COVID-19 and the impact on Alzheimer’s disease pathology

Abstract

Coronavirus disease 2019 (COVID-19) has rapidly escalated into a global pandemic that primarily affects older and immunocompromised individuals due to underlying clinical conditions and suppressed immune responses. Furthermore, COVID-19 patients exhibit a spectrum of neurological symptoms, indicating that COVID-19 can affect the brain in a variety of manners. Many studies, past and recent, suggest a connection between viral infections and an increased risk of neurodegeneration, raising concerns about the neurological effects of COVID-19 and the possibility that it may contribute to AD onset or worsen already existing AD- pathology through inflammatory processes given that both COVID-19 and Alzheimer’s disease (AD) share pathological features and risk factors. This leads us to question whether COVID-19 is a risk factor for AD and how these two conditions might influence each other. Considering the extensive reach of the COVID-19 pandemic and the devastating impact of the ongoing AD pandemic, their combined effects could have significant public health consequences worldwide.

Graphical abstract:

Overview of potential mechanisms by which SARS-CoV-2 infection can exacerbate molecular and cellular pathways associated with neurodegenerative diseases including Alzheimer’s disease.

Coronavirus disease 2019 (COVID-19) has rapidly escalated into a global pandemic. Many studies suggest a connection between viral infections and an increased risk of neurodegeneration, raising concerns about the neurological effects of COVID-19 and the possibility that it may contribute to AD onset or worsen already existing AD- pathology through inflammatory processes given that both. We here review the question whether COVID-19 is a risk factor for AD and how these two conditions might influence each other. The schematic shows an overview of potential mechanisms by which SARS-CoV-2 infection can exacerbate molecular and cellular pathways associated with neurodegenerative diseases including Alzheimer’s disease.

Introduction

1. Alzheimer’s disease

Alzheimer’s disease (AD) is the leading cause of age- related dementia and is defined as a slowly progressive neurodegenerative disease. It is characterized by an initial impaired ability to form recent memories, inevitably affecting all intellectual functions and impairing the ability to perform daily activities. The neuropathological hallmarks of AD can be characterized by the accumulation of amyloid plaques, neurofibrillary tangles (NFTs), neuronal loss and neuroinflammation (De-Paula et al., 2012). The presymptomatic stages and neuropathology can occur years before initial symptom onset and involve early pathological changes in the cortex and hippocampus (Dubois et al., 2016; Kumar et al., 2022). Extracellular amyloid plaques, predominantly present in the neocortex and hippocampus (Casanova et al., 1993), are due to the accumulation of amyloid beta (Aβ) peptides as a result of amyloidogenic processing involving the sequential proteolytic cleavage of amyloid precursor protein (APP) by the enzymes β- and γ-secretase (Chen et al., 2017; Joshi & Wang, 2015). NFTs are abnormal filaments composed of misfolded and abnormally hyperphosphorylated tau that can accumulate in the axon and dendrites resulting in neuronal loss due to increased levels of the tau protein. Accumulation of NFTs occurs in the entorhinal cortex, the CA1 and subiculum regions of the hippocampus, whereas other regions such as CA3 and dentate gyrus seem to be unaffected. Furthermore, other limbic structures such as the amygdala contain a high density of tangles (Arnold et al., 1991; Casanova et al., 1993)

