Evidence supports the Theory that patients with dementia have high COVID-19 risk (8, 18). Among CNS comorbidities of COVID-19, AD stands first (19), and both diseases share risk factors, including age, obesity, cardiovascular disease, hypertension and diabetes mellitus (20). It has been suggested that pre-existing brain pathology and more specific mechanistic aspects of dementia could increase the risk of neurological complications in COVID-19 (21). Blood-brain barrier (BBB) in patients with dementia is damaged, facilitating the access of certain bacteria and viruses to the brain (22, 23) thus increasing the susceptibility to infection (24, 25). Additionally, APOE4, which confers increased susceptibility in developing AD, has been considered as a marker that increases the severity of COVID-19 (26) therefore, AD patients who carry the APOE4 allele have a higher risk of developing COVID-19.

It has been already documented that patients with dementia are more susceptible to bacterial, viral, and fungal infection (24, 25, 27–30). These results included the presence of viral and bacterial DNA in post-mortem brain tissues, and/or their respective antibodies in the serum or cerebrospinal fluid (CSF). Based on all these studies, the “Infectious Hypothesis” has gained traction in recent years, which proposes that infectious agents may have a causal role in the development of AD. Moreover, and based in the close relationship between infections and inflammation, the Infectious Hypothesis presumably connects to the neuroinflammation in many ways (31). Systemic bacterial and viral infections may rise the inflammatory processes and the predisposition to develop AD (32, 33). Infectious factors are responsible for the activation of glial cells that produce several inflammatory molecules, including cytokines such as tumor necrosis factor (TNF)-α, interferon-γ (IFN-γ), interleukin (IL)-6, IL-1β, IL-18, chemokines, and reactive oxygen species (ROS) which in turn leads to exacerbation of other AD pathologies. It is important to underline that the iron homeostasis disorders, which lead to an iron overload, induce ROS formation (34).

In addition, the chronic inflammatory processes observed in AD, characterized by high levels of pro-inflammatory cytokines, can markedly influence iron homeostasis. In the brain, iron modulates different functions such as high aerobic metabolic ability of neurons, the synthesis of myelin, the synthesis and metabolism of neurotransmitters as well as the development of the neuronal dendritic tree (35). In AD patients, magnetic resonance imaging highlights an increase of iron content in the brains (36). The increase of free iron concentration in these patients, indicating a dysregulation of iron homeostasis, compromises brain functions due to the increase of oxidative stress associated with higher ROS and nitric oxide synthase (NOS) production (37–39). In the absence of inflammation, iron homeostasis guarantees a correct distribution of this metal between tissues/secretions and circulation. Every day 15 mg of iron are ingested from the diet but only 1-2 mg of iron are daily absorbed (34).

Therefore, in inflammatory processes must be taken into account that high levels of hepcidin and low levels of ferroportin (40) cause an iron overload in cells and secretions together with iron deficiency into the blood (41). These peptides are able to modulate iron homeostasis. It is well known that patients suffering from neurologic disorders such as AD or other kind of dementia, showed systemic metabolic disorders such as anemia or anemia of inflammation (42). Conversely, low levels of hepcidin and high levels of ferroportin, restore iron export thus decreasing intracellular iron load and increasing iron in the blood (43, 44).

Of note, viral infections are directly promoted by intracellular iron overload because their replication is dependent from host cell iron enzymes, some of which are involved in transcription, viral mRNA translation, and viral assembly (45). As AD patients are characterized by high concentration of intracellular iron (36), they have an increased replication rate of COVID-19 with the consequent neurological and systemic complications.

SARS-CoV-2 enters the body mainly as droplets during inhalation, and infiltrates the nasal and buccal cavities to gain access to the mucosa and the respiratory tract. But SARS-CoV-2 may also entry into the brain across the CNS vascular barriers (46). Pathogens can access to the CNS by several ways and possibly speed up the progression of AD. The first is through a compromised BBB. In a healthy situation, BBB provides a selective barrier to the passage of cells and molecules into the brain; however, in a pathological situation, a compromised BBB can allow direct entry into the brain through the passage of blood to the CSF (23, 24). Moreover, pathogens, including bacteria and viruses can bypass the BBB by entering via the olfactory system, because the nasal cavity connects the peripheral environment to brain regions such as the olfactory bulb, the entorhinal cortex and the hippocampus (47). SARS-CoV-2 infection is widespread in epithelial cells, particularly in the lungs, starting its invasion and entry into the respiratory tract. However, as with other viral infections, SARS-CoV-2 may enter the brain by its neuroinvasive properties, directly by infection of olfactory sensory neurons in the epithelium and then transported into the CNS through the olfactory nerve, or crossing the BBB (46, 48).

