Mutations in the two related genes, presenilin 1 (PS1) and presenilin 2 (PS2), which are predicted multispanning membrane proteins, are responsible for the majority of early-onset familial Alzheimer's disease (FAD). To demonstrate direct interactions between presenilins (PS) and amyloid precursor protein (APP), the authors utilized a yeast two-hybrid system. Various hydrophilic domains derived from PS and those of APP were coexpressed in yeast and tested for the interaction. No detectable interactions were found in any PS/APP set examined. The authors' studies suggest that PS and APP do not interact through their hydrophilic domains in yeast, raising the possibility that interaction may occur indirectly or require proper conformation or subunit formation.