Introduction

Alzheimer disease (AD) is a common neurological condition, characterized by a gradual onset of neurocognitive symptom that affects more than 35 million individuals around the world [1,2,3]. The brain tissue of AD patients show mainly two pathological features: (a) intraneuronal neurofibrillary tangles (NFTs)—formed with Tau protein—and (b) extracellular insoluble senile plaques—formed with amyloid-β (Aβ) peptide—[4, 5]. Additionally, other characteristic features of AD include granulovacuolar degeneration [6], synaptic and neuronal loss, microgliosis, reactive astrocytosis Hirano bodies [7], and the recently neuropil threads (curly fibers) [8].

NFTs and Aβ are not unique to AD, and also are produced in other central nervous system (CNS) conditions [9]. In addition, recent findings have established the potential anti-microbial property of Aβ. In fact, infectious agents may induce the production and deposition of Aβ in patients. Aβ has also been reported to inhibit the replication of pandemic and seasonal strains of influenza virus in vitro, thus further establishing the anti-viral activity of Aβ and its role in modulating the viral interactions with phagocytes [10].

Inflammation is associated to most infectious diseases, though it is not triggered only by infectious pathogens [9, 11]. A number of hypotheses have shown the association of accumulative infections with AD, thus proclaiming the role of neuroinflammation and neuroinfection in AD etiopathogenesis [12,13,14]. There are three primary contributors in the pathogenesis of AD: neuroinflammatory processes, oxidative stress, and vascular factors [15,16,17]. Enhanced deposits of pathological Aβ results in the activation of macrophages, microglia, lymphocytes, and astrocytes, which in turn stimulate the release of various inflammatory mediators [18]. The well-being of blood brain barrier (BBB) is of prime importance for CNS integrity. This process also leads to the recruitment of peripheral blood leukocytes (PBL) through the BBB and their active participation in local brain tissue inflammation. Leukocytes release more inflammatory factors, escalate the inflammatory state, and exacerbate other AD-related pathologies as well [11, 17, 19]. In the present manuscript, we discuss around the literature the potential risk of several infections for AD initiation and progression.

AD Pathogenesis by Neuroinflammation and Infection

Infectious factors could stimulate the activation of astrocytes in the brain; thus indicating that neuropathology can indeed be a manifestation of an infection (Fig. 1). Neuroinflammation is an injury/infection-induced inflammatory response in CNS. Immune response and inflammation are the two most critical components of AD pathology. The BBB protects CNS by microvascular endothelial cells (pericytes and astrocytes) that selectively control the flux of molecules in and out of the brain. However, a large spectrum of pathogens can gain access to BBB and may result in a number of grave illnesses. Viruses can directly infect endothelial cells to cross the BBB and then into the CNS, but bacteria can cross the BBB through different mechanisms including Trojan-horse, paracellular traversal, and transcellular traversal. Damage to CNS during infection triggers the release of inflammatory mediators and activation of the innate immune response, necessary to eliminate the invasive pathogens. The condition of health hazard switches the inflammatory state from acute to chronic [20, 21].

Fig. 1
figure 1

Bacteria involved in AD pathogenesis. Bacterial infection is likely associated with AD causation and develops. Growing evidence relates the infection of bacteria as Chlamydia pneumoniae, Treponema pallidum, and Helicobacter pylori to AD. Interestingly, the infection of such bacteria is a public health issue in human populations and to date, there is a devoid of studies to determine the relationship of bacterial infection and AD

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Inflammatory hypothesis of AD [22] is one of the three most important hypotheses proposed on AD etiopathogenesis [23, 24] which explains that a self-perpetuating progressive inflammation in CNS leads to the activation of molecular pathways and neurodegeneration. Neuroinflammation has been characterized by an accumulation and activation of microglia and astrocytes via cellular and molecular immune factors. A wide range of inflammatory mediators including anaphylatoxins, chemokines, Tau, prostaglandins, cytokines, proteases, free radicals, Aβ, pentraxins, adhesion molecules, activated complement proteins, and pattern-recognition receptors (PRR) has been reported to be present at cortical lesions’ site in AD [25,26,27,28,29]. Glial cells have been reported to produce pro-inflammatory cytokines, which in turn may stimulate glial cells to produce additional Aβ [30].

