Recent investigations of modeling FAD with patient-specific iPSCs showed relatively late pathological manifestations of AD related to APP metabolism, Aβ accumulation or tau phosphorylation in neuronal or glia cells [15–19, 21, 22]. Previous studies have reported premature differentiation of NPCs in PSEN1−/− mice [33]. It has been reported in vitro that NPCs isolated from 4 to 8-week-old PSEN1ΔE9 transgenic mouse brains exhibited reduction in self-renewal capacity and premature neuronal differentiation [34]. These research findings in mouse models indicated that premature neuronal differentiation might occur during early neurogenesis in AD patients. In the current study, we focused on earlier cellular and molecular changes, which could be identified uniquely utilizing AD patient-specific iPSCs. Thus, we propose that the premature neuronal differentiation, along with enhanced apoptosis and reduced cell growth, would give rise to the progressive depletion of the NPC pool, which ultimately causes neuronal loss in the brain of AD patients. The proposal is consistent with the recent report that cell number change in the certain brain region is closely related to patients with AD or other types of dementia [10].
