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Infectious origin of Alzheimer’s disease: Amyloid beta as a component of brain antimicrobial immunity


The amyloid cascade hypothesis, focusing on pathological proteins aggregation, has so far failed to uncover the root cause of Alzheimer’s disease (AD), or to provide an effective therapy. This traditional paradigm essentially explains a mechanism involved in the development of sporadic AD rather than its cause. The failure of an overwhelming majority of clinical studies (99.6%) demonstrates that a breakthrough in therapy would be difficult if not impossible without understanding the etiology of AD. It becomes more and more apparent that the AD pathology might originate from brain infection. In this review, we discuss a potential role of bacteria, viruses, fungi, and eukaryotic parasites as triggers of AD pathology. We show evidence from the current literature that amyloid beta, traditionally viewed as pathological, actually acts as an antimicrobial peptide, protecting the brain against pathogens. However, in case of a prolonged or excessive activation of a senescent immune system, amyloid beta accumulation and aggregation becomes damaging and supports runaway neurodegenerative processes in AD. This is paralleled by the recent study by Alam and colleagues (2022) who showed that alpha-synuclein, the protein accumulating in synucleinopathies, also plays a critical physiological role in immune reactions and inflammation, showing an unforeseen link between the 2 unrelated classes of neurodegenerative disorders. The multiplication of the amyloid precursor protein gene, recently described by Lee and collegues (2018), and possible reactivation of human endogenous retroviruses by pathogens fits well into the same picture. We discuss these new findings from the viewpoint of the infection hypothesis of AD and offer suggestions for future research.

Author summary

More than a century after its discovery, Alzheimer’s disease (AD) remains incurable and mysterious. The dominant hypothesis of amyloid cascade has succeeded in explaining the key pathological mechanism, but not its trigger. Amyloid beta has been traditionally considered a pathological peptide, and its physiological functions remain poorly known. These knowledge gaps have contributed to repeated failures of clinical studies. The emerging infectious hypothesis of AD considers central nervous system (CNS) infection the primary trigger of sporadic AD. A closely connected hypothesis claims that amyloid beta is an antimicrobial peptide. In this review, we discuss the available evidence for the involvement of infections in AD, coming from epidemiological studies, post mortem analyses of brain tissue, and experiments in vitro and in vivo. We argue there is no unique “Alzheimer’s germ,” instead, AD is a general reaction of the CNS to chronic infections, in the milieu of an aged immune system. The pathology may become self-sustained even without continuous presence of microbes in the brain. Importantly, the infectious hypothesis leads to testable predictions. Targeting amyloid beta should be ineffective, unless the triggering pathogen and inflammatory response are addressed as well. Meticulous control of selected infections might be the best near-term strategy for AD prevention.


Alzheimer’s disease (AD) belongs among the most feared diseases in the developed world. The available treatment is unable to affect the disease progress efficiently and offers only minor and temporary alleviation of some symptoms [1]. Search for novel therapeutics is ongoing, but no less than 413 trials have failed during 2002 to 2012 [2] and the drug failure rate has reached 99.6% [35]. It is the poorly known AD etiology that precludes causal treatment. The leading amyloid cascade hypothesis has provided many important insights and is supported by an impressive amount of experimental data, but it essentially explains an involved mechanism rather than the cause of the disease development. We propose that taking one step up the causal chain might be necessary for understanding the true nature of the disease. The main goal of this review is to explore the hypothesis of the essential role of pathogens and immune system activation in AD development and a protective role of amyloid beta peptide as a part of brain immunity. This might open the door to new approaches beyond the traditional paradigm and hopefully also new therapeutic strategies.

Alzheimer’s disease: Hallmarks, forms, and the amyloid cascade hypothesis

AD is a neurodegenerative disease with inconspicuous onset and usually slow progression, typically affecting the elderly. The clinical stage of the disease is preceded by a mild cognitive impairment (MCI), a cognitive decline more severe than expected at a particular age [6]. Then, AD clinical symptomatology starts with impairment of olfaction and odor memory [7], episodic memory and disruption of cognitive functions, emotional changes, and apathy or aggression. Later, impaired communication, disorientation, confusion, disrupted sleep–wake cycle, motor coordination deficit appear and in the late phase, patients suffer from disruption of social recognition including the family and caregivers, and overall personality transformation (Fig 1A) [8]. However, the pathophysiological processes start many years before the clinical symptoms are manifested [6].

Fig 1. AD: Clinical symptomatology, forms, and Aβ and tau protein pathologies.

(A) AD clinical symptomatology. The “down” arrows represent impairment or disruption of the brain functions in AD patients while “up” arrows symbolize the increase. (B) Two AD forms, familial and sporadic, differing in time of the onset, progression rate, and a cause, can be recognized. The familial form is associated with autosomal dominant mutations leading to inherently increased production of Aβ, especially the highly fibrillogenic Aβ ending at residue 42, (Aβ1–42). By contrast, the sporadic form does not follow mendelian inheritance and its causative triggers remain unknown. The strongest known genetic factor is APOE4. (C) In AD, the monomers of Aβ, which are cleavage fragments of APP, aggregate into oligomers. The oligomers, especially the cytoplasmic ones, are believed to be the most toxic, although extracellular amyloid plaques are the most conspicuous outcome of the process. (D) The tau protein normally binds to and stabilizes microtubules within neuronal axons. In an AD patient brain, tau protein is hyperphosphorylated and accumulates into neurofibrillary tangles, which leads to destabilization of cytoskeleton, disruption of synapses, and finally death of neurons. Aβ, amyloid beta; AD, Alzheimer’s disease; APOE4, apolipoprotein E4 allele; APP, amyloid precursor protein; BACE1, beta-site APP-cleaving enzyme.

Two AD forms with similar symptomatology, but different etiology, can be recognized (Fig 1B). The familial form is characterized by early onset (<65 years) and rapid progression. It is associated with mutations leading to increased production of amyloid beta (Aβ, see below), especially the highly fibrillogenic Aβ ending at residue 42, (Aβ1–42; [9]). By contrast, the sporadic form has late onset (>65 years) and unknown causative triggers. While identified familial genetic mutations in amyloid precursor protein (APP) and presenilin [1012], a component of gamma-secretase complex [13], are responsible for only about 1% of all AD cases, the sporadic form afflicts more than 95% of the patients [14], which is, however, not much reflected in animal AD models research. The strongest known genetic risk factor in the sporadic form is apolipoprotein E4 allele (APOE4) [15,16]. Although the knowledge about an involvement of APOE4 in AD pathology is rather poor, several hypotheses consider affecting Aβ clearance [17] and oligomerization [18].

Aβ peptide is one of the key molecules in the AD pathology. The monomers of Aβ are cleavage fragments of APP produced by the beta-secretase (beta-site APP-cleaving enzyme, BACE1) [1012] and gamma-secretase [13]. Aβ occurs in both intra- and extracellular space and is prone to aggregation. In AD, Aβ aggregates into extracellular amyloid plaques that are the most conspicuous outcome of the process (Fig 1C). However, it is the oligomers that are the most toxic and contribute the most to AD progress [1921]. Traditionally, Aβ peptide was believed to be the key cause of AD pathology, and considered only a byproduct of APP catabolism, lacking a normal physiological function. Later, it was found that Aβ is produced also under normal conditions [22] and plays an important role in many physiological processes, including response to cerebral infection [23]. Importance of Aβ is evidenced by its presence in all vertebrates, with high degree of sequence homology [14,23].

The tau protein is the second important molecule in AD pathology [24], normally binding to and stabilizing microtubules within axons. In an AD patient brain, tau protein is hyperphosphorylated, which leads to unbinding from microtubules and destabilization of cytoskeleton, contributing to final neuronal loss through synapse disruption (Fig 1D) [25]. Hyperphosphorylated tau is accumulated into neurofibrillary tangles intracellularly and later also outside the neurons [26]. It seems that both pathologies (Aβ overproduction and tau hyperphosphorylation) might influence or potentiate each other, and both contribute to synapse disruption leading to neurodegeneration [27,28]. Importantly, the presence of both pathologies is the necessary criterion for AD diagnosis [6]. Nevertheless, it is probable that the onset of AD requires a certain (not yet identified) trigger event, initiating the process of aberrant protein accumulation through a chain reaction or positive feedback.

The amyloid cascade hypothesis supposes that the deposition of Aβ peptide in the brain is the main cause of AD pathology [29,30]. In our view, the hypothesis offers a good description of the process of amyloid accumulation and the resulting pathology. However, it mostly does not consider the physiological roles of Aβ and is not concerned with the factors that initiate its (over)production in sporadic AD.