The acute inflammatory response to pathogen-associated molecular patterns (PAMP) may be impaired during aging, thus stimulating the infection sustainability. The pathogens during replication release PAMP (their component molecules) that can be identified by PRR expressed on antigen presenting cells. Examples of PRR include RIG-I-like receptors (RLR), toll-like receptors (TLR), receptors for advanced glycation endproducts (RAGE), c-type lectin receptors (CLR), nucleotide binding oligomerization domain (NOD) like receptors (NLR), and intra-cytosolic DNA sensors [31]. Key cellular mediators of the innate immune and neuroinflammatory response in the CNS are microglia, which express various PRR receptors. Moreover, a strong inflammatory response in the periphery from bacterial or viral infections leads to the peripheral leukocytes (T cells and macrophages) infiltration to the CNS, which share several functional features with microglia. Leukocytes express TLR and are able to be activated by abnormal proteins or PAMPs. Therefore, an acute inflammatory response in the brain is beneficial and leads to repair the affected area of the brain and help to restore brain homeostasis.

The role of inflammation in AD pathogenesis stimulates the research of possible involvement of various infectious agents in inflammatory reactions in the CNS. Recently, the role of infection in AD etiology has increased interest in the literature showing the possible association of various microbial infections with cognitive decline, as well as involvement in onset and AD progression. The evidence for an immune/infectious component in the pathogenesis of AD and for the causation of infection and AD has been shown recently [32]. Infectious factors are responsible for the activation of glial cells that produce several inflammatory molecules [cytokines like IL-1β, IL-6, IL-18, TNF-α, IFN-γ, chemokines, and reactive oxygen species (ROS)], which in turn leads to exacerbate other AD pathologies. Systemic viral, bacterial, fungal, and protozoan infections may enhance the inflammatory state, thereby promoting the susceptibility to develop AD [11, 33, 34]. Likewise, infection burden has been also associated to other NDDs like PD [35] and ALS [36].

Involvement of Microorganisms in AD Pathogenesis

The possibility of the likely involvement of microorganisms in the formation of senile plaques is now being postulated as “infectious etiology for AD” by researchers around the world [37]. A wide range of pathogens including bacteria, fungi, protozoa, and viruses is associated with AD etiology.

Bacteria Involved in AD Pathogenesis

Figure 2 summarizes the major bacteria involved in AD pathogenesis.

Fig. 2
figure 2

The relationship between periodontal disease and AD. Periodontal bacteria potentially may be involved with pro-inflammatory states in the human body that promotes the secretion of interleukins as IL-1, IL-6, and TNF-α via the recognition of PAMPs in the bacteria membrane. It is possible that the cytokines secretion involves a systemic infection and inflammation that modifies the protected brain environment, causing the activation of microglia with subsequent neuroinflammation. It is a well-known close relationship between neuroinflammation and AD

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Spirochetes

Spirochetes are likely to be involved in the pathogenesis of AD [38,39,40]. Spirochetes are gram-negative, helical bacteria distinguished from other bacteria by the presence of endoflagella, which can invade the brain and generate latent, persistent infection [39, 41, 42]. Spirochetes are the most neurotropic bacteria, which have been detected in the trigeminal ganglia and trigeminal nerve [43]. Indeed, infections with spirochetes can cause serious brain disturbances like cerebral hypoperfusion, cerebrovascular lesions, and a severely disturbed capillary network [44]. Spirochetes can be spread by several mechanism including: (a) hematogenous dissemination, (b) lymphatic path and along nerve fiber tracts, and (c) transmit along the tractus olfactorius and fila olfactoria [45]. Spirochetes and their DNA have been found to be associated with AD, and are strongly concerned as the causative agents leading to dementia [41, 46]. Various types of spirochetes might cause dementia and brain damage similar to AD, as reported by various authors who detected and cultivated spirochetes from AD brains. Miklossy et al. detected spirochetes in the cerebrospinal fluid (CSF), blood, and brain of definite AD cases [39, 41, 47]. In fact, brain tissue of seven demented patients from Brazil and Switzerland (aged 42–82 years) presented spirochetes and they all suffered from slowly progressive neurodegeneration [39]. The transmission of spirochetes along the tractus olfactorius and fila olfactoria confirmed the olfactory hypothesis, and investigations showed that the olfactory bulb and tract are affected in earliest stages of AD degenerative process [44, 48]. In this aspect, innate immune system plays an important role that recognizes spirochetes via PRR, executes pro-inflammatory reactions, and initiates adaptive immune responses.

