Alzheimer’s disease (AD) is the most common neurodegenerative disease and the main reason for dementia. Besides years of research there is still no cure, no prevention and no slow-down for the disease and the treatment remains symptomatic. Even though we do know many genes involved and many pathways have been unraveled that trigger neurodegeneration, we still don’t fully understand its underlying biology – probably because we are still lacking a disease model that fully recapitulates AD pathology. Using human induced pluripotent stem cells (hiPSCs) in concert with genome editing techniques I created an isogenic in vitro disease model that allows the study of the early-onset, familial form of Alzheimer’s disease (fAD) and its pathology. The first part of this thesis solely focuses on the generation of these isogenic lines, each of them carrying mutations in the amyloid precursor protein known to cause fAD. The second part characterizes the isogenic lines in a pluripotent state as well as being differentiated into cortical neurons to see if a phenotype seen in human AD pathology can be detected in this in vitro model. Finally systems biology analysis is performed to detect and unravel molecular players and signaling pathways underlying the disease.
