Although an association between the product of the familial Alzheimer’s disease (FAD) gene, presenilin 1 (PS1), and β-catenin has been reported recently, the cellular consequences of this interaction are unknown. Here, we show that both the full length and the C-terminal fragment of wild-type or FAD mutant PS1 interact with β-catenin from transfected cells and brains of transgenic mice, whereas E-cadherin and adenomatous polyposis coli (APC) are not detected in this complex. Inducible overexpression of PS1 led to increased association of β-catenin with glycogen synthase kinase-3β (GSK-3β), a negative regulator of β-catenin, and accelerated the turnover of endogenous β-catenin. In support of this finding, the β-catenin half-life was dramatically longer in fibroblasts deficient in PS1, and this phenotype was completely rescued by replacement of PS1, demonstrating that PS1 normally stimulates the degradation of β-catenin. In contrast, overexpression of FAD-linked PS1 mutants (M146L and ΔX9) failed to enhance the association between GSK-3β and β-catenin and interfered with the constitutive turnover of β-catenin. In vivo confirmation was demonstrated in the brains of transgenic mice in which the expression of the M146L mutant PS1 was correlated with increased steady-state levels of endogenous β-catenin. Thus, our results indicate that PS1 normally promotes the turnover of β-catenin, whereas PS1 mutants partially interfere with this process, possibly by failing to recruit GSK-3β into the PS1–β-catenin complex. These findings raise the intriguing possibility that PS1–β-catenin interactions and subsequent activities may be consequential for the pathogenesis of AD.