Beyond Aβ and tau pathologies, neuroinflammation has emerged as the third vital contributor to AD pathogenesis. Microglia are the key innate immune players in the central nervous system (CNS), and they can recognize and remove excessive Aβ deposits [31]. However, prolonged microglia activation triggers an inflammatory cascade leading to neuronal damage [32]. This might initiate hyperphosphorylation of tau protein that promotes AD pathology [33,34]. On the other hand, microglia lose their scavenging capacity in aging brains, which leads to reduced removal of Aβ deposits, facilitating AD pathology anyway [35,36]. Altogether, it demonstrates that neuroinflammation can enhance ongoing AD pathology. Moreover, Lee and colleagues demonstrated that systemic inflammation induced by bacterial endotoxin affects the pathological processing of APP [37]. The mechanism is presumably mediated by tumor necrosis factor (TNF) and interferon-gamma [38,39], pro-inflammatory cytokines commonly produced by activated innate immune cells. These data indicate that the pro-inflammatory milieu can initiate AD pathology via alteration of APP/Aβ homeostasis.

Another evidence showing that neuroinflammation plays an essential role in AD development, pushing the Aβ pathology to the sidelines, could be the existence of “resilient” individuals. In fact, some portion of individuals with high burden of amyloid plaques and tau tangles in the brain do not develop dementia. The reasons for such brain “resilience” have not been clarified so far. However, the lack of neuroinflammation represents one suggestion as the activated microglia and astroglia, present around synapses and accompanied by the release of pro-inflammatory cytokines, are typical only for AD brains, but not for the resilient brains [40].

We believe that no major breakthrough in sporadic AD therapy is conceivable without understanding the primary causes. Although over 40 genetic loci (related to APP/tau processing, immune response, or other cellular processes) have been linked to the AD risk in genome-wide association studies [41], it is reasonable to think that the primary trigger comes from the outside. In the following sections, we discuss the existing evidence linking AD with specific groups of pathogens, namely bacteria, viruses, fungi, and parasites (see the list of pathogens the most discussed here in the context of AD, and possible ways of their entry into the brain, in Fig 2).

Fig 2. Pathogens possibly associated with AD pathology and suggested ways of their entry into the brain.

On the left, the most important pathogens associated with AD discussed in this review. Pathogens inhabiting nasal and oral cavity can migrate through disrupted mucosa and then along the olfactory nerve (e.g., Chlamydia pneumoniae; left green arrow) or the trigeminal nerve (e.g., periodontal Treponema species and Herpes simplex virus type 1; middle yellow arrow). Microbes from both oronasal area and the periphery can enter the bloodstream during transient bacteremias or candidemias (e.g., Porphyromonas gingivalis, Candida albicans) and then attack the brain through disrupted BBB (right red arrow). Parasites like Toxocara canis also enter the CNS from the blood vessels. AD, Alzheimer’s disease; BBB, blood–brain barrier; CNS, central nervous system.

Infectious origin of Alzheimer’s disease as an emerging field

Bacteria and Alzheimer’s disease

The infectious hypothesis of AD, positing external pathogen as its primary cause, is hardly new. When AD was first described by Alois Alzheimer and Oskar Fischer in 1907 [42], the discoverers noticed similarities between AD and neurosyphilis, implying bacterial origin [43]. Infection of the CNS by bacteria Treponema pallidum in neurosyphilis causes microgliosis, cortical atrophy, amyloid plaques, and tauopathy [44]. Other spirochetes (such as Borrelia) are also known for their neurotropism [45]. Indeed, Borrelia spirochetes were repeatedly identified in the brain, cerebrospinal fluid, or blood of AD patients [43,44,46,47]. In some studies, the bacteria co-localized with amyloid plaques and neurofibrillary tangles in the brain tissue. The microbes were mostly identified as Borrelia burgdorferi, the causative agent of Lyme disease, a pathogen known for its ability to cause chronic CNS infections. Miklossy and colleagues demonstrated that exposure of human neurons and glia to B. burgdorferi cells in vitro leads to amyloid production and tau phosphorylation, showing the potential of spirochetes to facilitate AD-relevant processes [48].

Periodontal disease is a confirmed risk factor of AD, a predictor of faster disease onset, and is also known to accelerate the AD-like degenerative changes in Down syndrome [4952]. Riviere and colleagues found that periodontal Treponema species are capable of invading the brain, and spirochetal infestation is more severe in AD patients [53]. We must critically note that those studies could not demonstrate the actual direction of causality, and several other attempts have failed to detect oral spirochetes in AD tissue [5456]. Another member of oral microflora causing chronic periodontitis, Porphyromonas gingivalis, has been recently identified in the brain tissue of AD victims, and its ability to penetrate into the brain and stimulate Aβ production, neuroinflammation, and tau pathology was demonstrated in animal models and cell culture [57]. Of note, gingipains (proteases released by P. gingivalis) switch microglial activity toward neuroinflammatory response, leading to neuronal damage and impaired clearance of Aβ [58]. This opens the possibility that apart from effects of local brain infection, AD pathology could also be triggered indirectly by pathogen-derived molecules (virulence factors) produced elsewhere in the body. Although the clinical trial (NCT03823404) testing the gingipain inhibitor COR388 (atuzaginstat) failed [59], microbial toxigenic mechanism should not be generally rejected. For example, polysaccharide components of P. gingivalis extracellular capsule were also proposed to activate innate immunity and inflammation leading to AD-like pathology in a rat model [60].

Another line of research connects AD to infections by intracellular chlamydiae [61]. Chlamydia (Chlamydophila) pneumoniae is a prevalent respiratory pathogen, especially common in the elderly [62]. The infection may become systemic and enter the CNS [63,64]. Balin and colleagues reported C. pneumoniae in post mortem AD brain samples, with bacterial cells located inside pericytes, astroglia, and microglia [65]. Several later studies confirmed this association [6668], although some did not [6971]. Furthermore, the bacterial cells seem to be located in the areas primarily affected by the AD pathology, especially amyloid deposition [65,68,72]. The causal role of this pathogen in AD is strongly bolstered by murine model experiments, where C. pneumoniae is able to invade the brain through olfactory bulbs, triggering neuroinflammation, Aβ accumulation, and plaque formation, even in the absence of mutated APP [7377]. Other common bacteria, such as Helicobacter pylori [7881] and Propionibacterium acnes [82,83], have been implied in AD pathology; however, convincing evidence for the link is yet to be provided.

It seems that bacteria from very different taxonomical or ecological groups can all be relevant in the context of AD. Species capable of direct, chronic CNS infections seem to be particularly prominent, followed by bacteria characteristic for peripheral (oral) infections, which presumably invade the brain as opportunistic pathogens once the defense barrier is weakened by immunosenescence or chronic disease. However, brain invasion may not even be necessary as microbial virulence factors, such as lipopolysaccharide (produced by gram-negative bacteria) or gingipains (released by Porphyromonas gingivalis) can induce neuroinflammatory response, even in the absence of actual pathogen in the CNS [84].

Herpes viruses in Alzheimer’s disease

Neurotropic viruses of the Herpesviridae family, especially the Herpes simplex virus type 1 (HSV1), belong to the prime suspects, as they are highly prevalent, able to produce latent infections in neuronal cells, and preferentially infect brain structures typically affected in AD [85,86]. HSV1 infection initiates production of proinflammatory cytokines [87], which are also elevated in brains of AD patients [88]. In a mouse model of HSV1 recurrent infection, progressive accumulation of AD biomarkers (Aβ, hyperphosphorylated tau) was observed in the neocortex and hippocampus. It was triggered by repeated virus reactivations (typical for human herpes labialis) and correlated with cognitive deficits [89]. HSV1 infection could promote tau hyperphosphorylation via US3 viral kinase activating protein kinase A [86]. Of note, AD incidence was highly correlated with reactivation of HSV seropositivity in humans as well [90]. It was also suggested that proinflammatory cytokines released during peripheral infections could stimulate neuroinflammation and HSV1 reactivation in the CNS, leading to AD development [86].