It is known that SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as a receptor to enter the host cells and a recent article reports that ACE2 levels are upregulated in AD brains (49). Although some studies proposed that there was no clear evidence for human neuronal or astrocyte expression of ACE2 (50), more recent findings report robust ACE2 expression in human neurons, which is a target for SARS-CoV-2 infection (51). Moreover, Aβ₄₂ binds to ACE2 and the spike protein S1 subunit of SARS-CoV-2, enhancing SARS-CoV-2 infection/inflammation (52). Additionally, viral infection reciprocally affects Aβ₄₂ clearance, amplifying the progression and severity of AD. These results may indicate a higher risk of viral entry and loads in the brain in these patients, contributing to understand the relationships between COVID-19 and the brain, particularly in AD.

Most groups in this field have focused their research on vulnerability of people with dementia to SARS-CoV-2 infection because their impaired memory impedes them to comply with the suggested public health recommendations. Two attention-grabbing papers discussed this pandemic situation and its impact on demented patients. In one of them, Mok and colleagues discussed the worrying impact of COVID-19 upon patients with AD and other dementias, and proposed strategies for care and management of these patients and their caregivers (9). More recently, a retrospective study of adult and elderly patients in the United States up to 2020 showed that patients with dementia were at higher risk for COVID-19 than those without dementia, and interestingly they found black people with dementia had higher risk of COVID-19 than white people (8). Results of this study highlight the need to keep safe patients with AD or dementia, placing special emphasis on the black people, within the pandemic control.

In both studies, authors pointed out the particular vulnerability because the multiplicity of medical conditions and social/environmental factors. However, in Wang’s study, authors speculate that preexisting brain injury may allow more virus entry inducing the pathology of COVID-19 within the brain (8), but, they also draw attention to a poor immune response/immune dysregulation as others studies reported (53, 54).

Thus, an effective and robust immune response may face more effectively the outcomes of the SARS-CoV-2 infection (55). It is proposed that dysregulated immune function, including impaired antimicrobial function, is associated with increased susceptibility to infections (56).

As has been widely seen, patients suffering for severe COVID-19 develop high levels of proinflammatory cytokines and acute respiratory dysfunction. These inflammatory processes have been suggested to cause cognitive decline (32, 57, 58). Pathogenically, this situation may result from direct negative effects of the immune reaction, exacerbating of pre-existing cognitive deficits, or de novo induction of neurodegenerative disease ( Figure 1 ).

Understanding the relationship between immune dysregulation, infections and dementia has taken on new urgency in the COVID-19 pandemic.

The bidirectional pathways between the CNS and peripheral immunity are called the neuroimmune axis, and even if are far from being completely understood (59–62). Neurological inflammation disorders are thought to be caused by dysregulated afferent nerve neuroimmune pathways (62, 63). Regarding the possible roles that may play in the pathology of AD the dysbiosis or infections outside the CNS, there are limited data. However, given the role of innate immunity in AD has become clear in recent years, as well as the connection between the neuroimmune axis and neuroinflammation, we believe that more attention should be paid to the contributions of chronic peripheral infection on cerebral AD pathology.

As we recently discussed, the evolution of AD pathology is associated with immunity dysfuntion (56). Alterations in the immune responses may occur at early stages of AD and possibly are involved in the AD progression, as reported in previous experimental and clinical studies (64). Throughout aging, there is a loss of anatomical and physiological integrity, which causes a greater vulnerability to some diseases and death. Aging is induced by genetic, epigenetic and environmental factors and affects almost all organs, having a profound impact on the immune system (65, 66). Moreover, several studies postulated that AD pathology is under the control of the immune system in an age-dependent manner (67–69). Now, AD is consider a systemic disease with a strong central and peripheral neuroinflammatory component. Immune cells may travel to and from the brain due to the increased permeability of the BBB in AD, participating in the pathogenesis and progression of this neurodegenerative disorder (69). Growing evidence suggests that peripheral infections may trigger the build-up of amyloid plaques in the brain by modulating glial cells, eliciting an immune reaction and stimulating secretase activity that increase the production of amyloid peptides (70, 71). Over the last decade, the presence of a sustained immune response in the brain has been proposed as a key element in AD pathology. Neuroinflammation, including the activation of glial cells and other immune cells, has been demonstrated to aggravate AD–related pathology (72). Acute inflammatory responses are common to healthy individuals, however chronic inflammation impairs the natural balance of pro- and anti-inflammatory signaling in the brain, presumably leading to the development and progression of neurodegenerative diseases such as AD (72).

The innate immune system induces an essential control over salivary secretion in the oral cavity. The nasal cavity is the major portal of entry for pathogens as well as the oral cavity which homeostasis is maintained by saliva. The most relevant salivary agents responsible for the defense against microbial pathogens are antimicrobial peptides and proteins (AMPs), which are the primary innate immune effectors and constitute the first line of defense against pathogen invaders (73, 74).

