Part 2 of a two-part series. Click here for Part 1.
It turns out a person’s risk associated with ApoE4 goes beyond Alzheimer’s and vascular disease. This apolipoprotein allele can also worsen infections caused by certain viruses. One of those appears to be SARS-CoV-2, the cause of COVID-19, according to two epidemiological studies. In the January 11 Gerontology, researchers led by Miguel Calero, Queen Sofia Foundation Alzheimer Research Center, Madrid, Spain, reported that aged ApoE4 carriers are more likely to show COVID-19 symptoms than ApoE3 carriers. This supports a paper in the September 16, 2020, Journals of Gerontology. Researchers led by David Melzer, University of Exeter, England, U.K., reported that older ApoE4 carriers are more likely to test positive for the virus and more likely to die from COVID-19 than are ApoE3s carriers. Why might this be?

  • People who carry two copies of ApoE4 are more likely to get infected and die with COVID-19.
  • Astrocyte-neuron co-culture boosts viral infection of each cell.
  • Infected ApoE4 neurons have shorter neurites, fewer synapses, than E3s.

In the January 4 Cell Stem Cell, researchers led by Yanhong Shi, Beckman Research Institute, Duarte, California, and Vaithilingaraja Arumugaswami, University of California, Los Angeles, reported that the new coronavirus infected more ApoE4 neurons and astrocytes than their ApoE3 counterparts in cell culture. Astrocytes stoked the fire, upping the number of infected cells in co-cultures and in astrocyte-containing brain organoids. Infected neurons degenerated, while astrocytes swelled and their nuclei broke apart. Though this may not explain why ApoE4 carriers are at higher risk of COVID-19, it suggests that they may be more prone to long-term neurological symptoms of the disease (see Part 1 of this series).

To probe how various factors, including ApoE genotype, affect the severity of a person’s COVID-19, Calero and colleagues phoned people ages 75-94 who, as part of in the Vallecas Project in Madrid, had been genotyped for ApoE. From 2011–2013, this observational cohort study tracked markers that might predict future dementia (Olarzaran et al., 2015). In April 2020, first author Teodoro del Ser Claero asked Vallecas participants if they had any COVID-19 symptoms, and learned that ApoE4 carriers were 2.4 times as likely to reply in the affirmative, and to have had a COVID-19 diagnosis.

This aligns with Melzer and colleagues’ data. They sifted through the U.K. Biobank database, which now includes COVID-19 infection data. First author Chia-Ling Kuo stratified participants based on APOE genotype. ApoE4/4 carriers were 2.2 times as likely to have tested positive or have had severe disease, and 4.3 times as likely to have died from COVID-19 than were ApoE3/3s. These differences remained even after the researchers corrected for comorbidities known to worsen COVID-19, such as dementia, hypertension, and Type 2 diabetes.

Even so, Caleb Finch, University of Southern California, Los Angeles, and Alexander Kulminski, Duke University, Durham, North Carolina, think the comorbidities may explain the association. “ApoE cluster haplotypes associate with the same morbidities from cardiovascular disease and obesity that increase vulnerability to COVID-19,” they note in a review in the same journal. The ApoE locus was first recognized as a genetic determinant of cardiovascular disease in the 1980s, through its effect on blood lipid and cholesterol levels (Sing et al., 1985). Some research even indicated ApoE4 protected people from lipophilic pathogens (Martin, 1999). But at least for COVID, the latest data suggest the opposite. “The ApoE trail, like a Moebius strip, takes us back to where we started from, four decades ago, with another view,” wrote Finch and Kulminski. “To understand how ApoE4 may increase COVID-19 infectivity and mortality, we have returned to the original associations of ApoE variants with blood lipids, vascular disease, and cognition.”

Zooming in to the cellular level may provide insight on how ApoE4 renders cells more susceptible to viruses. For example, HIV more easily penetrates human cells if they are ApoE4/4 (Burt et al., 2008). In mice, herpes simplex virus (HSV) exploits the lipoprotein to enter brain cells, leading to a higher viral burden in ApoE4 than ApoE3 transgenic mice (Burgos et al., 2006). What about SARS-CoV-2?

