Glycogen synthase kinase-3 (GSK3), consisting of GSK3α and GSK3β subtypes, is a complex protein kinase that regulates numerous substrates. Research has observed increased GSK3 expression in the brains of Alzheimer's disease (AD) patients and models. AD is a neurodegenerative disorder with diverse pathogenesis and notable cognitive impairments, characterized by Aβ aggregation and excessive tau phosphorylation. This article provides an overview of GSK3's structure and regulation, extensively analyzing its relationship with AD factors. GSK3 overactivation disrupts neural growth, development, and function. It directly promotes tau phosphorylation, regulates amyloid precursor protein (APP) cleavage, leading to Aβ formation, and directly or indirectly triggers neuroinflammation and oxidative damage. Preclinical research highlights the inhibition of GSK3 activity as a primary therapeutic approach for AD. Pending issues, such as the lack of highly specific and affinity-driven GSK3 inhibitors, are raised. GSK3 represents a target in AD treatment, filled with hope, challenges, opportunities, and obstacles. Keywords: Alzheimer's disease, glycogen synthase kinase-3, targeted drug, therapeutic target. GSK3 was first identified in the 1980s as a protein kinase responsible for phosphorylating and deactivating glycogen synthase in rabbit skeletal muscle. GSK3 has been recognized as an evolutionarily conserved Ser/Thr protein kinase with a multitude of substrates. Over 100 substrates of GSK3 have been identified, with an additional 500 awaiting confirmation. GSK3 is one of the most functionally complex kinases involved in various cellular processes, including motility, metabolism, differentiation, proliferation, and apoptosis. The two isoforms of human GSK3, GSK3α and GSK3β, consist of 483 amino acids (51 kDa) and 420 amino acids (47 kDa), respectively. These isoforms are derived from chromosome 19 and chromosome 3, respectively. Both GSK3α and GSK3β have been detected in almost all species, with over 90% similarity across different species. In Homo sapiens, the amino acid sequences of GSK3α and GSK3β show 84%–85% similarity, while their kinase domains exhibit a high degree of homology, with 19 differential amino acids from the 285 amino acids that make up the kinase domains. Although no accurate structural information of GSK3α is obtained, predicted results suggest that the glycine-rich region distinguishes between these two isoforms and does not form a stable secondary structure. The secondary structures of GSK3α and GSK3β are also thought to be similar, especially in kinase domains. GSK3α and GSK3β showed approximate biologicalGlycogen synthase kinase-3 (GSK3), consisting of GSK3α and GSK3β subtypes, is a complex protein kinase that regulates numerous substrates. Research has observed increased GSK3 expression in the brains of Alzheimer's disease (AD) patients and models. AD is a neurodegenerative disorder with diverse pathogenesis and notable cognitive impairments, characterized by Aβ aggregation and excessive tau phosphorylation. This article provides an overview of GSK3's structure and regulation, extensively analyzing its relationship with AD factors. GSK3 overactivation disrupts neural growth, development, and function. It directly promotes tau phosphorylation, regulates amyloid precursor protein (APP) cleavage, leading to Aβ formation, and directly or indirectly triggers neuroinflammation and oxidative damage. Preclinical research highlights the inhibition of GSK3 activity as a primary therapeutic approach for AD. Pending issues, such as the lack of highly specific and affinity-driven GSK3 inhibitors, are raised. GSK3 represents a target in AD treatment, filled with hope, challenges, opportunities, and obstacles. Keywords: Alzheimer's disease, glycogen synthase kinase-3, targeted drug, therapeutic target. GSK3 was first identified in the 1980s as a protein kinase responsible for phosphorylating and deactivating glycogen synthase in rabbit skeletal muscle. GSK3 has been recognized as an evolutionarily conserved Ser/Thr protein kinase with a multitude of substrates. Over 100 substrates of GSK3 have been identified, with an additional 500 awaiting confirmation. GSK3 is one of the most functionally complex kinases involved in various cellular processes, including motility, metabolism, differentiation, proliferation, and apoptosis. The two isoforms of human GSK3, GSK3α and GSK3β, consist of 483 amino acids (51 kDa) and 420 amino acids (47 kDa), respectively. These isoforms are derived from chromosome 19 and chromosome 3, respectively. Both GSK3α and GSK3β have been detected in almost all species, with over 90% similarity across different species. In Homo sapiens, the amino acid sequences of GSK3α and GSK3β show 84%–85% similarity, while their kinase domains exhibit a high degree of homology, with 19 differential amino acids from the 285 amino acids that make up the kinase domains. Although no accurate structural information of GSK3α is obtained, predicted results suggest that the glycine-rich region distinguishes between these two isoforms and does not form a stable secondary structure. The secondary structures of GSK3α and GSK3β are also thought to be similar, especially in kinase domains. GSK3α and GSK3β showed approximate biological