The presenilin genes (PSEN1 and PSEN2) are mainly responsible for causing 
early-onset familial Alzheimer's disease, harboring ~300 causative mutations, 
and representing ~90% of all mutations associated with a very aggressive disease 
form. Presenilin 1 is the catalytic core of the γ-secretase complex that 
conducts the intramembranous proteolytic excision of multiple transmembrane 
proteins like the amyloid precursor protein, Notch-1, N- and E-cadherin, LRP, 
Syndecan, Delta, Jagged, CD44, ErbB4, and Nectin1a. Presenilin 1 plays an 
essential role in neural progenitor maintenance, neurogenesis, neurite 
outgrowth, synaptic function, neuronal function, myelination, and plasticity. 
Therefore, an imbalance caused by mutations in presenilin 1/γ-secretase might 
cause aberrant signaling, synaptic dysfunction, memory impairment, and increased 
Aβ42/Aβ40 ratio, contributing to neurodegeneration during the initial stages of 
Alzheimer's disease pathogenesis. This review focuses on the neuronal 
differentiation dysregulation mediated by PSEN1 mutations in Alzheimer's 
disease. Furthermore, we emphasize the importance of Alzheimer's disease-induced 
pluripotent stem cells models in analyzing PSEN1 mutations implication over the 
early stages of the Alzheimer's disease pathogenesis throughout neuronal 
differentiation impairment.