# APOE ε4 associates with increased risk of severe COVID-19, cerebral microhaemorrhages and post-COVID mental fatigue: a Finnish biobank, autopsy and clinical study

## TL;DR

This study shows that the APOE ε4 gene variant increases the risk of severe COVID-19, brain microhaemorrhages, and mental fatigue after recovery.

## Contribution

The study provides the first evidence that APOE4 may contribute to severe COVID-19 outcomes through cerebrovascular damage.

## Key findings

- APOE4 carriers are more likely to experience severe COVID-19 requiring intensive care.
- APOE4 carriers show more cerebral microhaemorrhages in brain autopsies.
- APOE4 carriers report higher mental fatigue six months after recovering from COVID-19.

## Abstract

Apolipoprotein E ε4 allele (APOE4) has been shown to associate with increased susceptibility to SARS-CoV-2 infection and COVID-19 mortality in some previous genetic studies, but information on the role of APOE4 on the underlying pathology and parallel clinical manifestations is scarce. Here we studied the genetic association between APOE and COVID-19 in Finnish biobank, autopsy and prospective clinical cohort datasets. In line with previous work, our data on 2611 cases showed that APOE4 carriership associates with severe COVID-19 in intensive care patients compared with non-infected population controls after matching for age, sex and cardiovascular disease status. Histopathological examination of brain autopsy material of 21 COVID-19 cases provided evidence that perivascular microhaemorrhages are more prevalent in APOE4 carriers. Finally, our analysis of post-COVID fatigue in a prospective clinical cohort of 156 subjects revealed that APOE4 carriership independently associates with higher mental fatigue compared to non-carriers at six months after initial illness. In conclusion, the present data on Finns suggests that APOE4 is a risk factor for severe COVID-19 and post-COVID mental fatigue and provides the first indication that some of this effect could be mediated via increased cerebrovascular damage. Further studies in larger cohorts and animal models are warranted.

The online version contains supplementary material available at 10.1186/s40478-021-01302-7.