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With the global rise in population aging, the incidence of Alzheimer’s disease (AD) continues to increase, posing a substantial burden on individuals, families, and healthcare systems. However, at present, the drugs approved by FDA for treating AD can only relieve symptoms, but cannot cure or reverse the disease. Therefore, it is urgent to study the signal pathways related to AD and the drugs to improve the pathological changes of AD.The Wnt/β-catenin signaling pathway, known for its functional diversity, evolutionary conservation, and relevance to multiple diseases, holds a pivotal role in both basic research and therapeutic development. This pathway is essential for regulating critical biological processes, including embryonic development, tissue homeostasis, cell proliferation, differentiation, and apoptosis.In AD , downregulation of the Wnt/β-catenin signaling pathway has been implicated in key pathological features, such as tau hyperphosphorylation, amyloid-β (Aβ) accumulation, neuronal degeneration, synaptic loss, cognitive impairment, oxidative stress, mitochondrial dysfunction, blood-brain barrier disruption, and neuroinflammation. This review comprehensively discusses the deregulation of the Wnt/β-catenin pathway in AD and how it contributes to disease progression. Furthermore, we highlighted emerging pharmacological activators of this pathway exhibiting potential as therapeutic agents for AD. • Comprehensive Review: This paper provides an in-depth analysis of the Wnt/β-catenin signaling pathway's role in Alzheimer's disease (AD), linking its downregulation to key pathological features such as Aβdeposition, tau hyperphosphorylation, synaptic dysfunction, and neuroinflammation. • Therapeutic Potential: The review highlights emerging pharmacological activators of the Wnt/β-catenin pathway, including natural compounds (e.g., resveratrol, curcumin) and synthetic agents (e.g., GSK3β inhibitors,DKK1 Inhibitors,LRP6 Regulators), which show promise in mitigating AD pathology by targeting multiple disease mechanisms. • Mechanistic Insights: The paper elucidates how Wnt/β-catenin signaling influences neuroprotection, synaptic plasticity, and neurogenesis, offering a novel perspective on AD treatment strategies beyond current symptomatic therapies. • Clinical Implications: While preclinical studies are promising, the review underscores the need for further clinical validation to address challenges such as blood-brain barrier permeability and precise pathway modulation to avoid oncogenic risks. • Future Directions: The review identifies gaps in current research and proposes future studies to explore the translational potential of Wnt/β-catenin activators, emphasizing their potential to modify disease progression in AD. • This structured format ensures clarity and aligns with the journal's focus on impactful aging-related research. Let me know if you'd like any refinements!
Ma et al. (Thu,) studied this question.