Modelling Sporadic Alzheimer's Disease Using Induced Pluripotent Stem Cells

Neurochem Res. 2018 Dec;43(12):2179-2198. doi: 10.1007/s11064-018-2663-z. Epub 2018 Nov 1.


Developing cellular models of sporadic Alzheimer's disease (sAD) is challenging due to the unknown initiator of disease onset and the slow disease progression that takes many years to develop in vivo. The use of human induced pluripotent stem cells (iPSCs) has revolutionised the opportunities to model AD pathology, investigate disease mechanisms and screen potential drugs. The majority of this work has, however, used cells derived from patients with familial AD (fAD) where specific genetic mutations drive disease onset. While these provide excellent models to investigate the downstream pathways involved in neuronal toxicity and ultimately neuronal death that leads to AD, they provide little insight into the causes and mechanisms driving the development of sAD. In this review we compare the data obtained from fAD and sAD iPSC-derived cell lines, identify the inconsistencies that exist in sAD models and highlight the potential role of Aβ clearance mechanisms, a relatively under-investigated area in iPSC-derived models, in the study of AD. We discuss the development of more physiologically relevant models using co-culture and three-dimensional culture of iPSC-derived neurons with glial cells. Finally, we evaluate whether we can develop better, more consistent models for sAD research using genetic stratification of iPSCs and identification of genetic and environmental risk factors that could be used to initiate disease onset for modelling sAD. These considerations provide exciting opportunities to develop more relevant iPSC models of sAD which can help drive our understanding of disease mechanisms and identify new therapeutic targets.

Keywords: Environmental risk factors; Genetic stratification; Glial cells; Induced pluripotent stem cells; Neurons; Sporadic Alzheimer’s disease.

Publication types

  • Review

MeSH terms

  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Cell Culture Techniques / methods*
  • Cells, Cultured
  • Coculture Techniques / methods
  • Humans
  • Induced Pluripotent Stem Cells / pathology
  • Induced Pluripotent Stem Cells / physiology*
  • tau Proteins / genetics
  • tau Proteins / metabolism


  • Amyloid beta-Peptides
  • MAPT protein, human
  • tau Proteins