ApoE4 Worsens SARS-CoV-2 Damage. The virus infected neurons and astrocytes in cell culture and brain organoids. ApoE4 cells fared worse, remdesivir protected them. [Courtesy of Wang et al., Cell Stem Cell, 2021.]

Shi wondered if ApoE4 could explain the neurological effects of SARS-CoV-2 in some people. To begin with, co-first authors Cheng Wang, Mingzi Zhang, and colleagues confirmed the virus’ penchant for certain brain cells (see Part 1 of this series). They differentiated human induced pluripotent stem cells (hiPSCs) into neuronal progenitors (NPCs), neurons, astrocytes, oligodendrocyte progenitor, or brain endothelial cells, then infected them with SARS-CoV-2. Immunostaining detected the viral spike protein in less than 5 percent of NPCs, neurons, and astrocytes, which Shi called a low-grade infection. The virus also infected 60-day-old brain organoids comprising NPCs and neurons.

Astrocytes are known to spread neurotropic viruses in the CNS, including Japanese encephalitis, West Nile, and Zika viruses (Soung et al., 2018; Potokar et al., 2019). Could astrocytes stoke the COVID fire in neurons and organoids? Indeed, more neurons tested positive for SARS-CoV-2 spike protein in neuron-astrocyte co-cultures than in monoculture. The scientists also saw higher viral RNA loads in neurons from organoids that had incorporated astrocytes than in those that did not.

Wang, Zhang, and colleagues then homed in on APOE genotype. They used CRISPR/Cas9 to create isogenic cell lines from iPSCs taken from ApoE3/3 and ApoE4/4 donors. They differentiated the cells into neurons and co-cultured them with ApoE3 astrocytes for three weeks. Then they added SARS-CoV-2, using one viral particle per cell. Immunostaining revealed spike protein in all neurons within 24 hours. After 72 hours, the viral protein content in all neurons had grown, but E4 neurons had 1.5 times more than E3 neurons (see image below).

Viral Invasion. After SARS-Cov-2 infects neurons (purple, left panels), its spike protein (green) popped up within 24 hours (middle) and accumulated over 72 hours (right panel). Infected ApoE4 neurons (bottom) had more viral protein than isogenic ApoE3 lines (top). [Courtesy of Wang et al., Cell Stem Cell, 2021.]

At that point, infected cells formed fewer neurites than did uninfected cells, and the neurites were short. Infected ApoE4 cells had even fewer neurites than ApoE3 cells, and they were shorter still. Staining with Syn 1 revealed fewer synapses in both infected neurons.

What about astrocytes? More iPSC-derived ApoE4/4 astrocytes were infected than iPSC-derived ApoE3/3 cells. The former had fatter somas, longer processes, and nuclei that were more fragmented compared to infected ApoE3 cells (see image below). Taken together, these findings hint at an ApoE-dependent reaction to viral infection, with ApoE4 neurons and astrocytes more severely damaged.

Angrier Astrocytes. SARS-CoV-2-infected (red) E4 astrocyte soma (right four panels) had fragmented nuclei (blue) and grew fatter (green) than E3 astrocyte soma (left four panels) whose nuclei remained intact. [Courtesy of Wang et al., Cell Stem Cell, 2021.]

Why were E4 astrocytes worse off than the E3 cells? Jessica Young, University of Washington, Seattle, thinks it may have to do with endosomes. Of 40 genes previously identified as crucial for SARS-CoV-2 infection, two, the endosomal entry receptor ACTR2 and the ATP6AP2 ATPase, are involved in endosome function (Daniloski et al., 2021). Both are more highly expressed in ApoE4 astrocytes, which have larger early endosomes than do E3 cells (Oct 2020 news). “Proteins involved in endosomal entry and transport are more abundant in APOE4 cells, which may facilitate the cellular infectivity of the virus,” Young told Alzforum (full comment below). G. William Rebeck, Georgetown University, Washington, D.C., agreed the endosome might be involved. “The speculation that these ApoE effects may be due to differentially expressed genes related to endosomal trafficking builds on a model that has been developed across several labs over the past two decades.” (Full comment below.)

