APOE4 allele gene more than doubles risk of severe COVID-19 and cerebral microhemorrhages

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Researchers from the University of Helsinki-Finland have discovered in a new study that the APOE4 allele gene more than doubles risk of severe COVID-19 besides increasing cerebral microhemorrhages related to COVID-19.

The study team also found that gene is also associate with mental fatigue related to long COVID or PASC (Post-acute Sequelae of COVID-19).
 
The 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.
 
The research team studied the genetic association between APOE and COVID-19 in Finnish biobank, autopsy and prospective clinical cohort datasets.

In line with previous work, the 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.
 
In addition, histopathological examination of brain autopsy material of 21 COVID-19 cases provided evidence that perivascular microhaemorrhages are more prevalent in APOE4 carriers.
 
The study team’s 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.
 
The study findings suggest 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 study findings were published in the peer reviewed journal: Acta Neuropathologica Communications (Springer)
https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-021-01302-7

Apolipoprotein E ε4 allele (APOE4) is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD), and it has also been linked to increased risk of other neurodegenerative conditions, such as dementia with Lewy bodies and Parkinson disease dementia [1, 2].

In addition, APOE4 has been shown to associate with increased susceptibility to SARS-CoV-2 infection and COVID-19 mortality in the UK Biobank Cohort [3, 4], and associations between APOE4 and COVID-19 have also been reported in some other candidate gene studies [5,6,7,8].

Interestingly, recent studies have revealed that similar genetic pathways are involved in AD and severe COVID-19 [9], also in direct linkage to APOE4 [10]. Furthermore, these diseases share many co-morbidities and risk factors, such as age, gender, hypertension, diabetes and obesity [11].

Damage to the cerebral microvasculature has been suggested to be a central mediator of the neurological complications often seen in hospitalised COVID-19 patients [11]. Similarly, blood–brain barrier (BBB) dysfunction and cerebrovascular pathology have been shown to be involved in APOE4-associated neurodegenerative conditions [12].

However, information on the role of APOE4 in COVID-19-associated pathology and parallel clinical manifestations remains scarce.

Here we studied the association between APOE and COVID-19 in FinnGen (https://www.finngen.fi/en) utilising the COVID-19 susceptibility GWAS release, and extended the work to include autopsy brain tissues and a prospective clinical cohort of Finnish COVID-19 patients.

The Finnish population is a genetically advantageous target to further assess initial genetic discoveries because the frequency of APOE4 is high, and its associations with related morbidity, such as AD and vascular pathology are exceptionally strong in Finland [13, 14].

figure2
Microvascular brain haemorrhages in RECOVID and AUTOPSY cohorts. a MRI showing cortical microhaemorrhages in a case with APOE ε4/ε4b MRI showing cerebellopontine microhaemorrhages in the same case as (a). c Brain subarachnoidal microhaemorrhages at autopsy in a case with APOE ε3/ε4. d Brain pontine microhaemorrhages at neuropathological examination in a case with APOE ε4/ε4e Histological H&E section showing pontine microhaemorrhages in the same case as (c). f Histological H&E section showing pontine microhaemorrhages in the same case as (d). Red arrows indicate microhaemorrhages. Scale bars represent 100 μm in (e) and (f)

Discussion

Previous studies [3, 4] showed a genetic association between APOE4 carriership and COVID-19 positivity, as well as mortality. Using Finnish biobank (FinnGen study), autopsy and clinical evidence, we confirm and extend these findings. First, we show an association between APOE4 carriership and COVID-19 patients requiring critical care. Second, our data suggests that APOE4 carriership increases the incidence of cerebral microhaemorrhages in COVID-19 patients, and that APOE4-associated COVID-19 neuropathology might be driven more by the perivascular damage than by microglial activation. Finally, our findings in the RECOVID cohort suggest that APOE4 carriership may be a risk factor for prolonged mental fatigue after severe COVID-19.

Several candidate-gene studies (Additional file 1: Supplementary Table 5a) have found an association between APOE4 and SARS-CoV-2 infection or the severity of COVID-19, whereas genome-wide association studies on COVID-19 (Additional file 1: Supplementary Table 5b) have failed to find evidence for an association between the APOE locus and COVID-19.