The presence of HSV1 was confirmed in various areas of AD brains [91,92], but not all AD patients seem to harbor the virus [93]. Moreover, HSV1 is not sufficient to cause AD by itself [91]. A strong risk emerges only in combination of latent infection with APOE4 [94,95]. APOE4 might facilitate entry of HSV1 virus into the brain or allow more efficient spread and replication of the virus in the brain. Both the virus and APOE protein compete for the same binding molecule, heparan sulfate proteoglycan, before entering the cell through specific receptors. The weaker binding of APOE4 makes it a weaker competitor, relative to the other APOE isoforms [86]. This is supported by the findings from APOE-transgenic mice, where the level of latent HSV1 DNA in the brain was much higher in mice expressing the human APOE4 compared to mice carrying the APOE3 allele [96,97].

In vitro observations confirmed that HSV1 infection increased intracellular Aβ levels [98] and activity of BACE1, the enzyme cleaving Aβ from APP [99]. It also induced AD-specific phosphorylation of tau protein [100], and neurite damage due to alterations in microtubule dynamics, followed by neuronal death [101]. In addition, HSV1 caused synaptic dysfunction in cell culture of cortical neurons [102] that is also one of the major hallmarks of AD [103]. Recent work by Cairns and colleagues used 3D cerebral organoids derived from human-induced neural stem cells to study the response to low-level infection by HSV1. The model replicates many AD hallmarks that could be prevented by timely application of valacyclovir [104].

The risk of senile dementia is higher in people infected with HSV. Conversely, anti-herpetic medications cause a dramatic decrease in the number of individuals who later develop dementia [105]. Furthermore, Wozniak and his colleagues found a great beneficial effect of antiviral agents on the levels of Aβ and abnormally phosphorylated tau protein in HSV1-infected cell cultures [106109]. The tested antiviral drugs (e.g., acyclovir) inhibited HSV1 DNA replication that led to decrease in hyperphosphorylated tau accumulation [108]. Valacyclovir is a pro-drug that is converted by viral enzymes to acyclovir, incorporating into viral DNA and inhibiting viral DNA polymerase activity [110]. For nearly 2 decades, valacyclovir has been the most widely used antiviral treatment of peripheral HSV1 (herpes labialis), HSV2 (genital herpes), and some other viral infections, with a good CNS penetration and a great safety profile. Currently, valacyclovir proceeded to be tested in clinical trials (NCT03282916; NCT02997982) as the first antiviral drug with the potential to treat AD [110,111]. Another clinical study employed combined antiviral therapy by apovir (pleconaril and ribavirin) in AD patients [112]. While some of the results were mildly encouraging, the tolerability of the treatment was low and the drop-out rate high, making the study inconclusive. So far, antiviral therapy has brought promising results in possible reduction of the risk for development of clinical HSV1-associated AD [113]. Therefore, specific anti-herpetic treatment, in combination with anti-inflammatory treatment, might represent a promising therapeutic strategy to prevent AD occurrence in people without any clinical signs, but further confirmation of its efficiency is required. The evidence for the effect of antiviral agents in patients already suffering from the disease is missing and more studies in this field are necessary [114].

Besides HSV1, other herpes viruses have also been linked to AD. Human herpes virus type 6 (HHV6) has been found in a higher proportion of AD patient brains in comparison to age-matched normal brains [115]. The risk was not associated with APOE4, but rather modulated by genes responsible for the NK-cell immune response [116]. HHV6 (and Epstein–Barr virus) positivity has been found to increase the risk of conversion to AD [117].

Several recent studies have also pointed at the Varicella zoster virus, responsible for herpes zoster, showing both its increased prevalence in AD patients and benefits of antiviral therapy and vaccination [118120]. Cairns and colleagues have demonstrated in vitro that the effect of Varicella zoster virus is likely indirect. The virus elicits neither amyloid nor tau pathology, although it induces gliosis and neuroinflammation. However, it can reactivate HSV1 in quiescently infected cells, which then triggers both Aβ and hyperphosphorylated tau production [121]. Infection by Cytomegalovirus, another member of Herpesviridae, is positively correlated with clinical markers of AD [122]. Interestingly, it seems that the concurrent presence of antibodies against both Cytomegalovirus and HSV1, rather than Cytomegalovirus or HSV1 alone, is a significant AD risk factor for future AD development [123]. This may point at interaction between the viruses, similar to the one found for Varicella zoster virus by [121]. Caruso and colleagues have hypothesized that Cytomegalovirus infection induces a general pro-inflammatory state, which might be beneficial for younger individuals as it protects them against other infections, but becomes deleterious in the elderly, leading to chronic/latent inflammation and increasing their morbidity and eventual mortality [124].

Human immunodeficiency virus (HIV)-infected patients develop a form of dementia accompanied by increased Aβ production and plaque formation (reviewed by [125]). The presence of APOE4 allele was found to facilitate its progress [126,127], similarly to HSV1 infection. However, very little is known so far about the role of non-herpetic viruses (such as HIV) in AD pathology, and further investigation is required.

Fungi and eukaryotic parasites in Alzheimer’s disease pathology

Besides bacteria and viruses, fungi and eukaryotic parasites have been implied in AD pathology. Wu and colleagues have recently demonstrated that a common pathogenic yeast Candida albicans crosses the mouse blood–brain barrier (BBB). Yeast aggregates in the brain induce local inflammation with microglial activation, production of inflammatory cytokines, and elevated production of APP and Aβ [128]. As for human samples, pathogenic yeasts or even other fungi (soil or phytopathogenic species) were proposed to be present in post mortem AD brains [93,129134]. However, the studies included only a low number of samples, the authors admit unspecific binding of antibodies used for immunohistochemical detection, and environmental contamination by exogenous DNA cannot be fully excluded. Additionally, some of the signals obtained from next-generation sequencing could stem from off-target amplification in low biomass samples leading to false-positive results [135]. We suggest that these results should be further validated in independent studies prior to making strong conclusions.

The role of eukaryotic parasites in AD etiology/pathology has been rather neglected although there are many species affecting the human CNS [136]. Of them, Toxocara canis (a dog roundworm) and Toxoplasma gondii (an intracellular protist) have sparked special interest as they are worldwide distributed and cause chronic infections in humans. Cerebral toxocarosis is caused by the migration of T. canis larvae into the CNS. While the disease is hardly traceable in humans, the experimental mouse model is available and well characterized. Besides neuroinflammation [137,138] and neurobehavioral changes [139] observed in infected mice, 2 specific features were proposed to be of particular importance regarding AD pathology. First, it is increased production and progressive accumulation of APP, Aβ, and phosphorylated tau in mouse brains [140,141]. While APP localizes mostly to axons, indicating axonal injury [142,143], the distribution of Aβ has not been examined. Hence, it is unclear whether Aβ concentrates around the migrating parasites and forms oligomers. Second, large amounts of transforming growth factor-beta (TGF-β) precursor, positively correlating with the infection dose, are produced in infected mouse brains [140]. Except for TGF-β immunosuppressive and neuroprotective functions [144], it was shown to promote amyloidogenesis both in vitro and in vivo [145,146]. Based on these hints, Fan and colleagues proposed a possible role of chronic neurotoxocarosis in the initiation of AD-like pathology or even AD itself [147]. Unfortunately, experimental data testing this intriguing hypothesis (especially in long-term settings) are not available.

Toxoplasma gondii causes chronic infections characterized by the life-long presence of cysts in various tissues, including the CNS. In immunocompetent hosts, the infection is clinically asymptomatic, but behavioral alterations have been linked with latent toxoplasmosis [148,149]. While Kusbeci and colleagues reported higher T. gondii seropositivity among AD patients [150], other studies failed to confirm toxoplasmosis as a risk factor for AD [151,152] or general cognitive decline [153]. Accordingly, meta-analyses also reported only marginal association between toxoplasmosis and AD [154,155]. T. gondii-infected mice prone to AD pathology exhibited reduced Aβ plaques and milder learning and memory deficits, likely thanks to increased production of anti-inflammatory cytokines (IL-10, TGF-β) and improved clearance of Aβ [156,157]. Suppression of the inflammatory and Aβ response of the host is probably a part of the immune evasion strategy of the parasite. Correspondingly, reduced Aβ deposition correlated with remarkably higher parasite burden and persistence of the infection [158]. This supports the view that Aβ has protective antimicrobial functions (it can even accumulate around T. gondii cysts; [159]), and its depletion facilitates spreading of the infection. Interestingly, this effect is strain specific, and T. gondii strains that cannot induce clearance of Aβ plaques have lower parasite burden in AD mice [158] and trigger cortical neurodegeneration [160].