The FDA-approved drug remdesivir quelled SARS-CoV-2 infection in cultured neurons and astrocytes. When Wang, Zhang, and colleagues pretreated cells with 10 μM remdesivir two hours before adding the virus, fewer neurons and astrocytes became infected. The drug also bumped up the number and length of neurites and reduced the number of fragmented nuclei in infected astrocytes compared to vehicle treatment.

Whether this remdesivir is relevant in the clinic remain to be seen. “Remdesivir is thought to poorly enter the brain,” Rik van der Kant, Vrije Universiteit Amsterdam, and Diederik van de Beek, Amsterdam UMC, wrote in a joint comment (below). David Clifford, Washington University, St. Louis, cautioned against overinterpreting these results based on what he hears from fellow clinicians who are treating COVID-19 patients. “Clinically, remdesivir appears minimally effective and is increasingly considered unimportant in COVID-19 patient care,” he wrote. “Treating the CNS is always more challenging than treating peripheral infections.”—Chelsea Weidman Burke


  1. This is an interesting paper by Wang et al. showing that APOE4 is a genetic modifier facilitating the direct infection of SARS-CoV-2 in human iPSC-derived neurons and astrocytes. I was surprised by this. Future studies should define if APOE4 causes this phenotype through gain of toxic effects or loss of protective function.

    These findings may be linked to neurological symptoms. When SARS-CoV-2 infects neurons, diverse neurological symptoms will be induced due to neuronal damage and subsequent neuroinflammation depending on affected brain regions and neuron subtypes. Loss of smell/taste may be induced by the direct infection of neurons. However, further studies are necessary to determine if SARS-CoV-2 predominantly invades the central nervous system and sufficiently infects neurons.

    APOE4 is associated with cerebrovascular dysfunction and altered microglial activation in AD. Thus, systemic inflammation and vascular damage in COVID-19 may be aggravated in APOE4 carriers, which could possibly be linked to the pathogenesis of COVID-induced delirium. It is also important to explore how SARS-CoV-2 infection influences Aβ and tau accumulation in future studies.

    If cell surface HSPG mediates the entrance of SARS-CoV-2, APOE may influence the infectivity by modulating the HSPG-virus interaction as APOE has heparin binding regions. In addition, since lipids are major components of virus envelopes, APOE may also modulate the interaction of a virus with the cell membrane by affecting membrane lipid distributions.

    In relation to Kuo et al.’s finding that APOE4/4 carriers had worse COVID-19 outcomes (Kuo et al., 2020), it is possible that APOE4 exacerbates SARS-CoV-2 infection in peripheral tissues, including lung and blood vessels, through common mechanisms, thereby increasing the severity of COVID-19 infection.


    . ApoE e4e4 Genotype and Mortality With COVID-19 in UK Biobank. J Gerontol A Biol Sci Med Sci. 2020 Sep 16;75(9):1801-1803. PubMed.

  2. ApoE isoform-dependent SARS-CoV-2 neurotropism and cellular response

    The paper by Wang, Zhang, and colleagues suggests that ApoE4/4 neurons and astrocytes are more readily infected by SARS-CoV2 than ApoE3/3 neurons. This finding is interesting but the clinical impact remains unclear. Patients with COVID-19 may have co-existing neurological symptoms, such as ageusia and stroke, but SARS-CoV-2 itself is often not detected in postmortem brain tissue in patients with COVID-19 (e.g., Lee et al., 2020). A number of groups have evaluated the efficiency of SARS-CoV-2 to infected cultured (human) neurons, with mixed results.

    The current study adds a new twist to the story. An epidemiological study had described the ApoE4 genotype as a risk factor for severe COVID-19 (Kuo et al., 2020). This could indicate that an ApoE4 genotype benefits SARS-CoV2 infection and/or replication or affects the host immune-response to SARS-CoV-2 driving more severe COVID-19. However, it is doubtful that brain cells play a major role in these initial steps that lead to severe COVID-19. Whether ApoE4 is also associated with neurological symptoms, as the authors in the current study suggest in their discussion, has not been addressed yet in clinical studies. The authors also claim, based on their findings in iPSC-neurons and astrocytes, that remdesivir could be used to treat neurological complications in COVID-19 patients. However, as remdesivir is thought to poorly enter the brain, it is unclear whether this has any clincial implication. 