Aβ accumulation results in glial cell activation (Selkoe, 2002) that has also been demonstrated to play a role by contributing to inflammation observed in AD (González-Reyes et al., 2017; McGeer et al., 1987; Shao et al., 1997; Wang et al., 2015). Other studies have demonstrated the co-localization of glial cells like astrocytes and microglia with Aβ deposition (Bolmont et al., 2008; Frackowiak et al., 1992). Microglia are the resident immune cells in the central nervous system (CNS), constituting around 10% of CNS cells (Lawson et al., 1990, 1992) and arise from progenitor cells in the embryonic yolk sac during development (Ginhoux et al., 2013). They monitor the CNS and play a role in homeostasis as well as respond to injury and inflammation. Under normal conditions they exist in a resting state that allows them to surveil the brain parenchyma (Nimmerjahn et al., 2005; Tremblay et al., 2011). When activated, microglia can undergo a series of morphological changes associated with a transition from an arborized state to a more ameboid morphology with a larger soma and fewer branched processes (Colonna & Butovsky, 2017; Woodburn et al., 2021). In response to CNS injury or infection, activated microglia respond by producing proinflammatory cytokines/chemokines that promote neuroinflammation and/or release anti-inflammatory cytokines that aid in tissue repair and angiogenesis (Solito & Sastre, 2012; Tang & Le, 2016; Wang et al., 2015; Colonna & Butovsky, 2017; Woodburn et al., 2021). During the progression of AD, these reactive inflammatory microglia also have the capacity to convert other glial cells such as resting astrocytes to reactive astrocytes (Liddelow et al., 2017). Astrocytes are the most abundant glial cell type in the CNS (Colombo & Farina, 2016). In a healthy environment, they perform several roles including ion homeostasis, synapse remodeling, neurotransmission, oxidative stress regulation, and maintenance and permeability of the blood brain barrier (BBB) (Abbott et al., 2006; Y. Kim et al., 2019; Scimemi, 2019; Sofroniew, 2009). Upon activation, astrocytes as well as microglia secrete pro-inflammatory cytokines: interferon-γ (IFN-γ), tissue necrosis factor-α (TNF-α), interleukins-1 and 6 (IL-1 and IL-6) which can induce neuronal damage and the production of Aβ (Blasko et al., 2000; Zhao et al., 2011).

2. Alzheimer’s disease hypothesis

The underlying mechanisms by which accumulation of Aβ within the brains has not definitively been identified; however, there are several causes associated with this process. The amyloid hypothesis proposes that there is an increase of Aβ, due to the accumulation of its peptides (Aβ40 and Aβ42). With the accumulation of these peptides, there is also an increase in Aβ42/Aβ40 ratio leading to fibril formation and resulting neurotoxicity, neuronal death and tau pathology (Paroni et al., 2019). This version of the amyloid hypothesis is more closely associated with inherited/familial forms of AD associated with genetic mutations that affect processing and production of Aβ. It is important to note that amyloid deposits are also found in the aged brain (Imhof et al., 2007) but given that plaque accumulation can occur years before clinical symptoms, it is possible that cognitively normal patients with amyloid deposits may have had early preclinical AD.

3. Risk factors of Alzheimer’s disease

Although many theories have been proposed to explain the development of AD, no single theory has gained universal acceptance. As a result, AD is proposed to be a more complex multifactorial disease where multiple risk factors are likely to contribute to its onset. AD can be divided into early-onset AD (EOAD) and late-onset AD (LOAD). EOAD can either be familial or sporadic, while LOAD is sporadic. Familial AD is a rare form of AD only accounting for 1–6% of cases usually associated with family members in more than one generation with AD, and usually occurring earlier in life from 30–65 years (Kvello-Alme et al., 2019). All familial cases of AD are linked to mutations in genes such as APP (Goate et al., 1991) Presenilin-1 (PSEN-1) (St George et al., 1992) and Presenilin-2 (PSEN-2) (Sherrington et al., 1996).

While mutations in disease-associated genes are thought to influence onset of familial AD; other genetic polymorphisms have been associated with the more common sporadic form. In LOAD, age is the most important risk factor (Henderson, 1988) as cases usually develop after 65 years of age (Guerreiro & Bras, 2015). Arguably the strongest genetic risk factor in LOAD is the apolipoprotein E (APOE) gene. Each person has two APOE alleles, and human APOE has three different alleles: ε2, ε3, and ε4. Alleles ε2, ε3 are associated with a lower risk of disease or are protective, while ε4 is associated with an increased risk (Kim et al., 2009). The presence of one ε4 allele increases the risk of AD by threefold, while the presence of two ε4 alleles increases risk by eightfold (Bertram et al., 2007). Additionally, ε4 is also associated with an earlier age of disease onset (Corder et al., 1993). A definite sex-linked effect for APOE has not been established; however, APOE4 carrier status and cerebrospinal fluid (CSF) tau levels have been more strongly correlated in women than in men (Hohman et al., 2018), providing supporting evidence that APOE4 may have a sex- specific effect on risk for neurodegeneration.

The APOE protein helps carry cholesterol and other types of fat in the bloodstream and is found in the liver and in the brain, including astrocytes and microglia (Fernandez et al., 2019).

