This review examines the roles and mechanisms of Wnt signaling in Alzheimer’s disease (AD). AD is pathologically defined by extracellular amyloid-β (Aβ) plaque deposition and neurofibrillary tangles composed of hyperphosphorylated tau, accompanied by synaptic loss, neuroinflammation, blood–brain barrier (BBB) dysfunction, and progressive brain atrophy. Growing evidence identifies Wnt signaling as a central regulatory system that maintains neuronal survival, synaptic plasticity, and neurovascular unit homeostasis. Disruption of Wnt signaling intersects with and amplifies AD pathology at multiple levels. Attenuated Wnt activity can derepress amyloidogenic pathways, including BACE1 expression, and compromise cellular environments that support Aβ clearance. Aberrant activation of glycogen synthase kinase-3β (GSK-3β) promotes tau hyperphosphorylation, while altered Wnt-dependent synaptic protein homeostasis and excitatory–inhibitory balance destabilize neuronal networks. In parallel, Wnt signaling modulates microglial and astrocytic inflammatory state transitions and contributes to BBB integrity and repair. Key regulators—including LRP5/6, LRP1, the Dickkopf (DKK) family (particularly DKK1 and the atypical DKK3), sFRP1, Kremen, Notum, and R-spondins—collectively shape Wnt signal strength, receptor availability, and antagonistic tone, forming a pathogenic network characterized by receptor gating, antagonist amplification, and clearance cross-talk. We summarize three major Wnt-oriented therapeutic strategies: enhancing canonical Wnt/β-catenin signaling, reducing antagonistic pressure on Wnt receptors, and modulating LRP family functions to coordinate synaptic protection, BBB repair, and Aβ clearance. Overall, Wnt signaling represents a promising disease-modifying axis centered on synaptic and network resilience; however, successful clinical translation will require refined understanding of cell-type specificity, disease-stage dependence, context-dependent effects of regulators such as DKK3, and the development of robust pharmacodynamic biomarkers.
Zhao et al. (Sun,) studied this question.