We previously reported that overexpression of presenilin 1 and 2 (PS1 and PS2) in HeLa cells leads to cell cycle arrest, and that the PS2(N141I) FAD mutant potentiates cell cycle arrest compared to wild-type PS2. Using similar BrdU incorporation studies we now report that three different PS1 FAD mutants also increase cell cycle arrest compared to wild-type PS1 when overexpressed in either HeLa cells or an ATM deficient cell line. We detected reproducible differences in the degrees to which these FAD mutants induced arrest. PS1(P117L) reduced BrdU incorporation the most (13 to 14%) followed by PS1(P267S) (7.5 to 9%), with the PS1(E280A) mutant inhibiting BrdU incorporation the least (6 to 7%), compared to wild-type PS1. The degree to which the different mutants inhibited cell cycle progression correlates somewhat with the age of AD onset induced by the mutations in carriers. Immunoblot analysis of protein extracts from presenilin-overexpressing cells indicates that the cell cycle-regulated cytoplasmic pool of beta-catenin is dramatically reduced, whereas the insoluble beta-catenin pool remains essentially unaffected. We discuss the implications of these findings in relationship to cell cycle arrest, apoptosis and AD.