Both astrocytes and microglia have roles on Aβ clearance (Ries & Sastre, 2016) and APOE4 expression alters normal function of both of these cells. APOE4 specifically, increases AD risk through impairing their ability to efficiently clear Aβ compared to APOE3 and APOE2 (Deane et al., 2008; Koistinaho et al., 2004; Simonovitch et al., 2016). APOE4 is also correlated with tau pathology where amyloid pathology is also present (Farfel et al., 2016) and has also been shown to worsen tau pathology in tau mouse models as well as in human primary tauopathies (Shi et al., 2017).

Aging, genetic risk factors and sex cannot account for all AD cases. Environmental risk factors linked to an increased risk of AD include inflammation and other medical comorbidities (Alford et al., 2018; Lee et al., 2018; Newman et al., 2005), air pollution and oxidative stress (Moulton & Yang, 2012), diet and nutrition (Hu et al., 2013), head injury (Ramos-Cejudo et al., 2018) and heavy metal exposure (Huat et al., 2019). Microbial and viral exposures have been suggested to be correlated with an increased risk of neurodegeneration including AD (Levine et al., 2023; Lotz et al., 2021). The possible involvement of infectious agents has been suggested as an emerging risk factor in the etiology of AD and many past studies have implicated several infectious agents in AD (Carbone et al., 2014; Esiri et al., 1998; Little et al., 2004; Miklossy, 2015). The increasing number of studies associating infections necessitates serious re-evaluation of the contribution of infections to AD and other associated dementias.

COVID-19

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent coronavirus disease-19 (COVID-19). COVID-19 has become a global pandemic that currently has affected hundreds of millions of people worldwide (COVID - Coronavirus Statistics - Worldometer, n.d.). Coronaviruses (CoVs) are nonsegmented positive-sense RNA viruses with among the largest viral genomes identified and can be subdivided into a variety of subfamilies that have a wide variety of vertebrate hosts (Su et al., 2016; Weiss & Navas-Martin, 2005). CoVs contain four main structural proteins that include the spike (S), membrane (M), envelope (E), and nucleocapsid (N). The S protein provides the characteristic crown-like appearance of CoVs as it extends from the surface of the virion and contains two subunits with the S1 subunit forming the head that contains a variable receptor binding domain (RBD) while S2 subunit forms the stalk (Weiss & Navas-Martin, 2005). Initial virion attachment is initiated by the S1 subunit which mediates binding a specific host cell receptor which initiates a conformational change to the S2 subunit resulting in fusion of the viral membrane to the cell membrane (Neuman et al., 2011).

CoV infections in humans can lead to a variety of clinical features ranging from gastrointestinal symptoms to mid-to-severe respiratory symptoms (Wevers & van der Hoek, 2009). To date, seven different CoVs are known to infect humans and these include Severe Acute Respiratory Syndrome SARS-CoV (SARS1) and Middle Eastern Respiratory Syndrome MERS-CoV which has been responsible for epidemics in 2003 and 2012 respectively (Peiris et al., 2003; Raj et al., 2014; Solomon & Liang, 2022) with survivors experiencing lingering symptoms after acute disease (Ahmed et al., 2020). SARS-CoV-2 shares about 80% of its genetic identity with SARS1 (Zhou, Yang et al., 2020) and both viruses use angiotensin converting enzyme 2 (ACE2) a host cell binding receptor (Li et al., 2003; Tai et al., 2020). ACE2 is thought to play a role in regulation of the renin-angiotensin-aldosterone system (RAAS) and be a regulator of cardiac function and blood pressure (Crackower et al., 2002; Gheblawi et al., 2020). It is mainly expressed in alveolar epithelial cells of the lungs and enterocytes of the small intestine (Hamming et al., 2004) but can be expressed in other tissues. High expression levels of ACE2 have been noted in the testis, kidneys, heart, thyroid, and adipose tissue, and in lower levels in blood, spleen, bone marrow, brain, blood vessels, and muscle. No difference in expression levels was noted between age and sex (Li et al., 2020).

There are several risk factors that increase disease severity and mortality related to COVID-19 and these comorbidities include conditions such as obesity, hypertension, cardiovascular disease, and diabetes (Karagiannidis et al., 2020; Parohan et al., 2020). To date, overwhelming evidence indicates that increased age is associated with not only a higher risk of disease severity, but also mortality (Chen, Klein et al., 2021; Mueller et al., 2020; O’Driscoll et al., 2021).

