Wnt/β-catenin signaling dysregulation in Alzheimer’s disease and therapeutic opportunities

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by neuronal and neurovascular dysfunction. Wnt/β-catenin signaling is a highly conserved pathway that plays essential roles in central nervous system development and homeostasis, including regulation of neurogenesis, synaptic plasticity, neuronal survival, cerebrovascular development, and blood–brain barrier (BBB) maintenance. Growing evidence increasingly implicates disruption of Wnt/β-catenin signaling in multiple neuronal and neurovascular processes relevant to AD. This review summarizes current knowledge of the Wnt/β-catenin pathway and examines evidence linking its dysregulation to AD from human studies, omics datasets, experimental models, and patient-derived cellular systems. It focuses on endothelial Wnt/β-catenin dysfunction as a potential early contributor to BBB breakdown, rather than on neuronal Wnt signaling. We also emphasize its role in BBB development and maintenance, neurovascular dysfunction, and emerging evidence that endothelial Wnt/β-catenin impairment may contribute to BBB dysfunction in AD. Additionally, we discuss cell-type-specific effects of Wnt signaling and therapeutic strategies targeting glycogen synthase kinase (GSK-3β), extracellular Wnt antagonists, and BBB integrity. Although challenges remain regarding cell-type specificity, disease-stage dependence, safety, biomarker development, and the efficacy of preclinical-to-clinical translation for targeting the Wnt/β-catenin pathway, modulating Wnt/β-catenin signaling represents a potential therapeutic approach to preserve neuronal and neurovascular function in AD.