Protective role of amyloid beta

The “antimicrobial protection hypothesis of AD” assumes that Aβ production, oligomerization, and fibrillization, in fact, represent an innate immunity of the brain aimed against pathogens [161,162]. It seems that Aβ exhibits many characteristics of the other known antimicrobial peptides [162,163]. In vitro studies combined with experiments on mice show a protective role of Aβ in case of bacterial, viral as well as fungal infections. Microbes or viruses were found to be associated with Aβ plaques [44,92]. Interestingly, experimental therapy targeting Aβ in AD patients results in increased infection incidence [23]. Recently, Alam and colleagues have shown a revolutionary finding that α-synuclein, a protein abnormally accumulated in the brains of patients suffering from Parkinson’s disease (and not previously suspected from immune actions), is an essential mediator of the immune responses and inflammation within the peritoneal cavity [164]. In comparison, Aβ physiological antimicrobial function and the accumulation within the brain contributing to AD development look markedly similar and are supported by independent observations from bacterial, viral, and fungal infections.


An antimicrobial activity of Aβ, able to agglutinate and entrap bacteria, was assessed in several clinically relevant species [165,166], and in some cases, the bactericidal activity of Aβ was greater compared to the archetypal human antimicrobial peptide LL-37 [165]. Moreover, the antimicrobial activity was higher in temporal lobe homogenates from AD patients than in age-matched samples from non-AD subjects, and was correlated with Aβ levels [165]. Recently, the possibility has been raised that aggregation of Aβ, α-synuclein and perhaps other pathological proteins could be seeded by functional bacterial amyloid proteins, normally involved in cell adhesion and biofilm formation [167,168]. As some bacteria evade antimicrobial peptides and defuse them by producing trapping proteins that bind them with high affinity [169], triggering Aβ or α-synuclein aggregation on extracellular “seeds” could arguably serve the same purpose.


Studies on cell cultures revealed that especially Aβ1–42 oligomers are able to interact with HSV1 (and also HHV6), prevent their entry into the host cell and inhibit its replication [161,170]. In case of HSV1, Aβ binds directly to the viral particles, entrapping viruses in insoluble deposits through generation of Aβ fibrils on the viral surface [161]. Aβ probably interacts with viral coat proteins, since the replication of non-enveloped human adenovirus was not prevented by Aβ1–42 [170]. Soluble Aβ1–42 protected human neuronal–glial cell culture against HSV1 pathological effects with similar efficiency as the “classical” antiviral agent acyclovir [171]. In addition, transgenic mice producing human Aβ with mutations known to cause familial AD showed higher survival after application of lethal viral dose in comparison to wild-type mice. Moreover, administration of nonlethal viral dose to these mice led to Aβ deposits surrounding the viruses [161]. These observations were questioned by some subsequent studies [172,173]. However, this discrepancy could be explained by viral particle doses or viral strains/species used, which may differ in their sensitivity to Aβ. In vitro experiments showed the antimicrobial activity of Aβ also against enveloped Influenza A virus, with the Aβ1–42 being more efficient compared to Aβ1–40. Aβ inhibited viral replication, caused aggregation of viral particles and also facilitated uptake of viruses by leukocytes [174].

Aβ fibrils with bound nucleic acids (that can originate either from viral particles of damaged host cells) are highly immunogenic and elicit robust type I interferon secretion by adjacent microglia [175,176], which promotes their antiviral response. Activated microglia or other cells infiltrating the infected brain can also produce interferon-γ (IFN-γ) [177,178], which facilitates Aβ production (see above). This shows that Aβ is an integral part of the innate immune system antiviral response. The suggested positive feedback loop between Aβ and interferon signaling perhaps makes the system prone to self-perpetuating or excessive inflammatory responses.


In case of low-grade candidemia caused by Candida albicans in mice, Wu and colleagues observed glial granulomas in brain tissue [128]. They consisted of Aβ peptides accumulating around the yeast cells and accumulation of activated microglia and astroglia surrounding these aggregates. The authors have shown that Aβ binds to fungal cells, and although it does not destroy them directly, it stimulates phagocytic activity of microglia that also produce not yet identified antifungal soluble factors. Transgenic mice expressing human Aβ with familial AD mutations showed faster clearance of C. albicans from brains compared to wild-types and transgenic mice missing gene for APP [128].

It seems that Aβ, as an antimicrobial peptide, acts through 2 direct pathways: (1) binding of soluble Aβ oligomers to microbial surface carbohydrates that causes agglutination of microbes, entraps them into the fibrillar network, and so prevents them from invading the host cells and spreading within the tissues; and (2) fibrillization of Aβ oligomers on microbial surface to perturb microbial membranes [179]. Indirect effects involve the stimulation of other humoral or cellular components of the immune innate system such as microglia.

If Aβ serves as a brain protector against pathogens, why does the protective response overturn into a pathology which slowly and unavoidably kills the host? Aβ is a potent weapon against microorganisms, but also a double-edged sword that can damage and destroy neurons as well, unless tightly regulated. Butterfield and Lashuel suggest that Aβ peptides are able to create annular protofibrils that in higher concentrations disrupt cellular membranes [180]. For reasons that are not yet fully clear, this mechanism may turn against neuronal plasma membranes instead of the microbial ones and lead to destruction of the neurons. Killing of infected neurons by intrinsic protective peptides could be a meaningful response in the case of intracellular pathogens (such as viruses) able to inhibit cell apoptosis. Moreover, the chronic accumulation and fibrillization of Aβ may trigger the cascade leading to hyperphosphorylation of the tau protein, formation of neurofibrillary tangles [181], and finally, neuronal death, as described by the “amyloid cascade hypothesis” [29,161]. Disruption of the cerebral glymphatic system may be the key factor mediating the transition between the physiological and pathological role of Aβ [182]. If the clearance of Aβ, as well as hyperphosphorylated tau protein [183,184], becomes impaired, the molecules accumulate in the brain tissue and support chronic neuroinflammation. Whether hyperphosphorylated tau protein is also part of brain innate immunity has not been clarified so far.

Under normal conditions, BBB presumably prevents most pathogens from entering the brain at all and the innate response involving Aβ is therefore rarely activated. Even then, it usually deals with the infection in a quick and constrained manner, causing only limited damage to neural cells. However, these “acceptable losses” might easily become excessive during chronic infections of the CNS, or when the defensive response fails to be terminated, leading to progressive neurodegeneration apparent in AD. This also explains why it is typically seen in an aging organism, where the peripheral defenses are weakened, the pathogen load is typically high, and the senescent immune system is inclined towards prolonged inflammatory responses.

Reverse transcription and genome insertion of APP mRNA: Friend or foe?

In recent years, the phenomena of somatic genomic mosaicism and somatic gene recombination in neuronal cells have been implied in the origin of neurodegenerative disorders, particularly AD, although some of the findings are disputed (reviewed in [185,186]). Bushman and colleagues [187] have observed that neurons from the AD brain cortex have increased DNA content by 8% relative to neurons from age-matched control brains. This increase, however, was not seen in cerebellar neurons and somatic cells of the same AD patients. In addition, the study reported increased copy numbers of the APP gene in cortical neurons from the AD brains relative to non-AD control tissue. A subsequent study by the same team [188] elaborated this observation and found neuron-specific insertions of DNA copies, derived from APP mRNA (termed genome-inserted complementary DNAs, gencDNAs), into the nuclear genome (Fig 3). These gencDNAs lack introns and often bear point mutations or exon deletions as both regular and reverse transcription is error prone, but can still be transcribed and translated, producing abnormal protein products. Moreover, the resulting mRNAs may undergo repeated cycles of retro-insertion, leading to cumulative errors. In AD patients, APP gencDNAs are not only more numerous, but also often bear harmful mutations usually linked to familial AD [188].

Fig 3. Somatic APP gene recombination.

In human neurons, additional copies of the APP gene are created by the process of somatic recombination. The original APP gene (1) is undergoing standard transcription and splicing. Mature APP mRNAs (2) can undergo the process of reverse transcription (3) to complementary DNAs (cDNAs; 4), which can be retro-inserted into genomic DNA as genome-inserted complementary DNAs (gencDNAs; 5). The resulting additional copies of APP gene lack introns and often bear point mutations or exon deletions as both regular and reverse transcription are error prone, but can still be transcribed and translated (6). Moreover, the resulting mRNAs may undergo repeated cycles of retro-insertion, leading to accumulation of errors. We propose that cerebral infection provides some of the necessary ingredients for this mechanism, namely activation of APP expression (7), oxidative damage leading to DNA breaks (8), and a source of reverse transcriptase (9). Enhanced APP production by gene multiplication, and even the production of aggregation-prone mutant forms of amyloid beta (10) might act as an antimicrobial defensive mechanism (11). However, it is also harmful to the tissue itself, and as the mutant gencDNA insertion is irreversible, it may easily open the door to progressive neurodegeneration. APP, amyloid precursor protein; gencDNA, genome-inserted complementary DNA.

