Familial Alzheimer's disease mutations in presenilin and the amyloid precursor protein (APP) are thought to cause Alzheimer's disease (AD) neurodegeneration by increasing production and aggregation of amyloid beta (Abeta). However, presenilin has functions that are distinct from its role in the gamma-secretase complex, while APP has signaling functions that transcend its role as the source of Abeta. Three recent papers highlight the potential importance of presenilin and APP signaling in the etiology of AD.