Accumulating evidence has shown that the processing of the amyloid precursor protein (APP) and the formation of amyloid-β are associated with the canonical Wnt/ β-catenin signalling pathway. It was recently published that the drosophila homologue of APP is a conserved modulator of Wnt PCP signalling, suggesting a potential regulation of this pathway by APP. The aim of this study was to investigate the potential interaction of APP with the canonical Wnt pathway. APP overexpression in N2a cells led to alterations in the subcellular distribution of β-catenin by physically binding to it, preventing its translocation to the nucleus and precluding the transcription of Wnt target genes. In addition, studies in APP transgenic mice and human Alzheimer’s disease (AD) brain tissue showed the cellular co-localization of APP and β-catenin and binding of both proteins, suggesting the formation physical complexes of APP and β-catenin, yet not present in healthy controls. Furthermore, a reduction in the levels of nuclear β-catenin was detected in AD brains compared to controls as well as a decrease in the expression of the inactive phosphorylated Glycogen synthase kinase 3 (GSK3) isoform. Therefore, these findings indicate a reciprocal regulation of Wnt/ β-catenin signalling pathway and APP processing involving a physical interaction between APP and β-catenin.