The course of SARS-CoV-2 infection varies greatly and ranges from asymptomatic infections to lethal cases. Now, Ostendorf et al. find that common variants of APOE — a gene involved in lipid metabolism that is also linked to Alzheimer disease, atherosclerosis and cancer metastasis — could partially explain the variation in SARS-CoV-2 outcome.

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In a murine model of SARS-CoV-2 infection, infected mice that were homozygous for the human APOE alleles APOE2 or APOE4 — which are collectively present in approximately 3% of the human population — showed elevated viral loads and markedly poorer survival outcomes relative to those with the APOE3 variant. Mechanistic data suggested that the detrimental effects of APOE2 and APOE4 are caused by impaired adaptive immune responses and enhanced viral entry, as early in the course of infection, APOE2 and APOE4 mice showed depletion of major lymphoid populations and the downregulation of genes involved in T cell and B cell activation in the lungs.

Analysis of human data in the UK Biobank supported a role for APOE in modulating SARS-CoV-2 risk, as individuals homozygous for the APOE4 variant showed a more than two-fold greater mortality rate over those homozygous for APOE3, and individuals homozygous for APOE2 also experienced worse survival outcomes — mirroring the mouse experimental findings. Further studies are needed to determine whether the APOE genotype could be used for risk stratification and to inform therapeutic approaches for individual patients.

Original reference: Nature (2020)