Introduction

Alzheimer’s disease (AD) is a progressive brain disorder that destroys memory and thinking skills, ultimately causing an inability to perform even simple tasks. AD causality is multifactorial. The main risk factors include age [1], genetic predisposition [2], cardiovascular disease [3], traumatic brain injury [4], and different environmental factors [5]. The disease is associated with the overproduction and accumulation of amyloid-β peptide and hyperphosphorylation of tau protein in the brain. Although amyloid-β peptide is well known for its neurotoxic potential in AD, there is enough evidence supporting its beneficial roles in protecting the body from infections [6], repairing leaks in the blood–brain barrier [7], promoting recovery from brain injury [8, 9], and regulating synaptic function [10, 11]. In particular, the recent discovery that the amyloid-β peptide has antimicrobial activities strongly supports the possibility of an infectious aetiology of AD and suggests that amyloid-β plaque formation might be induced by infection. The idea that infection may underpin the aetiology of AD was first raised in 1907 [12], and many scientists have since investigated the links between various pathogens and the development of the disease (Fig. 1). Most research in this area has focused on individual pathogens; studies of this type were recently reviewed by Sochocka [13]. However, a growing body of evidence supports the hypothesis of polymicrobial causality [14,50]. Next-generation sequencing was subsequently used to analyze fungal DNA in samples representing four brain regions from a single AD patient [51], revealing the presence of an impressive array of yeast species. Notably, Cryptococcus curvatus and Botrytis cinerea were detected in every studied region. Analysis of two brain regions from a healthy control sample also revealed the presence of diverse fungal species. However, the species identified in control differed from those in the AD samples [51].

Multi-taxon infections

Viruses and bacteria

The effect of the cumulative viral and bacterial burden on cognition was systematically investigated by Strandberg et al., who tested seropositivity towards HSV-1, HSV-2, CMV, Chlamydia pneumoniae, and Mycoplasma pneumoniae in an elderly Finnish population (Table 2). The results of this comprehensive study indicated that viral burden was associated with cognitive impairment, but no association with bacterial burden was observed [52]. A follow-up study investigated the presence of Helicobacter pylori in addition to the pathogens listed above: seropositivity towards 3 herpetic viruses and 3 bacteria along with APOE ε4 and several other factors was tested in a cohort of 357 elderly Finnish residents. An association between herpetic viruses and cognitive impairment was again observed. Besides, the presence of APOE ε4 and low education were shown to significantly affect cognitive impairment [53].

Katan and colleagues measured levels of antibodies against HSV-1, HSV-2, CMV, Chlamydia pneumoniae, and Helicobacter pylori in a population of 1625 elderly participants, and observed a positive correlation between infectious burden and cognitive impairment [54]. A similar association was observed even when only the viral infectious burden was considered. Another systematic and well-executed study supporting an association between infectious burden and cognitive functions was published by Wright et al., who demonstrated a strong association between infection with five pathogens (HSV-1, HSV-2, CMV, Chlamydia pneumoniae, and Helicobacter pylori) and cognitive decline in the memory domain by testing samples from 588 stroke-free participants [55]. Bu et al. tested titers of antibodies against HSV-1, CMV, Chlamydia pneumoniae, Helicobacter pylori, and Borrelia burgdorferi in a cohort of 128 AD patients and 135 controls and showed that the total burden of infection with these species was associated with AD [77]. The second study showed that treatment with antiviral agents reduced the risk of develo** dementia by 45% in patients infected with herpes zoster compared to that for untreated infected patients [78]. Another interesting case is that of two siblings with chromosomally-integrated HHV-6A who suffered from cognitive difficulties. Several repeated courses of treatment with valganciclovir led to a near-complete clinical resolution in both patients [79]. The most generally promising drug for the treatment of herpetic viral infections appears to be valacyclovir, a prodrug of acyclovir. Valacyclovir was one of the first antivirals to enter into clinical trials against AD because of its high selectivity towards infected cells, favourable safety profile, and ability to enter the CNS. Its most obvious disadvantage is its narrow anti-herpetic effectivity; it is most potent against HSV-1 and HSV-2 [80, 81].