Borrelia burgdorferi

MacDonald [49], and MacDonald and Miranda [50] for the first time detected B. burgdorferi from the cerebral cortex of AD brains by using a specific antibody against B. burgdorferi. B. burgdorferi is a causative agent of dementia associated with cortical atrophy and microgliosis occurring in late stages of Lyme disease (boreliosis). In recent years, there has been an increased incidence of boreliosis in European countries [51]. B. burgdorferi or their synthetic membrane lipoproteins have been reported to be major inflammatory mediators [52, 53]. NFTs have also been reported to be immunoreactive for B. burgdorferi [41]. According to recent proposed hypothesis, B. burgdorferi causes neurodegenerative changes through an induction of intracellular inflammation in neurons. As a consequence, inflammatory state leads to abnormal Tau phosphorylation, microtubular dysfunction, and NFTs generation. An expanding inflammatory process in the brain leads to the disruption of enzymatic homeostasis [54]. In AD patients who suffered from neuroborreliosis, B. burgdorferi antigens were detected in NFTs and Aβ, along with wide neurodegenerative changes in brain tissue [41]. However, exact pathway that involved in this process still remain unknown and requires more detailed study in the near future.

Chlamydia pneumonia

The existence of an association between C. pneumoniae and AD has been reported by several authors [55,56,57]. C. pneumoniae, an obligate intracellular respiratory pathogen, is currently the most plausible of all infectious bacterial agents proposed to be involved in AD [57]. C. pneumoniae may infect various cell types found in the brain [58], and may reside in an intracellular inclusion that resists immune recognition and lysosomal fusion. This intracellular pathogen interacts with and manipulates the host by gathering nutrients and energy (cholesterol and sphingomyelin) required for its replication [59]. In one study, C. pneumoniae-specific DNA was detected in 90% of the sporadic AD brains (it was found in 17 of 19 AD patients compare with other 19 control patients that were negative for C. pneumoniae) [60]. Two mRNAs specific to C. pneumoniae were also identified in frozen AD brain tissue by RT-PCR [60]. C. pneumoniae and related antigens may interact with extracellular proteins and lipids in the brain. The presence of C. pneumoniae in AD brain has been confirmed by electron microscopy, immunoelectron microscopy, and immunohistochemical techniques [55, 60,61,62]. The fascinating relationship between Chlamydia and amyloid (between infection and pathology) in the same cortical regions of the AD brains require further investigations. Manabe et al. successfully demonstrated an intricate relationship between complications of C. pneumonia infection and prognosis of dementia [63]. However, due to the complexity of C. pneumoniae infections and chronic nature of AD, it has become quite difficult to establish an association with the disease pathogenesis. Validating this association relies on a variety of detection methods for the organism. Currently, the use of immunohistochemistry with a battery of commercially available anti-chlamydia antibodies on cortical and frontal sections of human AD brains provide a valuable insight into the interrelationship between infection and AD pathology [58]. For example, C. pneumoniae was cultured from isolated CSF and various brain samples of AD patients originating from different geographic regions of North America [56, 60, 64, 65].

NFTs and amyloid plaques were reported to lead the neurodegeneration in the AD brain, which causes progressive dysfunction of cognitive symptoms like language problems and memory loss. However, the non-cognitive symptoms like psychosis, aggression, and agitation observed in AD patients can be triggered by an infection (e.g., by C. pneumoniae) in peripheral organs, and this suggests a contribution of peripheral inflammation in AD pathogenesis [66]. However, more studies require clarifying the exact nature of peripheral inflammation in the pathobiology of AD [67, 68].