The authors suggest that the somatic gene recombination of APP may induce sporadic AD via mechanisms partly analogous to familial AD. Whereas in familial AD, all neurons exhibit the disease-linked genotype, sporadic AD would be initiated by a subpopulation of neurons featuring somatic mutations with similar effects (overexpression of normal or mutated APP) [189]. Abnormal protein products of APP gencDNAs might be especially toxic, initiating amyloid aggregation or other pathological mechanisms [189]. As the insertions and mutations presumably accumulate during the lifetime, they may explain the age-dependent and seemingly random occurrence of sporadic AD.

Creation of gencDNA requires several ingredients: expression of the gene, reverse transcription of its mRNA into DNA, and breaks in the genomic DNA strands allowing integration of the gencDNA. The source of reverse transcriptase activity, in particular, is completely unknown, as humans lack intrinsic reverse transcriptase. We propose that cerebral infection may provide the necessary conditions. APP transcription is up-regulated as a consequence of infections, while DNA strand breaks are induced during neuroinflammation and oxidative stress, and are linked with AD pathology from early stages onwards [190192]. The last crucial mechanism, reverse transcriptase, might be provided by external retroviral infection, human endogenous retrovirus, or a retrotransposon. Retrotransposons and human endogenous retroviruses are activated under specific conditions, including herpetic infections [193], neuroinflammation, and aging [194,195]. Indeed, activation of retroviruses and transposable elements has been linked to aging-related neurodegenerative disorders [194,196]. Lee and colleagues suggest that patients receiving reverse transcriptase inhibitors may show lower AD risk, but the evidence for this correlation seems inconclusive [188] and requires further research.

We may speculate about the purpose of the gencDNA-creating mechanism (Fig 3). The discoverers consider that elevated gene dosage, leading to increased gene transcription with bypassing splicing, is beneficial for a cell when it needs a higher amount of APP [188]. If Aβ acts as an antimicrobial peptide, it is tempting to speculate that even the elevated mutagenesis might have its benefits, similarly to suggested enhancement of the function of some known antimicrobial peptides by polymorphism or posttranslational modifications [162]; however, this needs to be experimentally tested. Indeed, the APP mutations leading to familial AD may increase the antimicrobial activity of Aβ. However, it is also harmful to the tissue itself, and as the mutant gencDNA insertion is irreversible, it may easily open the door to progressive neurodegeneration.

There are still a lot of unknowns surrounding the somatic gene recombination mechanisms in AD. The very existence of gencDNAs has been questioned as an experimental artifact resulting from sample contamination [197], although the major part of the claims by [188] seem to be valid [198] and independently verified [199]. The physiological role of somatic gene recombination, if any, is unknown. The total number and diversity of gencDNAs might be underestimated by the current detection techniques [189]. It is not known whether the process is APP specific or also includes other genes. The evidence for gencDNA of the presenilin gene has been negative so far [188]. Somatic point mutations in AD brain tissue have been found in the genes contributing to tau hyperphosphorylation, although only in 27% of the examined brains [199]. Mutations in genes related to neuroprotection, cytoskeleton remodeling, autism, and intellectual disabilities have also been found to be more abundant in AD brains [200]. Interestingly, copy number variants of the gene for α-synuclein have been found in synucleinopathies [201], suggesting that the same mechanism may be common to this class of disorders as well.

Summary and concluding remarks

The literature evidence strongly indicates that Aβ production, apart from being hallmark of AD, is also an integral part of the brain innate immune response. Therefore, we may view AD as a pathological consequence of brain immunity activation, and search for its trigger, be it infection or another kind of insult. The existing body of evidence strongly suggests there is no specific “Alzheimer’s germ” (see Most probably, any microbe capable of entering the brain and causing a chronic infection could be a culprit, explaining the mixed results of many previous studies focused exclusively on certain classes or species of organisms. Some known or suspected AD risk factors may facilitate brain infection by promoting pathogen spread, compromising the BBB or peripheral immune system function. The most prominent risk factor of AD is aging. This fits the general picture well, as senescence of the immune system compromises its ability to suppress pathogens, and at the same time, makes it susceptible to prolonged and maladaptive inflammatory reactions.

When the immune system is unable to destroy or suppress the pathogen, chronic inflammation causes progressive damage to the cerebral tissue; runaway degenerative processes may ensue, including the amyloid cascade as implied by the classical hypothesis (Fig 4). Self-perpetuating inflammation with amyloid overproduction might then persist even after elimination of the invading pathogen.

Fig 4. Schematic illustrating the infectious hypothesis of AD.

The scheme follows the 3 main domains of AD: neuroinflammation, amyloid pathology, and tau protein pathology, progressing from the top to the bottom. Pathogens (bacteria, viruses, and/or fungi) entering the CNS activate the innate immunity. If the inflammatory process becomes chronic, the BBB is disrupted, facilitating entrance of further pathogens into the brain. Expression of APP and its cleavage to Aβ is enhanced in reaction to pathogens. Aβ monomers cluster into oligomers that can entrap various pathogens (agglutination or granuloma formation), which prevents them from entering into neurons, spreading or replicating, and facilitates their destruction by microglia. Aβ fibrils can directly disrupt pathogens’ membranes; however, they may attack neuronal membranes as well. During chronic or latent infections, Aβ fragments and fibrils accumulate, and finally create insoluble amyloid plaques. Tau pathology is stimulated by Aβ and neuroinflammation by several pathways and might be directly triggered by intracellular pathogens. An interesting question is whether tau protein could also serve as an intracellular antimicrobial peptide, similarly to Aβ oligomers. Accumulation of Aβ and tau is aggravated by impaired clearance activity of the brain glymphatic system, which is also compromised by neuroinflammatory processes. APOE4, the strongest known genetic risk factor of sporadic AD, apparently affects oligomerization or clearance of Aβ and facilitates entry of some pathogens (e.g., HSV1) into the cell. Aβ, amyloid beta; AD, Alzheimer’s disease; APOE4, apolipoprotein E4 allele; APP, amyloid precursor protein; BBB, blood–brain barrier; CNS, central nervous system; HSV1, Herpes simplex virus type 1; IL-6, interleukin-6; TNF, tumor necrosis factor.

Both chronic inflammation on the background of immunosenescence and advanced age weaken the BBB and mucosal barriers, offering opportunities for pathogens from the periphery to invade the brain, and coinfections may be a rule rather than exception. Future studies should encompass as broad a spectrum of pathogens as possible, since the contributions of different microbial species to the initiation and progression of AD are largely unexplored.

AD is most probably not a classical infectious disease in the sense of Koch’s postulates, as it lacks a specific infectious agent, and pathogen invasion may not be the exclusive trigger. This certainly poses a considerable challenge for further research. Perhaps, the major hurdle is establishing the direction of causality: Do microbes trigger AD or does AD make the patients more susceptible to opportune infections? The only solid evidence for a causal role of microbes so far comes from cell cultures and animal models, and any such finding should be translated to human patients with due caution.

Despite the mounting evidence for the infectious hypothesis, there are also other known triggers leading to Aβ response, e.g., traumatic or vascular damage, not to speak of idiopathic overexpression of Aβ in familial AD or Down syndrome. Future studies should take these differences into account, as they could be reflected in drug sensitivity. Infectious theory of AD also provides clear directions for future research into novel therapeutic strategies. Prevention of infections by the relevant pathogens including meticulous oral hygiene should be the first option if applicable, together with emphasis on correct diagnosis and thorough management of chronically infected patients. In the future, targeted antimicrobial therapy could be applied to MCI or AD patients. Untimely administration of anti-Aβ agents might do more harm than benefit by disinhibiting eventual pathogens, but in cases where the infection has been resolved, anti-inflammatory and anti-Aβ agents may still provide clinical benefits. Improved diagnostic methods would be required for both early recognition of MCI patients and identification of the relevant cerebral pathogens. As most of the microbes implicated in AD are very proficient in resisting both the host immune response and the available treatments, finding novel therapeutics suppressing such persistent infections of the CNS seems to be the second necessary step in that direction. Doxycycline-rifampicin treatment has been already tried with moderate success in a clinical study [202], and penicillin, combined with supplemental drugs disrupting biofilms, was suggested against cerebral spirochetes [203]. Some other antimicrobial and antiviral candidate drugs were nominated [204].

