# ApoE4 Homozygosity Is Associated With Increased Microglia Activation in Fatal COVID‐19

## TL;DR

APOE4 genotype is linked to increased microglia activation in the cerebellum of fatal COVID-19 cases, especially in men.

## Contribution

This study identifies a novel association between APOE4 homozygosity and microglial activation in the cerebellum during fatal COVID-19.

## Key findings

- APOE4 carriers showed increased microglial activation in the cerebellum in fatal COVID-19 cases.
- Microglial activation was more pronounced in men compared to women with the APOE4 genotype.
- Higher viral protein detection in lungs correlated with microglial activation in the cerebellum.

## Abstract

Apolipoprotein E4 (APOE4) is recognized as a major risk factor for disorders such as Alzheimer's disease and may play a role in the dysregulation of microglia in various neurodegenerative conditions. APOE variants have also been proposed as potential risk factors for severe outcomes in COVID‐19. While fatal COVID‐19 may be associated with increased neuroinflammatory changes especially in the brainstem, it is not fully understood whether APOE4 contributes to the latter. In this study, we determined the APOE genotype from archival paraffin tissue blocks of 38 patients with fatal COVID‐19 who died either from infection with ancient SARS‐CoV‐2 or with the Omicron variant. Our data show an overrepresentation of APOE4 carriers during the first infection wave. Immunohistochemical staining of HLA‐DR/DQ/DP was performed to determine the abundance of activated microglia in different brain regions. This analysis displayed a correlation of APOE4/E4 with increased microglial activation in the cerebellum in fatal COVID‐19. Our data show a significant association between the APOE4 genotype and increased microglial activation, particularly affecting men who exhibit more microglial activity than women. In parallel, staining of SARS‐CoV‐2 nucleocapsid protein was used to assess the infection in the corresponding lung tissues. We found that a higher abundance of virus protein detection in the lungs was correlated with activation of microglia in the cerebellum in the latter cohort. Our work suggests that the cerebellum should be included when studying the impact of infectious diseases on the brain.