Mutations in the presenilin genes PS1 and PS2, the major cause of familial Alzheimer's disease (FAD), are associated with alterations in Ca 2+ signalling. In contrast to the majority of FAD-linked PS1 mutations, which cause an overload of intracellular Ca 2+ pools, the FAD-linked PS2 mutation M239I reduces Ca 2+ release from intracellular stores [Zatti, G., Ghidoni, R., Barbiero, L., Binetti, G., Pozzan, T., Fasolato, C., Pizzo, P., 2004. The presenilin 2 M239I mutation associated with Familial Alzheimer's Disease reduces Ca 2+ release from intracellular stores. Neurobiol. Dis. 15/2, 269–278]. We here show that in human FAD fibroblasts another PS2 mutation (T122R) reduces both Ca 2+ release and capacitative Ca 2+ entry. The observation, done in two monozygotic twins, is of note since only one of the subjects showed overt signs of disease at the time of biopsy whereas the other one developed the disease 3 years later. This finding indicates that Ca 2+ dysregulation anticipates the onset of dementia. A similar Ca 2+ alteration occurred in HeLa and HEK293 cells transiently expressing PS2-T122R. Based on these data, the “Ca 2+ overload” hypothesis in AD pathogenesis is here discussed and reformulated.