Interrogating the role of APOE4 in Alzheimer’s disease and Down syndrome using human induced pluripotent stem cells (hiPSC)‐derived cerebral organoids

Nearly all adults with Down syndrome (DS) will develop Alzheimer’s disease (AD) brain pathology by their 40s, and most will become demented by age 50‐60. The inheritance of the apolipoprotein E (apoE) ε4 allele (APOE4) is the strongest risk factor for AD other than age, whereas the ε3 allele (APOE3) does not change AD risk. ApoE is a cholesterol carrier protein, and APOE4‐positive astrocytes have been demonstrated to exhibit impaired cholesterol transport. ApoE4 has also been shown to catalyze amyloid‐beta (Aβ) polymerization. As such, the APOE4 genotype is associated with earlier and more rapid cognitive decline in individuals with DS. Understanding the molecular changes in AD neuropathology resulting from APOE4 in DS would aid in the development of therapies to alleviate dementia risk, especially in individuals with DS.