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

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.

Longitudinal evaluation of neurologic‐post acute sequelae SARS‐CoV‐2 infection symptoms

“…Imaging in these patients was unremarkable, but this phenotype warrants further investigation, including serological and CSF characterization and advanced imaging modalities, especially given recent findings on the association of certain alleles (APOE4) and presenting with severe COVID-19 or post-COVID fatigue. 23 In our study, most patients reported mild or moderate COVID-19 infection, with only 8.9% requiring hospitalization. This is consistent with previous data showing that nonhospitalized patients, many with a mild infection, still experience long-haul neuro-PASC symptoms months after infection.…”

“…We observed a rare but concerning phenotype of tremor, ataxia, and cognitive dysfunction in a subset of patients without any known prior neurologic disease. Imaging in these patients was unremarkable, but this phenotype warrants further investigation, including serological and CSF characterization and advanced imaging modalities, especially given recent findings on the association of certain alleles (APOE4) and presenting with severe COVID‐19 or post‐COVID fatigue 23 …”

Peripheral Pathways to Neurovascular Unit Dysfunction, Cognitive Impairment, and Alzheimer’s Disease

“…Recent studies in mice found that ApoE in brain pericytes regulate endothelial function by modulating basement membrane components ( Yamazaki et al, 2020 ). APOE ε 4 increases the severity of infections such as herpes simplex virus type 1 (HSV-1) ( Linard et al, 2020 ; Zhao et al, 2020 ), HIV-1 ( Corder et al, 1998 ), and SARS-CoV-2 ( Kurki et al, 2021 ) and worsens cognitive impairment.…”

Dementia and COVID-19: A Case Report and Literature Review on Pain Management

“…This is demonstrated by the evidence of vascular and aberrant immune reaction-related factors [35]. Furthermore, after contracting COVID-19, the risk of being hospitalized is doubled in patients homozygous for APOEε4, a known risk factor for AD [36], that results in a predictor of doubled risk of severe infection and of quadruple risk of mortality [37][38][39]. The so-called, COVID-19-induced "brain fog" can be long-lasting, accelerating cognitive decline in AD patients, and this may be supported by the western blotting evidence of increased levels of ACE-2 in AD patients' hippocampal tissue [40].…”