There are several reasons for the discrepant results, such as different definitions for cases and controls, different age distributions and different ancestries. Candidate-gene studies may be more susceptible to false positive findings and publication bias. In genome-wide association analyses, reaching the genome-wide significance threshold requires a very large sample size or a very large effect size.

The largest genome-wide association studies published were multinational and it is known that APOE4 frequency varies in different populations. Moreover, genome-wide association studies test the association of individual variants. Thus, they did not directly test the association of APOE4, just the association of APOE4 proxy variants, which may decrease power.

The populations with APOE4 carrier frequency above the global average (like the Finns or in the UK) are ideal for studying the genetic association reported here, because the effect size of APOE4 carriership for increased susceptibility to severe COVID-19 is modest, and therefore likely to be masked in more heterogeneous transethnic populations, such as in a recent global genetic mapping of COVID-19 [38].

The key limitations of this study are the low number of ICU-treated subjects in our biobank data and subjects overall in the RECOVID study, which was not adequately powered to detect an effect of APOE4 on COVID-19 severity. Additionally, the association of APOE4 with mental fatigue was not consistent, as the control group also showed it, while the HOME group did not.

Selection bias could account for the finding in the NOCOV group, since the cohort was recruited via open invitation and, thus, individuals experiencing fatigue-like cognitive symptoms may have been more eager to participate. The HOME group on the other hand showed higher mental fatigue scores in general, which suggests that factors unrelated to COVID-19 could be masking an underlying effect of APOE4. Moreover, only the subcategory of mental fatigue (which comprises questions probing the subjects’ ability to direct attention and keep focused) differed significantly between genotypes, whereas the other dimensions of the MFI-20 questionnaire did not.

Therefore, further studies with more complete test batteries are warranted to study the link of APOE genotype and cognitive symptoms. Limitations of our AUTOPSY cohort include the small number of patients with variable comorbidities, COVID-19 disease courses and mechanisms of death. When assessing haemorrhages, even small bleeds were taken into account. It is noteworthy that in Finland anticoagulation treatment was routinely used in COVID-19 patients even in the early stages of the pandemic, and the majority of the autopsied patients were treated with anticoagulants. Many of them suffered from hypoxia and had been treated in ICU for varying lengths of times, affecting the bleeding tendency in variable ways. Most importantly, APOE4 is per se associated with early mortality and cognitive decline, and if and how this is modified by COVID-19 is a question that cannot be conclusively answered by this study alone.

APOE4 is the strongest common genetic risk factor for late-onset AD, and it has also been shown to associate with cognitive decline independently of AD pathology [39]. These effects have been mechanistically connected to the APOE4-induced compromised cerebrovascular integrity including the breakdown of the BBB in both humans and animal models, mediated by inflammatory pathways in BBB-forming pericytes, as well as in neurons [30]. COVID-19 has also been shown to damage the microvasculature of the brain [26] and lead to enhanced expression of APOE at the barriers of the CNS: the choroid plexus and in astrocytes, which participate in formation of the BBB [40].

Interestingly, an in vitro study based on human-induced pluripotent stem cell (hiPSC) models has suggested that astrocytes and neurons expressing APOE4 homozygously are more vulnerable to SARS-CoV-2 infection than those with APOE3, and APOE4 astrocytes also exhibit a more severe cytopathogenic effect to SARS-CoV-2 infection, which might mediate the severity of COVID-19 [41].

However, direct viral involvement and neurotropism seem to be rare events in human subjects [26]. Furthermore, the effects of APOE in the context of COVID-19 are likely not restricted to the brain—for instance, APOE has a pro-inflammatory role also in the lungs [42], and APOE4 is a well-known risk factor for atherosclerosis and organ damage outside the brain predisposing to life-threatening vicious cycles. Thus, we hypothesise that the severe multi-organ inflammatory and coagulopathic manifestations of COVID-19 are potentiated by the effects of APOE4, and therefore APOE4 carriers might be prone to developing a more severe course of disease. Studies in larger cohorts and animal models are warranted to investigate this hypothesis.

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