APOE4 Associated With Increased COVID-19 Infection Susceptibility, Severity


The SARS-CoV-2 infection was observed in pluripotent stem cells, as well as APOE4 and APOE3 neurons and astrocytes.

Yanhong Shi, PhD, director, Division of Stem Cell Biology, City of Hope

Yanhong Shi, PhD

Recent study data out of an independent biomedical research and treatment center called City of Hope suggest that APOE4, a gene implicated in an increased risk for Alzheimer disease, may also increase an individual’s susceptibility to COVID-19, as well as increased severity of the infection.

The results from the research were published in the journal Cell Stem Cell. The findings suggest that, when compared to the APOE3 pluripotent stem cells (iPSCs), APOE4 cells showed a significantly higher susceptibility to COVID-19 and more damage inflicted on their neurons and astrocytes.

"Our study provides a causal link between the Alzheimer's disease risk factor ApoE4 and COVID-19 and explains why some (e.g., APOE4 carriers) but not all COVID-19 patients exhibit neurological manifestations," Yanhong Shi, PhD, director, Division of Stem Cell Biology, City of Hope, and co-corresponding author, said in a statement.2 "Understanding how risk factors for neurodegenerative diseases impact COVID-19 susceptibility and severity will help us to better cope with COVID-19 and its potential long-term effects in different patient populations."

READ MORE: Reflections on COVID-19: What We Know About the Neurologic Symptoms

The study was originally conducted based on an interest in assessing how COVID-19 infection affects the human brain, in part due to the symptoms of the disease, such as loss of smell and taste, might have potential neurological effects. Additionally, the disease has been linked to neurological conditions such as stroke and migraine.

Shi and colleagues used iPSCs to create neurons and astrocytes, and then infected both cells with the SARS-CoV-2 virus, revealing that they were susceptible to the disease. Then, using 3D brain tissue models, called organoids, both with and without the astrocytes. This led to the observation that astrocytes actually amplified the infection. “Consistent with our findings in APOE4 neurons, we observed a statistically significant increase in the percentage of spike+ [SARS-CoV-2 spike protein-positive] cells in APOE4 astrocytes, compared to that in APOE3 astrocytes,” they wrote.

When measuring astrocyte soma size, the group found that spike+ APOE4 astrocytes had increased soma size and process length compared to their APOE3 counterparts. This, Shi et al noted, implied that APOE4 astrocytes react differently upon SARS-CoV-2 viral infection. As well, the APOE4 astrocytes displayed more fragmented nuclei after viral infection.

The next step in the process is anticipated to be the continuation of the study of the impact that COVID-19 has on the brain to further understand the potential long-term neurological impacts like severe headaches experienced by some months after the initial infection.

"COVID-19 is a complex disease, and we are beginning to understand the risk factors involved in the manifestation of the severe form of the disease," said Vaithilingaraja Arumugaswami, PhD, member, UCLA Broad Stem Cell Research Center, and co-corresponding author, in a statement. "Our cell-based study provides a possible explanation as to why individuals with Alzheimer's' disease are at increased risk of developing more severe COVID-19 symptoms."

A version of this story was originally published on ContagionLive.

1. Wang C, Zhang M, Garcia G, et al. ApoE-Isoform-Dependent SARS-CoV-2 Neurotropism and Cellular Response. Cell Stem Cell. 2020.28(2):331-342. doi: 10.1016/j.stem.2020.12.018.
2. Researchers explore link between 'Alzheimer's gene' and COVID-19. News release. February 3, 2021. Accessed February 5, 2021. eurekalert.org/pub_releases/2021-02/coh-rel020321.php
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