APOE4 impacts cortical neurodevelopment and alters network formation in human brain organoids

Apolipoprotein E4 (APOE4) is the leading genetic risk factor for Alzheimer’s disease. While most studies examine the role of APOE4 in aging, APOE4 causes persistent changes in brain structure as early as infancy and is associated with altered functional connectivity that extends beyond adolescence. Here, we used human induced pluripotent stem cell (iPSC) derived cortical and ganglionic eminence organoids (COs and GEOs) to examine APOE4’s influence during cortical development of excitatory and inhibitory neurons. We show that APOE4 reduced cortical neurons and increased glia by promoting gliogenic transcriptional programs. In contrast, increased proliferation and differentiation of GABAergic progenitors resulted in early and persistent increases in GABAergic neurons. Multi-electrode array recordings in assembloids revealed that APOE4 disrupted neural network function resulting in heightened excitability and synchronicity. Together, our data provides new insights on how APOE4 influences cortical neurodevelopmental processes and network formation.