Interestingly, pre-existing dementia has also been identified as a prominent risk factor for COVID-19. In a recent study it was discovered that among patients with dementia, Alzheimer’s disease (AD) was the most prevalent cognitive impairment observed in those who succumbed to COVID-19 (Martín-Jiménez et al., 2020). Additionally, patients with dementia typically experience more severe clinical disease and increased mortality due to infection (Atkins et al., 2020; Wang, Davis, Gurney et al., 2021). Whether this is due to those with dementia being less able to modify behavior to prevent infection or the majority of those with dementia being elderly, and therefore have a muted immune response rendering them more prone to infection (Dewan et al., 2012). However recent studies have found other links to risk genetic risk factors associated with AD to also be tied to COVID-19 risk.

Previous studies have reported on the APOE4 mutations and its effects on susceptibility to other viral infections such as HIV, HSV and hepatitis C (Burt et al., 2008; Linard et al., 2020; Mueller et al., 2016). APOE4 is also widely recognized to be the strongest genetic risk associated with the onset of sporadic AD (Kim et al., 2009), but it recently has also been identified as a genetic factor implicated in risk of infection, disease severity and mortality due to COVID-19. Recent studies have found that APOE4 homozygous carriers have a two-fold increase in risk for SARS-CoV-2 infection and a quadrupled increase in risk of death due to COVID-19, even controlling for other existing comorbidities including pre-existing dementia (Kuo et al., 2020b, 2020a). Additionally, APOE4 carrier status also correlated with higher mental fatigue post-infection compared to noncarriers and reported that these effects could partly be due to cerebrovascular damage (Kurki et al., 2021). This could partly explain its effects, given APOE dysfunction has been associated with cardiovascular disease and other comorbidities that increase vulnerability to COVID-19 (Kulminski et al., 2016). In vitro experiments have also generated data supporting greater susceptibility to SARS-CoV-2 infection in APOE4 human-induced pluripotent stem cell (hiPSC) derived neurons and astrocytes, demonstrating an increase in astrocytic nuclear fragmentation due to infection (Wang, Zhang et al., 2021). Lastly, in vivo mouse experiments indicate an increase in viral loads, worsened survival, and a dampened immune response in infected APOE4 knockin mice (Ostendorf et al., 2022).

The mechanisms by which APOE4 increases risk of COVID-19 infection and outcomes are still not fully understood; however, APOE4 is known to affect a variety of processes that are likely to facilitate infection and clinical disease outcomes. APOE4 is associated with increased BBB permeability and loss of integrity (Montagne et al., 2020) which could facilitate viral entry into the CNS. Other studies have postulated that APOE4 may enhance infection via the regulation of cholesterol homeostasis by elevating cholesterol levels (Dallongeville et al., 1992) which may facilitate binding of the viral S protein to its receptor ACE2 (H. Wang et al., 2021; Zhu et al., 2021). Additionally, APOE4 is reported to promote the production of some pro-inflammatory cytokines (de Leeuw et al., 2022; Konttinen et al., 2019; Vitek et al., 2009; Zhang et al., 2011) increasing the likelihood of a cytokine storm, often associated with more severe COVID-19 (Chen, Wu, Guo et al., 2020; Hu et al., 2021; Ragab et al., 2020).

Symptoms and transmission:

SARS-CoV-2 is primarily transmitted via respiratory droplets and aerosols, with a median incubation period of 4–5 days before symptom onset in the majority of individuals (Lauer et al., 2020). Although some cases are asymptomatic, infection in most patients presents with mild-to-moderate respiratory disease and other flu-like symptoms including fever, headache and gastrointestinal manifestations like diarrhea (Guan et al., 2020; Huang et al., 2020). The most common symptom is dyspnoea that can, in some severe cases, lead to hypoxaemia (Zhou, Yu et al., 2020). In more severe cases this can result in acute respiratory distress syndrome (ARDS). which is an inflammatory form of lung injury associated with alveolar damage that ultimately leads to respiratory failure (Diamond et al., 2022). While infection is more highly associated with respiratory symptoms and disease, other organ systems including cardiac, renal, gastrointestinal, and neurologic (Gupta et al., 2020; Tavazzi et al., 2020; Xiao et al., 2020) are targets of infection given the widespread expression of ACE2, with multiple organ failure observed in some patients (Du et al., 2020).