    We believe that the current findings give much food for thought. For example, it would be of interest to test if SARS-CoV-2 infection is also affected by ApoE4-genotype in (iPSC-derived) epithelial or alveolar cells. There are a lot of unknowns in this pandemic. So far there is no clear indication that COVID-19 enters the brain. However, if COVID-19 infects neurons and astrocytes in living humans and selectively causes neuronal death in ApoE4-genotypes, as suggested by this study, this is bad news for ApoE4/4 carriers who are already at higher risk for AD and possibly also severe COVID-19.

    Epidemiological data will be essential to further address this issue, before any far-reaching conclusions can be drawn.


    . Microvascular Injury in the Brains of Patients with Covid-19. N Engl J Med. 2020 Dec 30; PubMed.

    . ApoE e4e4 Genotype and Mortality With COVID-19 in UK Biobank. J Gerontol A Biol Sci Med Sci. 2020 Sep 16;75(9):1801-1803. PubMed.

  3. This is an interesting and timely work using hiPSC-derived neural models to understand the potential implications of SARS-CoV-2 infection in the brain. While neurological symptoms have been attributed to infection, the mechanisms behind these symptoms are not clear. This study uncovers several novel biological impacts: first showing that neurons are more highly infected in the presence of astrocytes, second, that APOE4 genotype cells have higher infectivity and stronger phenotypes, and finally that these cells may express higher levels of the receptors and machinery needed for endosomal entry and transport of viral particles.

    APOE4 is the strongest risk factor for development of Alzheimer’s disease as well, and likely plays a different role in the different CNS cell types in how that risk manifests on a cellular level. This study shows that to be the case in the face of the SARS-CoV-2 challenge. However, although this study shows that, in vitro, neurons and astrocytes are directly infected by SARS-CoV-2, in the human brain the role of the blood-brain barrier must be considered. The authors discuss this in the paper, however, it is still unclear whether the neurological phenotypes in patients are due to direct infection or due to neuroinflammation because of BBB breakdown. It will be necessary to follow COVID-19 survivors and monitor them for neurologic effects as they age.

  4. This fascinating study by Wang et al. further expands the already numerous roles of Apolipoprotein E (APOE) in health and disease to now include the world’s major public health challenge, COVID-19. The authors employ a variety of human iPSC lines and brain organoid systems to model the infectivity and susceptibility of various CNS cell types to SARS-CoV-2. They first confirm SARS-CoV-2 infection in human iPSC-derived neurons and astrocytes, as has been reported by several groups. Likely of more interest to the Alzheimer’s disease research community are the findings of an increased rate of SARS-CoV-2 infection, and more severe cellular responses, in neurons and astrocytes expressing the ε4 allele of APOE. As the authors themselves allude to, these data provide one potential explanation for why some individuals (i.e., those carrying APOE4), but not all COVID-19 patients, show neurological manifestations.

    Notably, a study published last year identified an association between E4 carriage and COVID-19 severity (Kuo et al., 2020). Analyzing over 400,000 individuals in the U.K. Biobank, the authors observed that ε4/ε4 individuals were more likely to be COVID-19-positive compared to ε3 homozygotes (odds ratio >2.0), and that this effect was independent of known comorbidities. Presciently, an opinion written one month earlier had raised this very possibility—that E4 may predict an individual’s propensity to manifest more severe illness with COVID-19 (Goldstein et al., 2020).

