The presenilin proteins are components of high–molecular–weight protein complexes in the endoplasmic reticulum and Golgi apparatus that also contain β-catenin. We report here that presenilin mutations associated with familial Alzheimer disease (but not the non–pathogenic Glu318Gly polymorphism) alter the intracellular trafficking of β-catenin after activation of the Wnt/β-catenin signal transduction pathway. As with their effect on βAPP processing, the effect of PS1 mutations on trafficking of β-catenin arises from a dominant'gain of aberrant function'activity. These results indicate that mistrafficking of selected presenilin ligands is a candidate mechanism for the genesis of Alzheimer disease associated with presenilin mutations, and that dysfunction in the presenilin–β-catenin protein complexes is central to this process.