While COVID-19 presents primarily with respiratory symptoms, neurological symptoms and complications have been extensively documented (Chen, Wu, Chen et al., 2020; Harapan & Yoo, 2021; Mao et al., 2020; Zubair et al., 2020), with the majority of neurological manifestations occurring in patients with severe disease (Liotta et al., 2020). Additionally, neurological symptoms can manifest before, during or after the onset of respiratory symptoms (Keyhanian et al., 2020) including confusion and delirium which can present without respiratory symptoms (Butt et al., 2020). More common neurological symptoms include myalgia, headache, dizziness, as well as olfactory and gustatory dysfunction that includes anosmia and ageusia (Cooper et al., 2020; Karadaş et al., 2020). Anosmia is thought to result from damage to olfactory epithelium, rather than neuronal injury (Brann et al., 2020). Other complications have also been observed with more severe disease including higher probability of ischemic strokes, cerebrovascular disease, coagulation abnormalities/hypercoagulation, seizures, meningitis and encephalitis (Fan et al., 2020; Favas et al., 2020; Mao et al., 2020; Merkler et al., 2020; Moriguchi et al., 2020; Sohal & Mansur, 2020; Tang et al., 2020).

Postacute Sequalae of SARS-CoV2 (PASC)

Most patients with COVID-19 recover with no symptoms associated with infection; however some report lingering symptoms and other health problems after the initial acute infection has resolved that vary from mild to severe. This is not unprecedented for individuals infected with coronaviruses as individuals infected with SARS-CoV and MERS-CoV have exhibited persistent lingering symptoms after acute disease (Ahmed et al., 2020). Moreover, Influenza is another RNA virus that is associated with re-occuring pandemics and infection is associated with a variety of effects on the nervous system (Cárdenas et al., 2014; Robinson & Busl, 2020). Indeed, overwhelming evidence indicates that long-term cognitive impairments are commonly followed by those that have experienced ARDS (Chrousos & Kaltsas, 2005). More recent studies, however, have indicated that even non-hospitalized patients with mild disease also experience prolonged symptoms post COVID-19 infection (Dennis et al., 2021). Additionally, other human CoVs such as H-CoV-OC43, more commonly associated with the common cold, have been reported to affect the hippocampus, especially regions associated with memory and cognition (Jacomy et al., 2006; Ritchie et al., 2020). Given that the hippocampus plays a pivotal role in learning and memory, there could be long-term negative consequences to cognition resulting from CoV infections. Long-term effects post COVID-19 are new and not yet fully understood and more studies are required to determine if SARS-COV-2 leads to hippocampal degeneration and if this can possibly induce or worsen the onset of neurodegenerative diseases such as AD.

COVID-19, neurodegeneration and AD

Given that viral infections already have been implicated with an increased risk of cognitive impairment and other neurodegenerative diseases (Levine et al., 2023), it is not surprising that COVID-19 has also recently been associated with the development of rapidly progressive dementia with an increased risk of a new AD diagnosis within 360 days after initial COVID-19 diagnosis (Wang et al., 2022). COVID-19 appears to affect brain structure and function in a variety of different manners, some of which could explain the association between COVID-19 infection and neurodegeneration. Although definitive causal links between COVID-19 and neurodegeneration have not been established, several mechanisms have been proposed by which COVID-19 could induce or accelerate changes related to neurodegeneration, dementia and ultimately AD.

Numerous neurodegenerative disorders, including AD, are linked to abnormal folding and aggregation of proteins. Additionally, being exposed to infectious agents—both viral and bacterial—appears to increase the risk of these disorders (Carbone et al., 2014; Esiri et al., 1998; Levine et al., 2023; Little et al., 2004; Miklossy, 2015). Recently, there is established evidence that many viruses including Influenza A, murine cytomegalovirus and SARS-CoV and their viral proteins have amyloidogenic properties and are prone to the formation of amyloid aggregates (Chevalier et al., 2010; Ghosh et al., 2015; Pham et al., 2019). Given the previously stated genetic similarity between SARS-CoV and SARS-CoV-2 (Zhou, Yang et al., 2020), there is a possibility that SARS-CoV-2 viral proteins, which are shared by other CoVs (Weiss & Navas-Martin, 2005) could be prone to aggregation. Supporting this, a study has indicated that SARS-CoV-2 viral proteins have been shown to form amyloid aggregates (Bhardwaj et al., 2023),