Once we accept that the etiology of sporadic AD could be linked to prolonged innate immune response in the brain, triggered by pathogen invasion on the background of immunosenescence and age-related biological changes, individual pieces of evidence start to come together, linking all the known risk factors of sporadic AD and also explaining the gulf between animal model studies and clinical trials. We hope this new paradigm may open the way toward better understanding of AD and, ultimately, also provide the means to treat or prevent this fearsome disease.


We thank Karel Vales for commenting on the manuscript.


  1. 1. Carreiras M, Mendes E, Perry M, Francisco A, Marco-Contelles J. The multifactorial nature of Alzheimer’s disease for developing potential therapeutics. Curr Top Med Chem. 2013;13:1745–1770. pmid:23931435
  2. 2. Itzhaki RF, Lathe R, Balin BJ, Ball MJ, Bearer EL, Braak H, et al. Microbes and Alzheimer’s disease. J Alzheimers Dis. 2016;51:979–984. pmid:26967229
  3. 3. Banik A, Brown RE, Bamburg J, Lahiri DK, Khurana D, Friedland RP, et al. Translation of pre-clinical studies into successful clinical trials for Alzheimer’s disease: What are the roadblocks and how can they be overcome? J Alzheimers Dis. 2015;47:815–843. pmid:26401762
  4. 4. Cummings JL, Morstorf T, Zhong K. Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther. 2014;6:37. pmid:25024750
  5. 5. Geldenhuys WJ, Darvesh AS. Pharmacotherapy of Alzheimer’s disease: current and future trends. Expert Rev Neurother. 2015;15:3–5. pmid:25481975
  6. 6. Budson AE, Solomon PR. New diagnostic criteria for Alzheimer’s disease and mild cognitive impairment for the practical neurologist. Pract Neurol. 2012;12:88–96. pmid:22450454
  7. 7. Murphy C. Olfactory and other sensory impairments in Alzheimer disease. Nat Rev Neurol. 2019;15:11–24. pmid:30532084
  8. 8. Alzheimer’s Association. Alzheimer’s disease facts and figures. Alzheimers Dement. 2017;2017(13):325–373.
  9. 9. Hardy J. Amyloid, the presenilins and Alzheimer’s disease. Trends Neurosci. 1997;20:154–159.
  10. 10. Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, Seubert P, et al. Mutation of the β-amyloid precursor protein in familial Alzheimer’s disease increases β-protein production. Nature. 1992;360:672–674. pmid:1465129
  11. 11. Haass C. Mutations associated with a locus for familial Alzheimer’s disease result in alternative processing of amyloid β-protein precursor. J Biol Chem. 1994;269:17741–17748.
  12. 12. Haass C, Lemere CA, Capell A, Citron M, Seubert P, Schenk D, et al. The Swedish mutation causes early-onset Alzheimer’s disease by β-secretase cleavage within the secretory pathway. Nat Med. 1995;1:1291–1296. pmid:7489411
  13. 13. Haass C, De Strooper B. The presenilins in Alzheimer’s disease—proteolysis holds the key. Science. 1999;286:916–919. pmid:10542139
  14. 14. Drummond E, Wisniewski T. Alzheimer’s disease: experimental models and reality. Acta Neuropathol (Berl). 2017;133:155–175. pmid:28025715
  15. 15. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261:921–923. pmid:8346443
  16. 16. Farrer LA. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. J Am Med Assoc. 1997;278:1349–1356.
  17. 17. Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB, Patterson BW, et al. Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci Transl Med. 2011;3:13. pmid:21715678
  18. 18. Cerf E, Gustot A, Goormaghtigh E, Ruysschaert J-M, Raussens V. High ability of apolipoprotein E4 to stabilize amyloid-β peptide oligomers, the pathological entities responsible for Alzheimer’s disease. FASEB J. 2011;25:1585–1595. pmid:21266538
  19. 19. Benilova I, Karran E, De Strooper B. The toxic Aβ oligomer and Alzheimer’s disease: an emperor in need of clothes. Nat Neurosci. 2012;15:349–357. pmid:22286176
  20. 20. Goedert M, Spillantini MG. A century of Alzheimer’s disease. Science. 2006;314:777–781. pmid:17082447
  21. 21. Wirths O, Multhaup G, Bayer TA. A modified β-amyloid hypothesis: intraneuronal accumulation of the β-amyloid peptide–the first step of a fatal cascade. J Neurochem. 2004;91:513–520. pmid:15485483
  22. 22. Haass C, Schlossmacher MG, Hung AY, Vigo-Pelfrey C, Mellon A, Ostaszewski BL, et al. Amyloid β-peptide is produced by cultured cells during normal metabolism. Nature. 1992;359:322–325. pmid:1383826
  23. 23. Brothers HM, Gosztyla ML, Robinson SR. The physiological roles of amyloid-ß peptide hint at new ways to treat Alzheimer’s disease. Front Aging Neurosci. 2018;10:118. pmid:29922148
  24. 24. James OG, Doraiswamy PM, Borges-Neto S. PET imaging of tau pathology in Alzheimer’s disease and tauopathies. Front Neurol. 2015:6. pmid:25806018
  25. 25. Iqbal K, Alonso Adel C, Chen S, Chohan MO, El-Akkad E, Gong C-X, et al. Tau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta. 2005;1739:198–210. pmid:15615638
  26. 26. Tabaton M, Cammarata S, Mancardi G, Manetto V, Autilio-Gambetti L, Perry G, et al. Ultrastructural localization of beta-amyloid, tau, and ubiquitin epitopes in extracellular neurofibrillary tangles. Proc Natl Acad Sci U S A. 1991;88:2098–2102. pmid:1706517
  27. 27. Selkoe DJ. Alzheimer’s disease is a synaptic failure. Science. 2002;298:789–791. pmid:12399581
  28. 28. Spires-Jones TL, Hyman BT. The intersection of amyloid beta and tau at synapses in Alzheimer’s disease. Neuron. 2014;82:756–771. pmid:24853936
  29. 29. Karran E, Mercken M, Strooper BD. The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov. 2011;10:698–712. pmid:21852788
  30. 30. Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med. 2016;8:595–608. pmid:27025652
  31. 31. Lee CYD, Landreth GE. The role of microglia in amyloid clearance from the AD brain. J Neural Transm. 2010;117:949–960. pmid:20552234
  32. 32. Wang W-Y, Tan M-S, Yu J-T, Tan L. Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease. Ann Transl Med. 2015a;3:136. pmid:26207229
  33. 33. Yoshiyama Y, Higuchi M, Zhang B, Huang S-M, Iwata N, Saido TC, et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron. 2007;53:337–351. pmid:17270732
  34. 34. Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM, Lamb BT. Regulation of tau pathology by the microglial fractalkine receptor. Neuron. 2010;68:19–31. pmid:20920788
  35. 35. Mosher KI, Wyss-Coray T. Microglial dysfunction in brain aging and Alzheimer’s disease. Biochem Pharmacol. 2014;88:594–604. pmid:24445162
  36. 36. von Bernhardi R, Eugenín-von Bernhardi L, Eugenín J. Microglial cell dysregulation in brain aging and neurodegeneration. Front Aging Neurosci. 2015;7:124. pmid:26257642
  37. 37. Lee JW, Lee YK, Yuk DY, Choi DY, Ban SB, Oh KW, et al. Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. J Neuroinflammation. 2008;5:37. pmid:18759972
  38. 38. Hur J-Y, Frost GR, Wu X, Crump C, Pan SJ, Wong E, et al. The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer’s disease. Nature. 2020;586:735–740. pmid:32879487