Treponema pallidum

In fact, Fischer (1907, 1910) has investigated whether the plaques could also be found within brains of patients with dementia paralytica (a common cause of illness associated with tertiary syphilis of the CNS) for almost a century [69,68,71]. However, although the author (1907, 1910) could not find plaques in the 45 cases with progressively paresis (dementia paralalytica), he has continued his studies. Later, Noguchi and Moore [72] observed the presence of T. pallidum in the cerebral cortex of patients with general paresis. Noguchi and Moore [72] also found that some of the patients with syphilis were associated with memory-related health issues. T. pallidum has been reported to be responsible for local amyloidosis, cortical atrophy, and slowly progressive dementia in the atrophic form of this chronic bacterial infection [73, 74]. T. pallidum can thus cause cortical atrophy, dementia, and the biological and pathological hallmarks of AD. Like B. burgdorferi, T. pallidum or their synthetic membrane lipoproteins have been reported to be major inflammatory mediators [52, 53]. T. pallidum has been reported to frequently co-infect with other bacteria like B. burgdorferi and herpes viruses in syphilis [45]. Still, research in this field is in early stage and more studies are needed to determine the association between T. pallidum and AD.

Helicobacter pylori

H. pylori is associated with stomach ulcers and gastric cancer [75]. A number of investigations has reported the role of H. pylori with respiratory, neurodegenerative, and other disorders [45]. Increased levels of H. pylori-specific IgG antibody were found in the serum and CSF of 27 AD patients in contrast with 27 control patients who did not presented high titter of H. pylori-specific IgG [76]. A number of varying pathogenic mechanisms have been hypothesized, including the occurrence of molecular mimicry mechanisms and the induction of a low-grade inflammatory state. The evidences compiled from the literature linking AD to H. pylori have been well discussed by Franchesi et al. and Mawanda et al. as well [9, 77]. A significantly higher level of H. pylori-specific IgG antibody was reported in the blood and CSF of AD patients [76]. Further research is needed to detect and confirm the presence of H. pylori in the brain and to analyze the possibility of a potential relation H. pylori and AD.

Actinomycetes

The association of Actinomycetes with AD has been suggested due to risk four times higher than in other pathological conditions [59, 78]. As revealed by ultrastructural analysis, the fibronectin-immunopositive fibrillary lesions in senile plaques were found to be compatible with filamentous microorganisms, and thus might correspond to Actinomycetes [78]. The fact that Actinobacillus actinomycetemcomitans is a frequent periodontal pathogen further adds to the possibility of the involvement of actinomycetes in various pathological conditions [79].

Propionibacterium acnes

P. acnes, an atypical anaerobic bacterium, has long been considered to be a commensal bacillus of the skin and is the causative agent of acne vulgaris. However, in a study where an elderly patient with cardiovascular risk factors and glioblastoma served as positive control, P. acnes was identified by gas chromatography and microbiological methods in biopsy specimens of the frontal cortex in three of the four AD patients [80]. P. acnes has been shown to be a predominant periodontal pathogen and can reach and infect various organs including the brain by hematogenous dissemination [81]. The involvement of P. acnes in various infections, including osteomyelitis, endophthalmitis, endocarditis, and brain abscesses, is now well established [82]. In two AD cases treated with P. acnes-sensitive cephalosporine combined with estrogen and enalapril, a remarkable memory improvement and stabilization of the clinical symptoms were observed [45, 80]. However, more studies are desired to establish definitive association between P. acnes with AD.

Other Bacteria

Many other pathogens like P. gingivalis, P. intermedia, T. forsythia, and F. nucleatum are implicated in the development of several inflammatory diseases at remote organ sites like AD [83]. Periodontitis is common problem in older age because of the poor state of oral hygiene, but it can also start in childhood. Periodontitis can be marked as a “low-grade systemic disease” by the release of pro-inflammatory cytokines into systemic circulation and elevation of C-reactive protein (CRP) [84]. Periodontal disease may in turn stimulate recurrent chronic oral infections, and the periodontal pathogens contribute to the destruction of soft and hard tissues supporting the teeth [85]. Moreover, bacterial LPS also add to the tissue destruction by inducing the immune response and production of pro-inflammatory molecules, like IL-1β, IL-6, and TNF-α. It is well known that inflammation play a pivotal role in periodontitis and AD, and acts as a connecting link between both the diseases [44, 46]. The leptomeningeal cells were shown to transmit systemic inflammatory signals from macrophages to brain-resident microglia by secreting inflammatory mediators during periodontitis. The pathogens can enter to the brain structures from mouth through two possible pathways. Firstly, the periodontal inflammatory process can expand on the brain through circulatory system with pro-inflammatory cytokines, but without the contact of bacteria with brain tissues. Secondly, periodontal bacteria or bacterial molecules can penetrate to the CNS either through blood stream or via peripheral nerves [86]. The relationship between periodontal disease and AD is presented in Fig. 2.

