ), and inflammatory responses in AD. The hypothesis suggests that over-activity of GSK3 contributes to memory impairment, neurofibrillary tangles (NFTs), and Aβ plaques, which are hallmarks of AD. GSK3 is regulated by insulin and Wnt signaling pathways. Insulin signaling leads to the activation of Akt, which phosphorylates GSK3, reducing its activity. Wnt signaling displaces GSK3 from regulatory complexes, preventing the degradation of β-catenin and promoting its nuclear translocation, which is essential for Wnt target gene expression. GSK3 also plays a role in the hyper-phosphorylation of tau, a key event in the formation of NFTs. GSK3 is involved in the production of Aβ from the amyloid precursor protein (APP) and contributes to the inflammatory response in AD. GSK3 is up-regulated in various brain regions in AD patients, and its activity is associated with memory impairment and neurodegeneration. Inhibitors of GSK3 may offer a novel therapeutic approach for AD. The GSK3 hypothesis integrates and extends the amyloid cascade hypothesis by linking GSK3 activity to key pathological features of AD, including tau hyper-phosphorylation, Aβ production, and inflammation. If validated, GSK3 inhibitors could provide a promising treatment strategy for AD.