  39. 39. Yamamoto M, Kiyota T, Horiba M, Buescher JL, Walsh SM, Gendelman HE, et al. Interferon-γ and tumor necrosis factor-α regulate amyloid-β plaque deposition and β-secretase expression in Swedish mutant APP transgenic mice. Am J Pathol. 2007;170:680–692. pmid:17255335
  40. 40. Gómez-Isla T, Frosch MP. Lesions without symptoms: Understanding resilience to Alzheimer disease neuropathological changes. Nat Rev Neurol. 2022;18:323–332. pmid:35332316
  41. 41. Bellenguez C, Grenier-Boley B, Lambert J-C. Genetics of Alzheimer’s disease: Where we are, and where we are going. Curr Opin Neurobiol. 2020;61:40–48. pmid:31863938
  42. 42. Goedert M. Oskar Fischer and the study of dementia. Brain. 2009;132:1102–1111. pmid:18952676
  43. 43. Miklossy J. Alzheimer’s disease—a neurospirochetosis. Analysis of the evidence following Koch’s and Hill’s criteria. J Neuroinflammation. 2011;8:90. pmid:21816039
  44. 44. Miklossy J, Khalili K, Gern L, Ericson RL, Darekar P, Bolle L, et al. Borrelia burgdorferi persists in the brain in chronic lyme neuroborreliosis and may be associated with Alzheimer disease. J Alzheimers Dis. 2004;6:639–649, discussion 673–681. pmid:15665404
  45. 45. Livengood JA, Gilmore RD. Invasion of human neuronal and glial cells by an infectious strain of Borrelia burgdorferi. Microbes Infect. 2006;8:2832–2840. pmid:17045505
  46. 46. MacDonald AB, Miranda JM. Concurrent neocortical borreliosis and Alzheimer’s disease. Hum Pathol. 1987;18:759–761. pmid:3297997
  47. 47. Miklossy J. Alzheimer Disease—A Spirochetosis? In: Giacobini E, Becker RE, editors. Alzheimer Disease. Boston, MA: Birkhäuser Boston; 1994. p. 41–45.
  48. 48. Miklossy J, Kis A, Radenovic A, Miller L, Forro L, Martins R, et al. Beta-amyloid deposition and Alzheimer’s type changes induced by Borrelia spirochetes. Neurobiol Aging. 2006;27:228–236. pmid:15894409
  49. 49. Ide M, Harris M, Stevens A, Sussams R, Hopkins V, Culliford D, et al. Periodontitis and cognitive decline in Alzheimer’s disease. PLoS ONE. 2016;11:e0151081. pmid:26963387
  50. 50. Kamer AR, Craig RG, Dasanayake AP, Brys M, Glodzik-Sobanska L, de Leon MJ. Inflammation and Alzheimer’s disease: possible role of periodontal diseases. Alzheimers Dement. 2008;4:242–250. pmid:18631974
  51. 51. Kamer AR, Fortea JO, Videla S, Mayoral A, Janal M, Carmona-Iragui M, et al. Periodontal disease’s contribution to Alzheimer’s disease progression in Down syndrome. Alzheimers Dement Diagn Assess Dis Monit. 2016;2:49–57. pmid:27239536
  52. 52. Leira Y, Domínguez C, Seoane J, Seoane-Romero J, Pías-Peleteiro JM, Takkouche B, et al. Is periodontal disease associated with Alzheimer’s disease? A systematic review with meta-analysis. Neuroepidemiology. 2017;48:21–31. pmid:28219071
  53. 53. Riviere GR, Riviere KH, Smith KS. Molecular and immunological evidence of oral Treponema in the human brain and their association with Alzheimer’s disease. Oral Microbiol Immunol. 2002;17:113–118. pmid:11929559
  54. 54. Gutacker M, Valsangiacomo C, Balmelli T, Bernasconi MV, Bouras C, Piffaretti JC. Arguments against the involvement of Borrelia burgdorferi sensu lato in Alzheimer’s disease. Res Microbiol. 1998;149:31–37.
  55. 55. McLaughlin R, Kin NM, Chen MF, Nair NP, Chan EC. Alzheimer’s disease may not be a spirochetosis. Neuroreport. 1999;10:1489–1491. pmid:10380968
  56. 56. Pappolla MA, Omar R, Saran B, Andorn A, Suarez M, Pavia C, et al. Concurrent neuroborreliosis and Alzheimer’s disease: Analysis of the evidence. Hum Pathol. 1989;20:753–757. pmid:2744748
  57. 57. Dominy SS, Lynch C, Ermini F, Benedyk M, Marczyk A, Konradi A, et al. Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv. 2019;5:eaau3333. pmid:30746447
  58. 58. Liu Y, Wu Z, Nakanishi Y, Ni J, Hayashi Y, Takayama F, et al. Infection of microglia with Porphyromonas gingivalis promotes cell migration and an inflammatory response through the gingipain-mediated activation of protease-activated receptor-2 in mice. Sci Rep. 2017;7:11759. pmid:28924232
  59. 59. GlobalData Healthcare. Despite new biomarker data for AD drug COR388, clinical efficacy remains unproven. In: Clinical Trials Arena [Internet]. 24 Mar 2022 [cited 2022 Sep 21].
  60. 60. Díaz-Zúñiga J, More J, Melgar-Rodríguez S, Jiménez-Unión M, Villalobos-Orchard F, Muñoz-Manríquez C, et al. Alzheimer’s disease-like pathology triggered by Porphyromonas gingivalis in wild type rats is serotype dependent. Front Immunol. 2020;11:588036. pmid:33240277
  61. 61. Balin BJ, Hammond CJ, Little CS, Hingley ST, Al-Atrache Z, Appelt DM, et al. Chlamydia pneumoniae: An etiologic agent for late-onset dementia. Front Aging Neurosci. 2018;10:302. pmid:30356749
  62. 62. Grayston JT. Chlamydia pneumoniae, strain TWAR pneumonia. Annu Rev Med. 1992;43:317–323. pmid:1580592
  63. 63. Koskiniemi M, Gencay M, Salonen O, Puolakkainen M, Färkkilä M, Saikku P, et al. Chlamydia pneumoniae associated with central nervous system infections. Eur Neurol. 1996;36:160–163. pmid:8738947
  64. 64. Wimmer M, Sandmann-Strupp R, Saikku P, Haberl RL. Association of chlamydial infection with cerebrovascular disease. Stroke. 1996;27:2207–2210. pmid:8969782
  65. 65. Balin BJ, Gérard HC, Arking EJ, Appelt DM, Branigan PJ, Abrams JT, et al. Identification and localization of Chlamydia pneumoniae in the Alzheimer’s brain. Med Microbiol Immunol (Berl). 1998;187:23–42. pmid:9749980
  66. 66. Dreses-Werringloer U, Bhuiyan M, Zhao Y, Gérard HC, Whittum-Hudson JA, Hudson AP. Initial characterization of Chlamydophila (Chlamydia) pneumoniae cultured from the late-onset Alzheimer brain. Int J Med Microbiol. 2009;299:187–201. pmid:18829386
  67. 67. Gérard HC, Wildt KL, Whittum-Hudson JA, Lai Z, Ager J, Hudson AP. The load of Chlamydia pneumoniae in the Alzheimer’s brain varies with APOE genotype. Microb Pathog. 2005;39:19–26. pmid:15998578
  68. 68. Gérard HC, Dreses-Werringloer U, Wildt KS, Deka S, Oszust C, Balin BJ, et al. Chlamydophila (Chlamydia) pneumoniae in the Alzheimer’s brain. FEMS Immunol Med Microbiol. 2006;48:355–366. pmid:17052268
  69. 69. Gieffers J, Reusche E, Solbach W, Maass M. Failure to detect Chlamydia pneumoniae in brain sections of Alzheimer’s disease patients. J Clin Microbiol. 2000;38:881–882.
  70. 70. Ring RH, Lyons JM. Failure to detect Chlamydia pneumoniae in the late-onset Alzheimer’s brain. J Clin Microbiol. 2000;38:2591–2594.
  71. 71. Taylor GS, Vipond IB, Paul ID, Matthews S, Wilcock GK, Caul EO. Failure to correlate C. pneumoniae with late onset Alzheimer’s disease. Neurology. 2002;59:142–143. pmid:12105327
  72. 72. Hammond CJ, Hallock LR, Howanski RJ, Appelt DM, Little CS, Balin BJ. Immunohistological detection of Chlamydia pneumoniae in the Alzheimer’s disease brain. BMC Neurosci. 2010;11:121. pmid:20863379
  73. 73. Balin B. Proof of concept studies of Chlamydia pneumoniae infection as a trigger for late-onset Alzheimer disease. Neurodegener Dis. 2017;17:243.
  74. 74. Itzhaki RF, Wozniak MA, Appelt DM, Balin BJ. Infiltration of the brain by pathogens causes Alzheimer’s disease. Neurobiol Aging. 2004;25:619–627. pmid:15172740