The hypothesis of an association between oral health status and cognitive decline in AD suggests that chronic oral infection promotes inflammation [87], and several pro-inflammatory cytokines enhance the pool of inflammatory mediators in the brain, and lead to confusion and dementia [5, 46]. Therefore, periodontal disease may be a significant source of systemic inflammatory molecules [78]. A link between periodontal disease and AD was tried to be established with a view of identifying the major periodontal disease bacteria and/or bacterial components in brain tissue from 12-h postmortem delay. They confirmed that LPS from periodontal bacteria can access the AD brain during life. The intense neuroinflammation evoked by senescent-type microglia may contribute to the initiation and progression of AD, resulting in the cognitive deficits [88]. Elevated level of TNF-α has been reported in serum of AD patients with periodontal disease [89, 90]. The most neurotropic bacteria are Spirochetes, which have been detected in the trigeminal nerve and trigeminal ganglia [43]. Spirochetes and their DNA have been found to be associated with AD, and are strongly concerned as the causative agents leading to dementia [41, 46]. Indeed, infections with spirochetes can cause serious brain disturbances like cerebral hypoperfusion, cerebrovascular lesions, and a severely disturbed capillary network [44] that outcome in most of cases associated with the memory decline and amyloid deposition.

Fungi Involved in AD Pathogenesis

Recently, some authors provided strong evidence for fungal infection in AD patients [91]. Alonso et al. reveal that fungal proteins can be detected in CSF of AD patients with different anti-fungal antibodies [91]. Fungal DNA and proteins were also found in frozen brain tissue from AD patients, but not from control patient tissues. Fungal material was detected both intra-and extracellularly using specific antibodies against several fungi: C. famata, C. albicans, C. glabrata, P. betae, and S. racemosum. Analysis of different brain sections, including external frontal cortex, cerebellar hemisphere, entorhinal cortex/hippocampus, and choroid plexus of AD patients, revealed the presence of fungal infections [74]. Fungal infection is associated with inflammation, as well as with AD [92]. However, detailed investigations are needed to demonstrate the association between fungal infection-mediated inflammation and AD.

Protozoa Involved in AD Pathogenesis

Chronic infection with the protozoon T. gondii results in neuroinflammation, which may explain pathophysiology of AD [73]. This study demonstrated that the protozoon T. gondii is involved in pathophysiological process of AD mediated through inducing neuroinflammation [73]. In three studies done in 2010–2011, Prandota suggested that chronic T. Gondii infection was the infectious agent responsible for triggering the development of several neurodegenerative diseases associated with an enhanced production of pro- and anti-inflammatory cytokines [93,92,95]. In a more recent study performed in 2014, Prandota showed that the olfactory dysfunction reported in AD, MS, and schizophrenia was frequently associated with the significantly enhanced levels of serum anti-T. gondii immunoglobulin G antibody [96].

Viruses Involved in AD Pathogenesis

Figure 3 summarizes the major viruses involved in AD pathogenesis.

Fig. 3
figure 3

Viruses involved in AD pathogenesis. A growing body of evidence associates the infection of several virus including HCV, HHV-1, HHV-2, CMV, EBV, and Herpes-Zoster virus with the risk to undergo and develop AD. Currently, it is necessary to perform big-scale studies to confirm that danger