Treatment with antibacterial agents

Antibiotics are very important drugs used to treat bacterial and fungal infections. The antibacterial agents most commonly investigated in the context of AD are doxycycline and rifampicin (rifampin). Twenty-eight years ago, Namba et al. reported an absence of senile plaques in leprosy patients who had undergone long-term treatment with rifampicin [82]. Twelve years later, Loeb et al. performed a controlled trial with 101 patients diagnosed with mild to moderate AD, who were randomly split into two groups. Over 3 months, one group received combined therapy with rifampin (300 mg) and doxycycline (200 mg), while the second group received a placebo [83]. Cognitive function evaluations revealed that the antibiotic-treated group exhibited significantly lower levels of cognitive decline after six months. Interestingly, both of these antibiotics also exhibit anti-amyloidogenic activity [84,85,86,87]. Balducci and Forloni also showed that doxycycline could abolish amyloid-β oligomer-mediated memory impairment and reduce neuroinflammation in mouse models of AD [88]. Kountouras et al. found that AD patients who received a successful triple eradication therapy with omeprazole, clarithromycin, and amoxicillin had better cognitive and functional results at a 2-year check-up than patients who did not receive such treatment [89]. Another antibiotic with promising anti-neuroinflammatory and the neuroprotective effect is minocycline [90,91,92]. In a mouse model of AD, minocycline reversed memory impairment caused by the administration of amyloid-β oligomers and reduced levels of the inflammatory cytokines L-1β, TNF-α, IL-4 and IL-10 in the brain and serum [93]. On the other hand, Howard et al. reported that minocycline did not delay the progress of cognitive or functional impairment in patients with mild AD over 2 years [94]. In addition to antibiotics, small-molecule inhibitors targeting gingipains, toxic proteases from P. gingivalis, have been developed [95]. One such compound, COR388, is currently being tested against AD in a Phase 2/3 clinical trial. In a recent study, aged dogs with oral infections of P. gulae and periodontal disease were treated with COR388 by oral administration. COR388 inhibited the lysine-gingipain target and reduced the P. gulae load in the saliva, buccal cells, and gingival crevicular fluid [96].

Treatment with antifungal agents

Clinical trials with antifungal compounds were proposed by Alonso et al. [48]. Voriconazole, fluconazole, flucytosine and amphotericin B deoxycholate are antifungals with good CNS permeability that may be suitable for this purpose. In some cases, it may be beneficial to combine such treatments with neurosurgery, as noted in a recent review by Goralska et al. [97]. Combined therapies should also be considered for AD patients exhibiting signs of a multifungal infectious burden [51].

Treatment with antiparasitic agents

Antiparasitic treatments targeting Toxoplasma gondii rely on two types of drugs, namely inhibitors of dihydrofolate reductase and dihydropteroate synthetase [98]. The first choice agent for treating neurotoxocariasis is likely to be albendazole, which exhibits good blood–brain permeability [99]. Because achieving efficient uptake of such drugs into tissues (particularly the brain) is very challenging, considerable efforts have been made to develop alternative derivatives, formulations, or delivery vehicles. Polyethylene glycol-conjugated and chitosan- or liposome-encapsulated compounds resulting from these efforts have demonstrated significant efficiency gains [100]. Albendazole combined with praziquantel is also an effective treatment for neurocysticercosis [101].

Treatment with anti-biofilm agents

An important aspect of AD’s infection hypothesis is that some microorganisms can evade immune responses by various mechanisms, particularly by forming biofilms. Biofilms were first described by Costerton et al., who observed clustering of bacteria in a polysaccharide matrix [102]. These structures are organized systems that protect microorganisms against stressful conditions and are formed by both bacteria and fungi [103]. Interestingly, viruses have also been shown to form biofilm-like assemblies [104]. Additionally, biofilms can be polymicrobial, allowing multiple microbe species to co-exist in one community [105]. For example, Mazaheritehrani et al. showed that Candida biofilms also shield HSV-1 viruses, which remain infective and releasable under this protection [106]. A subsequent study showed that this shelter protects HSV-1 against physical and chemical treatments, including laser and aciclovir or foscarnet therapy [107]. Coexistence of bacteria and fungi has also been reported [108]. In the context of AD pathology, some researchers have suggested that amyloid senile plaques in CNS tissues are biofilms [109, 110]. If so, biofilms are important therapeutic targets. This may also be true for Toxoplasma gondii because current treatments are effective against the active (tachyzoites) stage but ineffective against the latent cystic stage (bradyzoites) [98].