    The authors based their hypothesis on several factors that parallel questions raised by this current study. First, E4 is associated with several comorbidities that put one at higher risk for severe illness with COVID-19, including dementia, atherosclerosis, and hypertension (Mahley et al., 2009; Niu et al., 2009). Second, as severe COVID-19 is characterized by acute respiratory distress syndrome (ARDS), they note that ApoE is expressed in several cell types in the lung, and that ApoE has been shown to act as a concentration-dependent activation signal in asthmatic individuals. Third, harkening back to the cytokine storm that drives ARDS, possession of E4 has been associated with an amplified innate immune response (e.g., higher cytokine levels and hyperthermia in E4+ subjects injected with LPS (Gale et al., 2014). Last, and perhaps most notably, APOE has an established role in modulating infectivity and symptomology of several common viruses, including HIV, hepatitis C virus (HCV), and herpes simplex virus 1 (reviewed by Kuhlman et al., 2010). Further, this modulatory role of APOE includes effects on cognitive processes (e.g., E4 allele status modifies the relationship between herpes simplex virus 1 (HSV-1) and total infectious burden and cognitive function (Zhao et al., 2020)). 

    So, does the pleiotropic ApoE protein simply modulate entry into the cell, or does it regulate pathways downstream of entry, including replication, trafficking, or associated damage? Although the current study does not dissect these two factors, Wang et al.’s data suggest that E4 results in both increased infection rate (higher percent of spike-protein-positive cells) and more exaggerated viral-associated neuropathology (neuritic degeneration, synapse loss, enlarged cell bodies, and syncytia formation).

    How might ApoE modulate these processes? In regard to entry, the literature may provide some clues in that both ApoE and several viruses compete for entry into the cell via heparin sulfate proteoglycans (HSPGs). Interestingly, ACE2 receptor-mediated entry of SARS-CoV-2 into a cell requires heparan sulfate as a co-factor (Zhang et al., 2020). Perhaps the increased infectivity observed in the presence of APOE4 is a result of isoform-specific differences in ApoE availability and/or binding to HSPGs.

    In regard to replication, one potential explanation may trace back to ApoE’s essential role as a lipid carrier. Lipid droplets, neutral lipid-rich intracellular organelles that regulate lipid storage and utilization, are used as a replication center for several viruses, including HCV, dengue virus, and rotavirus (Dias et al., 2020). Several groups, including our own, have described increases in lipid droplet formation and metabolism in cells expressing E4 (reviewed by Farmer et al., 2020). Perhaps these organelles—and their differential regulation by E4—provide a link to the SARS-CoV-2 dynamics in neurons and astrocytes described here by Wang et al.?

    Speaking of astrocytes, the authors show that the rate of infection was about twofold higher in iPSC-derived astrocytes than in neurons (although this reflects a change from only ~1 percent to ~2 percent spike-protein-positive cells). Also of note was that the presence of astrocytes significantly increased the infection rates of neurons, both in two-dimensional co-culture systems and in three-dimensional brain organoid models. Knowing that astrocytes (normally) secrete substantially higher levels of ApoE than neurons, this raises several questions. Are cells that synthesize more ApoE at higher risk for SARS-CoV-2 infection (i.e., does infectivity and/or cellular pathology correlate with local ApoE concentrations)?

    And what about microglia? While the study here by Wang et al. shows exciting results in astrocytes, neurons, neural progenitor cells, and oligodendrocyte progenitor cells, the jury is still out on a central player in the CNS, and a known ApoE factory (at least upon activation). There is a growing consensus that microglia-derived ApoE is central to Alzheimer’s disease pathogenesis (Keren-Shaul et al., 2017; Krasemann et al., 2017Shi et al., 2017). So how do these brain-resident immune cells respond to SARS-CoV-2? Does the dramatic upregulation of ApoE during microglia activation play a role? Do microglial ApoE-related pathways help determine which individuals infected with COVID-19 will suffer neurological symptoms and which won’t?

    As with any interesting finding, many more questions now arise. Given the ubiquitous and persistent threat of COVID-19, and the high population frequency and dramatic AD risk associated with APOE4, answering those questions will be an important and pressing new challenge for researchers.


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  5. These studies did not examine brain capillary pericytes, which, unlike endothelial cells or other perivascular cell types, express ACE2, the receptor for SARS-CoV-2 (He et al., 2020). Within pericytes of APOE4 carriers, APOE and NFAT are selectively dysregulated (Blanchard et al., 2020), and APOE4 leads to accelerated breakdown of the blood-brain barrier which is in part maintained by brain capillary pericytes (Montagne et al., 2020). Infection or dysfunction of these pericytes might cause white matter disruptions in addition to various brain vasculature problems.