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Herpes Simplex Virus-1

Herpes simplex virus (HSV)-1, also known as human herpes virus (HHV)-1, is a common neurotropic virus present in approx. Seventy percent of American population aged above 50 [97]. The reactivation of latent infection of HHV-1 has been suggested as one of the hypothesis behind AD development. Studies with the distribution of HHV-1 DNA in human brains revealed that viral DNA is located primarily within senile plaques. In some elderly dementia patients, HSV-1 DNA was detected in brain samples using in situ hybridization (ISH) [98]. This was probably the first report on the possible association between HSV-1 and dementia. Later on, the role of HHV-1 in AD was proposed by other researchers as well [99, 100]. It was noted that damage of brain tissue in early stages of the disease includes the same areas, which are covered by brain inflammation caused by HHV-1 [33, 99]. Based on the presence of antibodies in the blood, it is estimated that approx. 80% population is infected with HHV-1. A large number of recent findings have detected HSV-1 DNA in AD brains [101,100,101,102,105]. HSV-1 has been reported to be a significant risk factor when present in AD patients who are carriers of apolipoprotein E-e4 (APOE-e4) [30, 103, 106]. The HSV-1 and APOE-e4 combination results in the accumulation of Aβ and AD-like tau, which in turn are the primary components of the characteristic NFTs and amyloid plaques of AD brains [30, 103, 106]; it was observed in brain tissue of 46 AD patients compared with the brain tissue of 44 non-AD elderly people. APOE-e4 has also been reported to modulate the severity of microbial diseases or infection susceptibility, including HHV-1 as well as HHV-2 [102]. It has been demonstrated in studies with neural cells infected with HHV-1 that the reactivation of their infection may induce AD-relevant cellular changes like the formation of Tau protein and Aβ plaques [102, 107]. A high frequency of HHV-1 DNA was reportedly present in elderly brains, which normally was restricted to very small proportion in the brains of children and young people, which in turn can be attributed to the declined immune system of elderly population [108].

Anti-HSV-1 antibodies detected in the CSF by ELISA were found to be significantly higher in AD patients [109]. In long-term studies on elderly population, a significant association was observed between the presence of anti-HSV-1 IgG antibodies and AD [110]. A prospective study with over 3000 participants showed that positivity for anti-HSV-1 IgM, which is a sign of reactivated infection, almost doubled the risk for AD [111]. With the suggested role of HHV-1 in AD, it can be concluded that herpes simplex encephalitis (HSE) causes serious brain damage in a quick time, whereas the neurocognitive changes in AD are gradual and accumulate over the years. This suggests that HSV-1 reactivation probably produce a milder and recurrent disease as described in many cases of recurrent HSE [103, 112, 113], thus proposing that AD might be caused by incidences of mild HSE. The fact that HSE survivors (mild as well as full-blown) experience memory loss, which is the primary symptom of AD, proclaims HHV-1 as the primary reason behind the same. The possible role of HHV-1 contribution in AD pathogenesis is depicted in Fig. 4.

Fig. 4
figure 4

Possible role of HHV-1 contribution in AD pathogenesis. HHV-1 infections include a lytic and latent state in the individual. Several factors as aging, stress, peripheral infections, and immune system decline predispose the individual to HHV-1 reactivation, for example, in the nerve tissue. The reactivation of HHV-1 in the brain may be related with AD occurrence and Aβ-Tau formation in the neural tissue

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Other HHV

HHV-2 (also known as herpes type 2) infection results in strong accumulation of Aβ peptides and hyperphosphorylated tau in human SK-N-MC neuroblastoma cells [114]. Infection is also associated with a marked reduction in the amount of Aβ40 secreted and in the proteolytic fragments of Aβ precursor protein (APP). Nimgaonkar et al. determined whether the temporal trajectories of multiple cognitive domains are associated with the exposure to CMV, HHV-1, HHV-2, or T. gondii [115]. They showed that exposure to these viruses is associated with cognitive deterioration in older individuals, independent of general age-related variables. The exposure to T. gondii, CMV, or HSV-2 has been reported to be associated with cognitive deterioration in elderly population, which is independent of general age-related variables [115].

HHV-3 (Varicella zoster virus, VZV) reactivation are relatively frequent in older people, because of the natural immune system dysfunction and other chronic diseases (diabetes, cancers, immunosuppressive therapy), [116]. Data from Center for Disease Control and Prevention in Atlanta (CDC) indicate that in the USA, one in three people aged over 60 suffers or will suffer from shingles, which indicate toward growing health problem mainly because of recurrent nerve pain. For this reason, shingles is extremely troublesome disease in AD patients as well. It is a growing health problem in Europe and Asia as well.