There are ongoing efforts to develop treatments targeting fungal and bacterial biofilms [111, 112] and Toxoplasma tissue cysts [113]. In addition to the compounds mentioned above, there is considerable interest in the opportunities offered by N-acetylcysteine, which was repeatedly found to have beneficial effects in the treatment of neurodegenerative diseases including AD [114]. Importantly, this compound exhibits strong activity against biofilms of both bacteria and Candida [115, 116]. Supportive treatments based on essential oils have also shown promise. For example, experimental studies performed by Feng et al. revealed that certain essential oils are highly effective against the stationary phase of Borrelia burgdorferi [117, 118] and various fungi [119].

Conclusions

A growing number of research projects are probing the roles of pathogens in the development of AD. In the past, studies of this type focused mainly on individual pathogens [120, 121]. However, a growing body of evidence suggests that the aetiology of AD is driven at least in part by the coexistence of multiple pathogens. This insight may open up new ways of understanding, studying, and treating this disease, or even of preventing its onset altogether.

From the standpoint of prevention, it is noteworthy that changes in brain functionality appear long before the onset of AD-induced cognitive dysfunction [122]. Moreover, various fungi and bacteria have been detected in disease-free control subjects [14, 51], and several studies have demonstrated connections between infectious burden and reduced cognitive function in adults [25, 66, 69]. This suggests a need for further research on screening for various pathogens in multiple matrices using a battery of diagnostic methods. The detection of specific pathogens or pathogen classes in middle-aged adults showing early signs of reduced cognitive function could then be followed by personalized preventative anti-microbial treatment (Fig. 3). Similar procedures could also be applied to patients already suffering from AD. Additionally, pathogens’ natural tendency to evade the immune system should be taken into account during diagnosis and when choosing treatments.

Fig. 3
figure 3

Potential antimicrobial treatment of patients with AD. The proposed therapeutic strategy consists of a combination of antiviral, antibacterial, antifungal, and anti-biofilm agents. Selected antimicrobial agents represent examples of potential therapeutics for the treatment of patients with AD. Degenerated brain tissue is represented by a yellow cartoon

Full size image

It is well established that the microbiomes of our bodies host vast microbial communities. These microbial communities communicate with each other internally, but they also communicate externally with the human host, affecting many metabolic processes [123]. They influence the immune system but also modulate the development of neural tissues in conjunction with neuromodulators and neurotransmitters. As a result, they can profoundly influence health [124]. The influence of changes in the gut microbiome on AD has been investigated [125, 126]. Several environmental factors, including antibiotic and antifungal treatments, can cause the development of a dysbiotic state within these communities [127, 128]. Mounting evidence indicates that gut dysbiosis may promote Aβ aggregation and neuroinflammation in AD development [129]. Broad-spectrum antimicrobials can be thus “two-edged swords”. Therefore, additional measures to optimize the gut microbiota composition, including probiotics, specific foods, and dietary patterns, should be taken into account when considering potential antimicrobial AD treatments.

Another recent discovery that could play an incredibly important role in diagnosing and treating AD, particularly when considering treatments targeting polymicrobial infections, is that the brain might have its unique microbiome [130]. This theory is supported by the results of Alonso et al., who demonstrated the presence of various bacterial and fungal species in both AD patients and healthy controls [14]. Further research on AD from the poly-microbial-inflammatory-microbiome point of view is therefore needed. The results of such studies may reveal a need for more personalized and complex ways of both diagnosing and treating the disease.