ApoE4, a strong genetic risk factor for Alzheimer’s disease, has been associated with increased risk for severe COVID-19. However, it is unclear whether ApoE4 alters COVID-19 susceptibility or severity and the role of direct viral infection in brain cells remains obscure.

In this paper, published in Cell Stem Cells, the Authors tested the neurotropism of SARS-CoV2 in human induced pluripotent stem cell (hiPSC) models and observed low-grade infection of neurons and astrocytes that is boosted in neuron-astrocyte co-cultures and organoids.

They then generated isogenic ApoE3/3 and ApoE4/4 hiPSCs and found an increased rate of SARS-CoV-2 infection in ApoE4/4 neurons and astrocytes. ApoE4 astrocytes exhibited enlarged size and elevated nuclear fragmentation upon SARS-CoV-2 infection.

Finally, it was shown that remdesivir treatment prevents SARS-CoV2 infection of hiPSCneurons and astrocytes.

These findings suggest that ApoE4 may play a causal role in COVID-19
severity. Understanding how risk factors impact COVID-19 susceptibility and severity will help us understand potential long-term effects in different patient populations.