Recent evidence also suggests that SARS-CoV-2 infection appears to disrupt Aβ42 and tau homeostasis. Hyperphosphorylation and altered distribution of tau has been observed in in vitro organoid models infected with SARS-CoV-2 (Ramani et al., 2020). Studies also indicated that infection has shown to enhance Aβ42 neurotoxicity in the brain, impair clearance in blood serum, and induce amyloid aggregation of proteins in CSF (Chiricosta et al., 2021; Christ et al., 2022; Hsu et al., 2021). Specifically, the presence of Aβ42 has been observed to increase binding of ACE2 to the S1 viral subunit, possibly resulting in increased facilitation of viral entry, as well as increased production of proinflammatory mediators such as IL-6 (Hsu et al., 2021) which is associated with impaired hippocampal neurogenesis (Kong et al., 2019).

Enhancement of ACE2 activity in AD mouse models has indicated a reduction in hippocampal Aβ42 deposition, as well as reduction in hyperphosphorylated tau and inflammatory cytokines in the brain, and improved cognition (Duan et al., 2020; Evans et al., 2020); therefore inhibition of ACE2 activity might implicate worsened AD- associated pathology and neuroinflammation. Animal experiments have shown that infection with SARS-CoV or injection of SARS S glycoprotein is associated with a significant downregulation of ACE2 activity (Kuba et al., 2005). Given that SARS-CoV and SARS-CoV-2 share ACE2 as a functional receptor this implies that ACE2 activity and function can also be inhibited by SARS-CoV-2 infection. An important function of ACE2 includes the regulation of brain-derived neurotrophic factor (BDNF) release (Motaghinejad & Gholami, 2020) and BDNF has important roles in neurogenesis, as well as other processes in neurodegenerative diseases, like cognition, neurodevelopment and plasticity (Edelmann et al., 2015; Mizui et al., 2015; Motaghinejad et al., 2016). BDNF reduction has been linked with Aβ accumulation, tau phosphorylation, and neuroinflammation (Gao et al., 2022). Given this evidence, some hypothesize that downstream inhibition of BDNF via an ACE2 mechanism in COVID-19 can instigate neurodegeneration (Motaghinejad & Gholami, 2020).

In the context of COVID-19, microglia and other CNS cells including astrocytes, oligodendrocytes and neurons have been identified as potential targets for infection as these cells express ACE2 (Chen, Wang et al., 2020; Singh et al., 2020). It is also known that experimental CNS infection of susceptible mice with neurotropic strains of murine coronaviruses induce widespread activation of microglia and astrocytes associated with the release of pro-inflammatory chemokines and cytokines as well as the activation of both the innate and adaptive immune responses (Hosking et al., 2009; Lane et al., 2006; Skinner et al., 2019). More recently, experimental infection of mice with mouse-adapted SARS-CoV-2 results in glial activation associated with cytokine production and neuroinflammation in the absence of viral infection of the CNS emphasizing that lung infection can induce changes within the CNS (Amruta et al., 2022). Additionally, the N protein of SARS-CoV-2 has been co-localized in microglia, astrocytes and oligodendrocytes in the cortex of some COVID-19 patients (Cama et al., 2021) as well as in microglia in the brains of other animal models (de Melo et al., 2021). Other studies have reported that SARS-CoV-2 infection of microglia, in vitro and as well as in vivo, have elicited pro-inflammatory activation in microglia (Jeong et al., 2022). The systemic inflammation that results from infection is mediated partly by NLRP3 inflammasome. NLRP3 activation can affect microglial function by facilitating the polarization of microglia towards an inflammatory phenotype leading to a reduction in phagocytic function and impairing Aβ clearance (Jones et al., 2014; Tejera et al., 2019). Additionally, an inflammatory phenotype in microglia has been shown to induce expression of genes that contribute to neuroinflammation (Murta et al., 2020) which is also associated with neuronal damage (Ising & Heneka, 2018; Rock et al., 2004).