    . Pericyte-specific vascular expression of SARS-CoV-2 receptor ACE2 – implications for microvascular inflammation and hypercoagulopathy in COVID-19. bioRxiv, July 20, 2020

    . Reconstruction of the human blood-brain barrier in vitro reveals a pathogenic mechanism of APOE4 in pericytes. Nat Med. 2020 Jun;26(6):952-963. Epub 2020 Jun 8 PubMed.

    . APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline. Nature. 2020 May;581(7806):71-76. Epub 2020 Apr 29 PubMed.

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News Citations

  1. How Does COVID-19 Affect the Brain?
  2. In Astrocytes, ApoE4 Bungles Endocytosis, PICALM Picks Up the Slack

Paper Citations

  1. . The Vallecas Project: A Cohort to Identify Early Markers and Mechanisms of Alzheimer's Disease. Front Aging Neurosci. 2015;7:181. Epub 2015 Sep 30 PubMed.
  2. . Role of the apolipoprotein E polymorphism in determining normal plasma lipid and lipoprotein variation. Am J Hum Genet. 1985 Mar;37(2):268-85. PubMed.
  3. . APOE alleles and lipophylic pathogens. Neurobiol Aging. 1999 Jul-Aug;20(4):441-3. PubMed.
  4. . Apolipoprotein (apo) E4 enhances HIV-1 cell entry in vitro, and the APOE epsilon4/epsilon4 genotype accelerates HIV disease progression. Proc Natl Acad Sci U S A. 2008 Jun 24;105(25):8718-23. PubMed.
  5. . Effect of apolipoprotein E on the cerebral load of latent herpes simplex virus type 1 DNA. J Virol. 2006 Jun;80(11):5383-7. PubMed.
  6. . Viral Encephalitis and Neurologic Diseases: Focus on Astrocytes. Trends Mol Med. 2018 Nov;24(11):950-962. Epub 2018 Oct 9 PubMed.
  7. . Astrocytes in Flavivirus Infections. Int J Mol Sci. 2019 Feb 6;20(3) PubMed.
  8. . Identification of Required Host Factors for SARS-CoV-2 Infection in Human Cells. Cell. 2021 Jan 7;184(1):92-105.e16. Epub 2020 Oct 24 PubMed.

Further Reading


  1. . Biological Factors Linking ApoE ε4 Variant and Severe COVID-19. Curr Atheroscler Rep. 2020 Oct 2;22(11):70. PubMed.
  2. . Lipoprotein(a) and Its Potential Association with Thrombosis and Inflammation in COVID-19: a Testable Hypothesis. Curr Atheroscler Rep. 2020 Jul 25;22(9):48. PubMed.
  3. . Neurobiochemical Cross-talk Between COVID-19 and Alzheimer's Disease. Mol Neurobiol. 2021 Mar;58(3):1017-1023. Epub 2020 Oct 19 PubMed.
  4. . Neurobiology of COVID-19. J Alzheimers Dis. 2020;76(1):3-19. PubMed.
  5. . Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer's disease to AIDS. J Lipid Res. 2009 Apr;50 Suppl:S183-8. PubMed.

Primary Papers

  1. . ApoE-Isoform-Dependent SARS-CoV-2 Neurotropism and Cellular Response. Cell Stem Cell. 2021 Feb 4;28(2):331-342.e5. Epub 2021 Jan 4 PubMed.
  2. . Residence, Clinical Features, and Genetic Risk Factors Associated with Symptoms of COVID-19 in a Cohort of Older People in Madrid. Gerontology. 2021 Jan 11;:1-9. PubMed.
  3. . ApoE e4e4 Genotype and Mortality With COVID-19 in UK Biobank. J Gerontol A Biol Sci Med Sci. 2020 Sep 16;75(9):1801-1803. PubMed.
  4. . The ApoE Locus and COVID-19: Are We Going Where We Have Been?. J Gerontol A Biol Sci Med Sci. 2021 Jan 18;76(2):e1-e3. PubMed.