Mutations in presenilins 1 and 2 (PS1 and PS2) are responsible for approximately 40% of all early onset familial Alzheimer's disease (FAD) monogenic cases. Presenilins (PSs) function as the catalytic subunit of γ-secretase and support cleavage of the amyloid-β protein precursor (AβPP). We previously discovered that PSs also function as passive endoplasmic reticulum (ER) calcium (Ca 2+) leak channels and that most FAD mutations in PSs affected their ER Ca 2+ leak function. To further validate the relevance of our findings to human disease, we here performed Ca 2+ imaging experiments with lymphoblasts established from FAD patients. We discovered that most FAD mutations in PSs disrupted ER Ca 2+ leak function and resulted in increased ER Ca 2+ pool in human lymphoblasts. However, we found that a subset of PS1 FAD mutants supported ER Ca 2+ leak activity, as ER Ca 2+ pool was unaffected in lymphoblasts. Most of the “functional” mutations for ER Ca 2+ leak were clustered in the exon 8–9 area of PSEN1 gene and segregated with the cotton wool plaques and spastic paraparesis clinical phenotype occasionally observed in PS1 FAD patients. Our findings with the “functional” and “non-functional” PS1 FAD mutants were confirmed in Ca 2+ rescue experiments with PS double-knockout mouse embryonic fibroblasts. Based on the combined effects of the PS1 FAD mutations on ER Ca 2+ leak and γ-secretase activities we propose a model that explains the heterogeneity observed in FAD. The proposed model has implications for understanding the pathogenesis of both familial and sporadic AD.