Post-mortem analysis of brains from COVID-19 patients have reported gliosis and immune cell accumulation linked to axonal damage and BBB disruption and leakage (Matschke et al., 2020); (Bellon et al., 2021; Schwabenland et al., 2021). The BBB consists of endothelial cells, pericytes and astrocytes and infection results in endothelial damage and increased capillary permeability (Helms et al., 2020; Magro et al., 2020). Astrocytes, already vulnerable to the effects of infection (Chen, Wang et al., 2020; Singh et al., 2020) secrete pro-inflammatory cytokines and contribute to production of Aβ (Blasko et al., 2000; Zhao et al., 2011). These detrimental effects to BBB permeability and integrity can then contribute to the development of neuroinflammatory diseases of the CNS, such as AD (Daneman & Prat, 2015; Knox et al., 2022).

Although cytokine storm is considered to be a major cause of ARDS and multiple organ failure (Chousterman et al., 2017), it has also been recently associated as a major contributing factor of neurological complications of COVID-19. It has been observed that patients with more severe COVID-19 have a more drastic inflammatory immune response (Chen, Wu et al., 2020; Huang et al., 2020) leading to the release of proinflammatory cytokines (Hu et al., 2021; Ragab et al., 2020; Ye et al., 2020). Some of these inflammatory markers including IL-6 and IL-1β are also elevated in animal models (Klein et al., 2021) and associated with impaired neurogenesis and hippocampal dependent memory (Garber et al., 2018; Kong et al., 2019). Elevated levels of IL-6 are associated with increased viral loads and disease severity (Chen, Hoiland et al., 2021; Chen, Zhao et al., 2020) and have been demonstrated to be involved in neurodegenerative diseases mediated by neuroinflammation (Strafella et al., 2020). Elevated levels of IL-1 have also been correlated with Aβ accumulation and NFTs (Griffin & Mrak, 2002). Elevated cytokine levels have also been seen in patients experiencing pneumonia and hypoxia (Arnaldez et al., 2020) and hypoxic changes in vitro and in patients have been associated with neuronal death and loss (in cortex and hippocampus) respectively (Solomon & Liang, 2022; Song et al., 2021). Additionally, evidence of neuronal degeneration and changes in glial cell morphology are also present in some hippocampal tissues derived from COVID-19 patients (Bayat et al., 2022).

There are also elevated markers of neurodegeneration that result from COVID-19. Elevated blood plasma markers for Glial fibrillary acidic protein (GFAP) and Neurofilament Light Chain (NfL) have been observed in patients with moderate to severe COVID-19 indicating astrocytic and neuronal injury (Kanberg et al., 2020). Additionally, a significant increase in both total and phosphorylated tau (t-tau and p-tau-181), and UCHL1 were also observed in infected patient plasma (Frontera et al., 2022). A separate study found that the increase in these markers was also associated with the presence of neurological symptoms (Boutajangout et al., 2021) and interestingly, plasma levels of Aβ, NfL, neurogranin, t-tau, p-tau-181 remained elevated post- COVID-19 recovery (Sun et al., 2021). Overall, given evidence linking COVID-19 with neuroinflammation and distinct neurodegenerative processes, it is possible that some neurological manifestations of COVID-19 are likely to result, in part from hippocampal injury and neuronal death and may be contributing to long-term neurological sequelae such as cognitive impairment in patients with Long COVID.

One study investigated white matter changes one year after initial COVID-19 diagnosis and found that those that had recovered from COVID-19 had decreased axonal density compared to healthy controls, and this was more pronounced in patients that had experienced severe disease versus mild disease. The specific areas affected included the corona radiata, corpus callosum, and superior longitudinal fasciculus, which play important roles in connection between different brain regions as well as hemispheres. While these structural changes persisted in recovered patients even after one year, interestingly they were not associated with decline in cognitive function (Huang et al., 2022).

Other changes in brain structure have been associated with even mild COVID-19. A recent study has found changes in the limbic and olfactory cortical system, including tissue damage and reductions in gray matter thickness, specifically orbitofrontal cortex and parahippocampal gyrus, as well as other regions functionally connected to olfactory cortex and a greater reduction in global brain size. Interestingly in this study, infection was associated with greater cognitive decline measured by a variety of cognitive tests (Douaud et al., 2022). However, other studies have reported contradicting results, reporting significant increases in bilateral gray matter volumes in district anatomical regions in the brains of patients post-COVID-19 (Besteher et al., 2022; Lu et al., 2020). Lu et al., acknowledge that these contradicting results could be due to differences in methodology, participant characteristics, severity of disease, as well as temporal trajectories in pathophysiological mechanisms related to the presence of neurological symptoms in their cohort of participants versus those of Douaud et al., 2022.

