Abstract Alzheimer’s disease (AD) is the most common form of neurodegenerative disorder during aging and an unmet medical challenge. AD is a complex multi-factorial disease clinically characterized by a decline in cognitive function and pathologically defined by the accumulation of extracellular β-amyloid (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). AD can be caused by both genetic defects and environmental factors and genetic mutations and risk factors have been identified that are either causal or modify the disease progression. Cellular and molecular alterations in the neuronal, astroglial, microglial/immune, and endothelial/vascular cells that modify the AD pathological hallmarks in the brain have been the focus of studies. The Wnt signaling pathways have been found to be involved causatively in the pathogenesis of AD. However, most of the research has been focused on the Wnt/b-catenin pathway. The role of the Wnt/planar cell polarity (PCP) signaling pathway in AD, though important, was understudied. The Wnt/PCP pathway is a highly conserved regulator of cellular orientation within the plane of an epithelium and has been found to be essential for brain development and function. Intriguingly, the Wnt-PCP pathway regulates axon outgrowth rather than neuronal polarity during brain development of both vertebrates and Drosophila. Despite the conservation of Wnt/PCP signaling from Drosophila to mammals, PCP regulation in vertebrates is more complex, functionally diverse and requires additional regulatory schemes and vertebrate-specific PCP component such as Ror2. It has been found that PCP signaling components play essential roles in glutamatergic synapse formation in development and Wnt/PCP signaling interacts with the amyloid precursor protein (APP) that is cleaved to become Aβ and such interaction alters Wnt/PCP signaling, which drives tau pathology and neuronal death causing AD. The majority of AD clinical trials have focused on reducing Ab load and unfortunately, these trials have been unsuccessful so far. Thus, there is an urgent need to pursue other disease modifying mechanisms and therapies. In our previous studies before and after the support of the parental grant, we have made the novel discovery for the regulation of Vangl2 phosphorylation by Wnt5a and Ror2, which exhibits fundamental difference when flies evolve to mammals. We will expand our investigation of functional requirement of Vangl2 phosphorylation in vivo in pathogenesis and progression of AD in two genetic mouse models focused respectively on APP/Ab production (5XFAD Tg6799) and tau hyper-phosphorylation (PS19). We will also determine the role of APP in Wnt5a-induced PCP signalosome. In so doing, we will gain critically important new insights into the pathophysiological mechanism underlying Wnt/PCP signaling in AD, as well as identify potential targets for manipulating Wnt/PCP signaling as an approach for AD treatment.