In humans, AMPs are produced by many cells, including phagocytes, epithelial and endothelial cells (75). Particularly, AMPs are highly expressed in the brain and other immunoprivileged organs where the activities of adaptive immunity are constrained, and low AMP levels can result in seriously compromised immunity. AMP expression can be induced during inflammation or after microbial infections. It has proposed that dysregulation of AMP activities may be involved in the pathology of chronic inflammatory diseases and neurodegenerative disorders (76). The normal production of AMPs may be reduced as a result of factors such as a debilitated immune system, damaged defense cells (by either intracellular infections or apoptotic processes), or structural vitamin D deficiency (77). Down-regulation of AMPs is associated with chronic inflammatory diseases, including Crohn’s disease (78).

As previously discussed, the innate immune system utilizes AMPs as the primary effector proteins to attack invading microorganisms, such as bacteria, viruses or fungi (79). By binding host biomolecules linked to immunity, AMPs are also potent immunomodulators that play an important role in combating infection. AMPs modulate both innate and adaptive immune systems which normally work as a continuum (80). In fact, AMPs are sometimes known as alarmins due to their role in stimulating adaptive immune pathways, including the complement system.

Since the immune status plays a crucial role in disease severity, immunotherapies are used in severely ill COVID-19 patients (130). Based on the anti-inflammatory, anti-viral and immune-regulating properties of bLf (95), which are in accordance with the treatment supplies for SARS-CoV-2 infection, bLf might be useful in the prevention and/or management of COVID-19.

Indeed, bLf could exert multiple functions, including a primary defense factor against mucosal infections, and a modulator of viral infectious processes. Its antiviral activity is mediated by the Lf binding to heparan sulphate glycosaminoglycans (HSPGs) of host cells, viral particles or both (93).

Recently, many in vitro studies shown that bLf is active against SARS-CoV-2 (11, 12, 131, 132). In these studies, bLf shows antiviral activity against SARS-CoV-2 with a multimodal mechanism: (i) through its binding with HPSGs of host cells, which blocks the transport of viral particles to the high-affinity specific entry as ACE-2 (131); (ii) through its binding to spike glycoproteins of SARS-CoV-2, thus hindering the viral adhesion to host cells surface (12); and (iii) through the upregulation of interferon I system thus activating the host antiviral response (11, 132). All these findings propose the beneficial bLf effects in host defense against SARS-CoV-2.

As reported in the prestigious Lancet journal, mortality from COVID-19 is not simply due to viral infection but is a result of a cytokine storm syndrome associated with hyperinflammation leading to acute respiratory distress and subsequent mortality (133). By the way, many studies shown that bLf was able to modulate this cytokine profile in COVID-19 cases by reducing reduce IL-6 and TNFα levels (126, 134–138). Moreover, bLf may diminish inflammatory factor release by promoting different actions (139). It was reported that after oral administration of bLf, the killing activity of NK cells was higher against virus-infected cells, enhancing the production of IL-18 (140). Also, bLf may rise IL-12 levels in macrophagocytes, promoting the migration of macrophages to inflammatory sites (141).

As Zimecki and colleagues summarize in their recent review, several studies strongly suggest the utility of bLf to silence the “cytokine storm”, supporting its potential for the handling of SARS-CoV-2 infection (142).

Based on preclinical studies, Rosa and colleagues developed a recent study to assess the efficacy of oral bLf on ambulatory COVID-19 patients (13). Results of this study revealed that the time required achieving SARS-CoV-2 RNA negativization in bLf-treated patients was lower compared to that reported in bLf untreated patients (15 versus 24 days). This means that the bLf treatment may improve outcomes in patients suffering from COVID-19, including those with comorbid diseases, and advanced age. Furthermore, they detected a very interesting association between symptom reduction and age: bLf was able to reduce the time to symptom resolution with advancing age (13). This fact could be associated with the hormonal control of hLf synthesis (143), and that decreases with age. The latter is particularly relevant for AD patients showing lower salivary hLf levels (16, 17).

In another clinical study in Tor Vergata University Hospital (Rome, Italy), oral and intranasal liposomal bLf was administered in asymptomatic and mild-to-moderate COVID-19 patients compared to standard of care (SOC)-treated and untreated COVID-19 patients (14). In agreement with previously reported data (13), significantly less mean time to SARS-CoV-2 RNA negative conversion was detected in a liposomal bLf-treated group compared to SOC-treated and untreated patients (14 versus 27 days), with fast clinical symptoms recovery (14). Moreover, in liposomal bLf-treated patients, a significant reduction in serum IL-6, ferritin and D-dimers levels was shown (14).

Overall, even if the randomized clinical trials on a large number of COVID-19 patients are required, these clinical experiences indicate that early treatment of bLf on COVID-19 patients could be the winning strategy to avoid the disease progression and severity, especially in the patients suffering from comorbid diseases and advanced age.