Given that the patients in the studies mentioned above recovered from COVID-19, it was not possible to directly evaluate for the presence of SARS-CoV-2 within the brains of participants, specifically in the distinct anatomical regions where changes were reported. Unfortunately, it is still unclear whether SARS-CoV-2 within the brain can contribute to these changes given that some autopsy studies have failed to detect virus, or only small traces of RNA have been found within the brain, often only in those with severe disease (Matschke et al., 2020; Solomon et al., 2020; Stein et al., 2022; Thakur et al., 2021).

Conclusion

Alzheimer’s disease (AD) is linked to many risk factors including genetic mutations, aging, and other environmental factors such as viral and bacterial infections. SARS-CoV-2, the viral pathogen responsible for COVID-19, has been linked to a variety of comorbidities and risk factors shared by AD. While COVID-19 usually results in a wide range of symptoms, including respiratory distress, infection has been associated with changes in brain structure and function which are also associated with neuroinflammation and potential neurodegeneration. Additionally, long-term cognitive impairments have been observed post-COVID-19.

Age is the biggest contributing factor to AD and COVID-19, and both - regardless of their etiology- appear to enhance the effects of one another. Regardless of how these processes occur, the long-term consequences of two colliding diseases (AD and COVID-19) and their synergistic effects on neurodegeneration are yet to be seen and further research is needed to understand the impact of COVID-19 on neurodegenerative diseases like AD. Ongoing research holds promise, with the potential to offer interventions that could improve public health outcomes amid an aging population. A summary of the mechanistic functions and shared factors that impact both AD pathogenesis and COVID-19 are provided in Figure 1.

Figure 1. Schematic representation of the mechanistic functions and shared influence of AD and COVID-19 risk factors.

Old age is the most significant risk factor for AD. A genetic risk factor, the APOE gene, has been shown to also increase the AD risk. It has been associated with worsened tau pathology and the presence of the APOE4 allele in astrocytes and microglia can impair their ability to efficiently clear Aβ. Other risk factors linked to AD include inflammation well as microbial and viral exposures. Old age and APOE4 also influence COVID-19 risk. APOE4 facilitates binding of the viral S protein to its receptor, ACE2. It is also associated with increased BBB permeability as well as promoting production of pro-inflammatory cytokines, leading to neuroinflammation and ultimately neurodegeneration.

Abbreviations:

Aβ

Amyloid beta

AD

Alzheimer’s disease

ACE2

Angiotensin converting enzyme 2

APOE

Apolipoprotein E

APP

Amyloid precursor protein

ARDS

Acute respiratory distress syndrome

BBB

Blood brain barrier

BDNF

Brain-derived neurotrophic factor

CA1

cornu Ammonis 1, region of hippocampus

CA3

cornu Ammonis 3, region of hippocampus

CoVs

Coronaviruses

CNS

Central nervous system

COVID-19

Coronavirus disease 2019

CSF

Cerebrospinal fluid

E

Envelope

EOAD

Early-onset Alzheimer’s disease

EBV

Epstein-Barr virus

GFAP

Glial fibrillary acidic protein

H-CoV-OC43

Human coronavirus OC43

HIV

Human immunodeficiency virus

HHV-6

Human herpesvirus- 6

HSV-1

Herpes simplex virus- 1

IFN-γ

Interferon-γ

IL-1/ IL-6

Interleukins-1 and 6

LOAD

Late-onset Alzheimer’s disease

M

Membrane

MCI

Mild cognitive impairment

MERS-CoV

Middle east respiratory syndrome coronavirus

N

Nucleocapsid

NfL

Neurofilament light chain

NLRP3

Nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3

NFTs

Neurofibrillary tangles

PASC

Postacute sequalae of SARS-CoV-2

P-tau181

Phosphorylated tau

PSEN-1

Presenilin-1

PSEN-2

Presenilin-2

RAAS

Renin-angiotensin-aldosterone system

RBD

Receptor binding domain

S

Spike

SARS-CoV/SARS1

Severe acute respiratory syndrome coronavirus

SARS-CoV-2

Severe acute respiratory syndrome coronavirus 2

TNF-α

Tissue necrosis factor-α

T-tau

Total tau

UCHL1

Ubiquitin C-terminal hydrolase L1

hiPSC

Human-induced pluripotent stem cell