A relationship between HHV-5 (Cytomegalovirus, CMV) infection and AD risk has been reported as well [113]. CMV seropositivity was reported to be associated with a faster rate of decline in global cognition and an enhanced risk of AD [117]. By demonstrating significant association between CMV-specific serum IgG antibody levels and NFTs, direct and indirect links between CMV and AD pathology were confirmed [118]. DNA obtained from problem-based learning (PBL) brain samples and analyzed for the presence of CMV, EBV, and HHV-6 showed that all samples were negative for CMV but positive for EBV and HHV-6 [119]. During a follow-up period of 5 years within a group of elderly population, EBV- or HHV-6-positive PBL was found to be enhanced in the individuals who developed clinical AD. Moreover, IgG levels for EBV and CMV antigens were also found to be enhanced in the individuals who developed AD during the follow-up period.

Hepatitis C Virus

Recent investigations suggest a relationship between hepatitis C virus (HCV) infection and the risk of dementia. HCV infection was reported to be an independent risk factor for dementia, AD, and vascular dementia [120]. However, the mechanisms by which HCV infection enhances the dementia risk are not well understood [120]. Since the first marked role of HCV in the causation of abnormalities in cerebral function about 10 years ago, many researchers have evaluated neuropsychiatric performance in HCV-infected patients with different degrees of hepatic impairment [121]. There are two hypotheses suggesting HCV infection in dementia patients. According to the first hypothesis, the virus causes indirect neurotoxicity via systemic and/or cerebral inflammation. According to the second hypothesis, the virus infects the brain by exerting a direct neurotoxic effect.

HCV RNA has been reported to be associated with CNS tissue, and reports of viral sequence diversity between liver and brain tissues suggest independent viral evolution in the CNS and liver [122]. HCV has the ability to cross BBB and can infect macrophages/monocytes, which secrete large amount of cytokines such as IL-6 and TNF-α, and cause excitotoxicity in the brain tissues. In patients with mild hepatitis C, activation of microglia cells was found to be positively correlated with altered cerebral metabolism and HCV infection [123]. Virus infection caused upregulation of cholesterol 25-hydroxylase (CH25H) gene and production of 25-hydroxycholesterol (25OHC), which induces innate anti-viral immunity [124, 125]. Human CH25H is susceptible for the AD, as well as deposition of Aβ [126]. These studies are providing a potential mechanistic link between infection and AD [127].

Strategies for AD Therapy

Standard anti-viral drugs inhibit pathological changes observed in AD caused by viral infections. The involvement of HSV-1 in AD suggests that anti-viral agents might prevent further deterioration of patients, and it is possible in the future that vaccination against HSV-1 might prevent the development of AD [128, 129]. The main anti-HHV-1 anti-viral agent is acyclovir (ACV), which targets infected cells and viral DNA replication [130]. Future clinical trials should investigate the usage of anti-herpetics such as ACV and its biodrug VCV (which is converted to ACV) in AD sufferers. ACV does not affect uninfected cells or the normal metabolism of infected cells, so has no harmful side effects like many other treatments. ACV crosses the normal BBB and causes few side effects, apart from patients with renal impairment. Promising results offer studies involving valacyclovir (VCV), which is characterized by high bioavailability and does not cause any obvious adverse effects [69]. ACV has been used for treating MS patients and a clinical trial showed that it crossed the BBB, and no patient demonstrated a damaged barrier [128].

As we have suggested in current study, virus infections are not the unique challenge for the immune system in AD. In fact, persistent and chronic bacterial infections may also play a role in inducing and amplifying chronic neuroinflammation in AD. Based on the study performed by Fillit et al., it was concluded that unlike other available treatments, anti-viral agents would provide a completely new approach by inhibiting the major cause of the AD rather than just inhibiting the AD-related symptoms [131].

