APOE4: A Culprit for the Vulnerability of COVID-19 in Alzheimer's Patients

Abstract

Apolipoprotein E4 (APOE4) is one of the primary genetic risk factors for late-onset of Alzheimer's disease (AD). While its primary function is to transport cholesterol, it also regulates metabolism, aggregation, and deposition of amyloid-β (Aβ) in the brain. The disruption in the generation and removal of Aβ in the brain is the primary cause of memory and cognitive loss and thus plays a significant role in the development of AD. In several prior genetic investigations, the APOE4 allele has been linked to higher susceptibility to severe acute respiratory syndrome (SARS-CoV-2) infection and COVID-19 mortality. However, information on the involvement of APOE4 in the underlying pathology and clinical symptoms is limited. Due to the high infection and mortality rate of COVID-19 in AD individuals, challenges have been identified in the management of AD patients during the COVID-19 pandemic. In order to provide evidence-based, more effective healthcare, it is critical to identify underlying concerns and, preferably, biomarkers. The risk variant APOE4 imparts enhanced infectivity by the underlying coronavirus SARS-CoV-2 at a cellular level, genetic level, and route level. Here we review existing advances in clinical and basic research on the AD-related gene APOE, as well as the role of APOE in AD pathogenesis, using neurobiological evidence. Moreover, the role of APOE in severe COVID-19 in Alzheimer's patients has also been reviewed.

Viral Infections, Are They a Trigger and Risk Factor of Alzheimer’s Disease?

“…During SARS-CoV-2 infection, there are potential mechanisms that may be involved in the development of AD and its corresponding sequelae, which comprise Aβ accumulation, genetic factors like the pathway of the APOE ε4, neuroinflammation (signatures such as cytokines of IL-6, IL-1, and Gal-3), and microglial activation. Some common biomarkers that can be considered for neuronal injury during COVID-19 and AD include p-tau, neurofilament light chain protein (NFL), and glial fibrillary acidic protein (GFAp) microvascular injury [ 107 , 108 , 109 , 110 , 111 , 112 ]. These are all reported to be increased in both COVID-19 patients and AD patients [ 100 , 113 ].…”

“…Establishing the viability of this model is a key step toward the rapid development of novel therapeutic strategies to ameliorate neuroinflammation and restore brain function in those suffering from the persistent cognitive dysfunction of “Long-COVID”. Using this model as a base, we could study the potential mechanisms that may be involved in the development of AD and its corresponding sequelae, which comprise Aβ accumulation, the expression of p-tau, NFL and GFAp, microvascular injury, genetic factors like the pathway of the APOE ε4, neuroinflammation (signatures such as cytokines of IL-6, IL-1, and Gal-3), and microglial activation [ 107 , 108 , 109 , 110 , 111 , 112 ]. Particularly, it could be noted that to further strengthen the knowledge of neuroinflammation during COVID-19 and its implication as a contributing factor to AD, experiments should investigate these cytokines and their effects in mouse models, such as with Tg2576 mice, which is a widely used mouse model for studying AD through the overexpression of human APP 695 along with a Swedish mutation (KM670/671NL) under a hamster prion promoter that results in an elevation of Aβ levels and amyloid plaques [ 125 ], and APP NL-F and APP NL-G-F knock-in mice, both of which express the Swedish and Iberian mutations and accumulate Aβ and recapitulate amyloid plaques, synaptic loss, and neuroinflammation through astrocytosis and microgliosis [ 126 , 127 ].…”

Viral Infections, a Trigger and Risk Factor of Alzheimer’s Disease?

“…During SARS-CoV-2 infection, there are potential mechanisms that may be involved in the development of AD and its corresponding sequelae, which comprise Aβ accumulation, genetic factors like the pathway of the APOE ε4, neuroinflammation (signatures such as cytokines of IL-6, IL-1, and Gal-3), and microglial activation. Some common biomarkers that can be considered for neuronal injury during COVID-19 and AD include p-tau, neurofilament light chain protein (NFL), and glial fibrillary acidic protein (GFAp) microvascular injury [107][108][109][110][111][112]. These are all reported to be increased in both COVID-19 patients and AD patients [100,113].…”

“…Establishing the viability of this model is a key step toward the rapid development of novel therapeutic strategies to ameliorate neuroinflammation and restore brain function in those suffering from the persistent cognitive dysfunction of "Long-COVID". Using this model as a base, we could study the potential mechanisms that may be involved in the development of AD and its corresponding sequelae, which comprise Aβ accumulation, the expression of p-tau, NFL and GFAp, microvascular injury, genetic factors like the pathway of the APOE ε4, neuroinflammation (signatures such as cytokines of IL-6, IL-1, and Gal-3), and microglial activation [107][108][109][110][111][112]. Particularly, it could be noted that to further strengthen the knowledge of neuroinflammation during COVID-19 and its implication as a contributing factor to AD, experiments should investigate these cytokines and their effects in mouse models, such as with Tg2576 mice, which is a widely used mouse model for studying AD through the overexpression of human APP 695 along with a Swedish mutation (KM670/671NL) under a hamster prion promoter that results in an elevation of Aβ levels and amyloid plaques [125], and APP NL-F and APP NL-G-F knock-in mice, both of which express the Swedish and Iberian mutations and accumulate Aβ and recapitulate amyloid plaques, synaptic loss, and neuroinflammation through astrocytosis and microgliosis [126,127].…”

Do APOE4 and long COVID-19 increase the risk for neurodegenerative diseases in adverse environments and poverty?

“…Notably, it has been recognized that Alzheimer's disease patients harboring APOE 4 are more at risk for high infectivity and worse COVID-19 outcomes (Goyal et al, 2023 ). In mice, SARS-CoV-2 can cross the blood-brain barrier through adsorptive transcytosis and this is strongly dependent on glycoproteins' sugars of the virus and targeted cell.…”