Human-induced pluripotent stem cells as a model for studying sporadic Alzheimer’s disease

•Description of induced pluripotent stem cells derived models forsporadic Alzheimer’s disease.•Discussion on sources of variation related to studies with pluripotent stem cells.•Description of advanced models for studying sporadic Alzheimer’s disease with increased clinical translatability. The discovery of induced pluripotent stem cell (iPSC) technology has the potential to accelerate scientific research for Alzheimer’s disease (AD). iPSCs are therefore increasingly considered for AD modeling and drug development. Nevertheless, most of the work conducted so far has mainly focused on iPSC models from patients with familial AD (fAD), while actually sporadic AD (sAD) is more prevalent and represents over 90% of the AD cases in the population. The development of more sAD models is therefore key for studying this multifactorial disorder. In fact, probing the unique genomes of sAD patients and their interaction with AD-associated environmental factors could contribute to a better understanding of this disease. However, initial iPSC-based models for sAD have shown a high degree of variability and inconsistencies in terms of AD hallmarks. In this review, we provide an overview of the studies that have been conducted for sAD so far. In addition, we critically assess important sources of variability related to the model in addition to those that might be explained by the heterogeneous nature of sAD. These considerations might aid in developing more consistent iPSC models of sAD, which could help in developing a better understanding of the molecular mechanisms underlying the disease.