Colostrinin, a proline-rich polypeptide (PRP) complex, showed immunomodulatory properties in various animal models, by inducing maturation and differentiation of thymocytes, and was also found to improve the outcome of AD patients with mild to moderate dementia [132, 133]. This context led us to explore the anti-inflammatory activity of acetylcholinesterase (AChE) inhibitors like donepezil [134]. Increasing evidence now points toward an anti-inflammatory role for AChE inhibitors through their action against free radical generation and by decreasing cytokine release from activated microglia, mostly by enhancement of ACh action on cholinergic receptors on glial cells. Donepezil treatment of AD patients for 1 month caused marked attenuation of the release of cytokines from peripheral blood monocytes and lymphocytes [135]. Donepezil revealed anti-inflammatory activity in experimental animal models [136,135,138]. Donepezil have been reported to block lipid peroxidation, preclude an increase of malondialdehyde (MDA) in experimental oxidative stress in mice [139], prevent the depletion of reduced glutathione (GSH), and show an efficient neuroprotective effect [140]. Donepezil has also been reported to directly inhibit the canonical inflammatory NF-kβ signaling, decrease the TNF-α level, and suppress the gene expression of inducible nitric oxide synthase (iNOS), interleukin-1, and TNF-β in purified cultures of microglia [141]. These effects were independent of ACh receptors, but well pronounced when the donepezil dose was significantly higher than the therapeutic dose of the drug, demonstrating a potential and novel therapeutic strategy against AD [142, 143]. It is possible that donepezil and other cholinesterase inhibitors exert their anti-inflammatory activity by elevation of the level of acetylcholine (ACh), and ACh-activated cholinergic receptors on glial cells. For example, ACh is perceived as an important modulator of the neuro-immune-endocrine axis [144], and astrocytes and microglia carry cholinergic receptors and adrenergic receptors and activation of adrenergic receptors leads to release of pro-inflammatory cytokines, whereas activation of cholinergic receptors decreases cytokine deliverance from glial cells [145, 146]. Elevation of ACh level in the brain induced by donepezil increases the activation of cholinergic (nicotinic) receptors on microglia, thus leading to decreased release of cytokines [146]. Donepezil may also restore the proper balance between H1R and H2R expression [147].

Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) has been shown to lower the risk of AD by inhibiting the production of prostaglandin inflammatory mediators [148]. Recent findings show that NSAIDs that attenuate the inflammatory processes in the brain may decrease the production of Aβ peptides and might reduce the risk of developing the disease [148]. NSAIDs have also been suggested to have no effect in patients who have already developed AD, and it was shown that treatment with COX-2 inhibitor increases the amount of Aβ in the brain. Some reports also suggest that NSAIDs might prevent the onset of AD, but it remains controversial [149]. Observational studies in humans provide the evidence that the use of NSAIDs is associated with low AD risk.

Several natural products have also been reported to possess anti-inflammatory activity and can be promising agents to treat microbes-mediated inflammation associated AD [149, 150]. More recent reports demonstrated the efficacy of the natural immunosuppressive drugs for AD treatment [149, 150]. For example, Abraham and Johnson (2009) reported that Resveratrol, a polyphenol, supplemented with diet reduced infection-related neuroinflammation and deficits in working memory in aged mice [151]. Probiotics are beneficial microorganisms to human health and reported to possess anti-microbial and anti-inflammatory activities [152,151,154] It has been demonstrated that probiotics can be therapeutic agents for AD [155]. Hence, more clinical investigations are needed to develop anti-inflammatory and anti-microbial probiotics for therapy and prevention of AD. Figure 5 depicts the most common and effective strategies for AD therapy.

Fig. 5
figure 5

Currently used therapeutic options for AD treatment. Due that there is no cure for AD, the treatments are intended to diminish the symptoms and reduce the neurodegeneration and cell death. By increasing the levels of acetylcholine in the brain via AChE inhibitors, some treatments reduce the time that brain functions continues to be affected. On the other hand, NSAIDs diminish the constitutive neuroinflammation process triggered by AD. Anti-viral treatments potentially reduce the viral infections that may be associated with the development of AD mainly, by Herpes virus, CMV, EBV, and hepatitis C virus

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Conclusion and Future Perspectives

The possibility of an infectious etiology for AD, especially late-onset of AD (LOAD), has been postulated repeatedly over the past three decades [138, 149]. This suggests the crucial role of chronic bacterial, viral, and fungal infections as causative inflammatory pathways for AD. Several studies suggest that certain pathogens are major factors in AD. Anti-microbial therapy has been explored by several investigators to treat AD (Fig. 5). Several natural products have been reported to possess anti-inflammatory and anti-microbial activities, and can be promising agents to treat microbes-mediated inflammation-associated AD [138, 149]. However, it should be noticed that all anti-viral preparations have limited effectiveness against certain viruses. Moreover, the side effects often limited application of these drugs especially in elderly population. This underscores the need for new effective anti-viral therapies and necessity for a vaccine to prevent viral infections, and therefore prevention of AD and/or Ad-like pathology that very often coexist in elderly population [67, 68].