  75. 75. Little CS, Bowe A, Lin R, Litsky J, Fogel RM, Balin BJ, et al. Age alterations in extent and severity of experimental intranasal infection with Chlamydophila pneumoniae in BALB/c mice. Infect Immun. 2005;73:1723–1734.
  76. 76. Little CS, Joyce TA, Hammond CJ, Matta H, Cahn D, Appelt DM, et al. Detection of bacterial antigens and Alzheimer’s disease-like pathology in the central nervous system of BALB/c mice following intranasal infection with a laboratory isolate of Chlamydia pneumoniae. Front Aging Neurosci. 2014;6:304. pmid:25538615
  77. 77. Little CS, Hammond CJ, MacIntyre A, Balin BJ, Appelt DM. Chlamydia pneumoniae induces Alzheimer-like amyloid plaques in brains of BALB/c mice. Neurobiol Aging. 2004;25:419–429.
  78. 78. Malaguarnera M, Bella R, Alagona G, Ferri R, Carnemolla A, Pennisi G. Helicobacter pylori and Alzheimer’s disease: a possible link. Eur J Intern Med. 2004;15:381–386. pmid:15522573
  79. 79. Roubaud-Baudron C, Krolak-Salmon P, Quadrio I, Mégraud F, Salles N. Impact of chronic Helicobacter pylori infection on Alzheimer’s disease: Preliminary results. Neurobiol Aging. 2012;33(1009):e11–1009.e19. pmid:22133280
  80. 80. Wang X-L, Zeng J, Yang Y, Xiong Y, Zhang Z-H, Qiu M, et al. Helicobacter pylori filtrate induces Alzheimer-like tau hyperphosphorylation by activating glycogen synthase kinase-3β. J Alzheimers Dis. 2015b;43:153–165. pmid:25079798
  81. 81. Kountouras J, Boziki M, Gavalas E, Zavos C, Deretzi G, Chatzigeorgiou S, et al. Five-year survival after Helicobacter pylori eradication in Alzheimer disease patients. Cogn Behav Neurol. 2010;23:199–204. pmid:20829670
  82. 82. Emery DC, Shoemark DK, Batstone TE, Waterfall CM, Coghill JA, Cerajewska TL, et al. 16S rRNA next generation sequencing analysis shows bacteria in Alzheimer’s post-mortem brain. Front Aging Neurosci. 2017;9:195. pmid:28676754
  83. 83. Kornhuber HH. Propionibacterium acnes in the cortex of patients with Alzheimer’s disease. Eur Arch Psychiatry Clin Neurosci. 1996;246:108–109. pmid:9063907
  84. 84. Li F, Hearn M, Bennett LE. The role of microbial infection in the pathogenesis of Alzheimer’s disease and the opportunity for protection by anti-microbial peptides. Crit Rev Microbiol. 2021;47:240–253. pmid:33555958
  85. 85. Ball MJ. Herpesvirus in the hippocampus as a cause of Alzheimer’s disease. Arch Neurol. 1986;43:313–313. pmid:3006646
  86. 86. Itzhaki RF, Wozniak MA. Herpes simplex virus type 1 in Alzheimer’s disease: The enemy within. J Alzheimers Dis. 2008;13:393–405. pmid:18487848
  87. 87. Aravalli RN, Hu S, Rowen TN, Palmquist JM, Lokensgard JR. Cutting edge: TLR2-mediated proinflammatory cytokine and chemokine production by microglial cells in response to Herpes simplex virus. J Immunol. 2005;175:4189–4193. pmid:16177057
  88. 88. Cacquevel M, Lebeurrier N, Cheenne S, Vivien D. Cytokines in neuroinflammation and Alzheimer’s disease. Curr Drug Targets. 2004;5:529–534. pmid:15270199
  89. 89. De Chiara G, Piacentini R, Fabiani M, Mastrodonato A, Marcocci ME, Limongi D, et al. Recurrent herpes simplex virus-1 infection induces hallmarks of neurodegeneration and cognitive deficits in mice. PLoS Pathog. 2019;15:e1007617. pmid:30870531
  90. 90. Letenneur L, Pérès K, Fleury H, Garrigue I, Barberger-Gateau P, Helmer C, et al. Seropositivity to herpes simplex virus antibodies and risk of Alzheimer’s disease: A population-based cohort study. PLoS ONE. 2008;3:e3637. pmid:18982063
  91. 91. Jamieson GA, Maitland NJ, Wilcock GK, Craske J, Itzhaki RF. Latent Herpes simplex virus type 1 in normal and Alzheimer’s disease brains. J Med Virol. 1991;33:224–227. pmid:1649907
  92. 92. Wozniak M, Mee A, Itzhaki R. Herpes simplex virus type 1 DNA is located within Alzheimer’s disease amyloid plaques. J Pathol. 2009b;217:131–138. pmid:18973185
  93. 93. Pisa D, Alonso R, Fernández-Fernández AM, Rábano A, Carrasco L. Polymicrobial infections in brain tissue from Alzheimer’s disease patients. Sci Rep. 2017;7:5559. pmid:28717130
  94. 94. Itzhaki RF, Lin W-R, Shang D, Wilcock GK, Faragher B, Jamieson GA. Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. Lancet. 1997;349:241–244.
  95. 95. Linard M, Letenneur L, Garrigue I, Doize A, Dartigues J-F, Helmer C. Interaction between APOE4 and herpes simplex virus type 1 in Alzheimer’s disease. Alzheimers Dement. 2020;16:200–208. pmid:31914220
  96. 96. Burgos JS, Ramirez C, Sastre I, Bullido MJ, Valdivieso F. ApoE4 is more effcient than E3 in brain access by herpes simplex virus type 1. Neuroreport. 2003;14:1825–1827. pmid:14534428
  97. 97. Burgos JS, Ramirez C, Sastre I, Valdivieso F. Effect of apolipoprotein E on the cerebral load of latent herpes simplex virus type 1 DNA. J Virol. 2006;80:5383–5387. pmid:16699018
  98. 98. Wozniak MA, Itzhaki RF, Shipley SJ, Dobson CB. Herpes simplex virus infection causes cellular β-amyloid accumulation and secretase upregulation. Neurosci Lett. 2007;429:95–100. pmid:17980964
  99. 99. Ill-Raga G, Palomer E, Wozniak MA, Ramos-Fernández E, Bosch-Morató M, Tajes M, et al. Activation of PKR causes amyloid ß-peptide accumulation via de-repression of BACE1 expression. PLoS ONE. 2011;6:e21456. pmid:21738672
  100. 100. Wozniak MA, Frost AL, Itzhaki RF. Alzheimer’s disease-specific tau phosphorylation is induced by herpes simplex virus type 1. J Alzheimers Dis. 2009a;16:341–350. pmid:19221424
  101. 101. Zambrano Á, Solis L, Salvadores N, Cortés M, Lerchundi R, Otth C. Neuronal cytoskeletal dynamic modification and neurodegeneration induced by infection with Herpes simplex virus type 1. J Alzheimers Dis. 2008;14:259–269. pmid:18599953
  102. 102. Piacentini R, Li Puma DD, Ripoli C, Marcocci ME, De Chiara G, Garaci E, et al. Herpes simplex virus type-1 infection induces synaptic dysfunction in cultured cortical neurons via GSK-3 activation and intraneuronal amyloid-β protein accumulation. Sci Rep. 2015;5:15444. pmid:26487282
  103. 103. Penzes P, Cahill ME, Jones KA, VanLeeuwen J-E, Woolfrey KM. Dendritic spine pathology in neuropsychiatric disorders. Nat Neurosci. 2011;14:285–293. pmid:21346746
  104. 104. Cairns DM, Rouleau N, Parker RN, Walsh KG, Gehrke L, Kaplan DL. A 3D human brain–like tissue model of herpes-induced Alzheimer’s disease. Sci Adv. 2020;6:eaay8828. pmid:32494701
  105. 105. Tzeng N-S, Chung C-H, Lin F-H, Chiang C-P, Yeh C-B, Huang S-Y, et al. Anti-herpetic medications and reduced risk of dementia in patients with Herpes simplex virus infections—a nationwide, population-based cohort study in Taiwan. Neurotherapeutics. 2018;15:417–429. pmid:29488144
  106. 106. Wozniak MA, Frost AL, Itzhaki RF. The helicase-primase inhibitor BAY 57–1293 reduces the Alzheimer’s disease-related molecules induced by Herpes simplex virus type 1. Antivir Res. 2013;99:401–404. pmid:23867133
  107. 107. Wozniak M, Bell T, Dénes Á, Falshaw R, Itzhaki R. Anti-HSV1 activity of brown algal polysaccharides and possible relevance to the treatment of Alzheimer’s disease. