Thirty-seven missense mutations and a splice-site mutation in the presenilin gene PS1 on chromosome 14 and two missense mutations PS2 on chromosome 1 co-segregate with early-onset familial Alzheimer's disease (AD). The presenilins belong to a family of conserved integral membrane proteins which include Caenorhabditis elegans SPE4 and SEL12 and the rat apoptosis-linked gene, ALG3. This review summarizes the genetics of presenilins in AD and indicators of putative function based on cellular localization and the functions of non-human homologues. Findings to date suggest an important role of presenilins in beta-amyloid (A beta) production: in vitro and in vivo studies have shown that presenilin mutations are associated with relatively increased production of the longer, and highly fibrillogenic A beta 42(43) peptide, and a marked elevation in the number of A beta 42-immunoreactive plaques in the brains of individuals with familial AD who carry PS1 and PS2 mutations. There is growing evidence that the deposition of A beta 42(43) could in some cases be an early and key event in the AD pathogenic cascade. The genetic and molecular biological data discussed in this review describe mechanisms by which presenilin mutations could lead to the development of AD. Also, mutant presenilins may be more proapoptotic. It is argued that the understanding of the processes by which presenilin mutations lead to the development of AD will help in devising a coherent framework for therapeutic strategies.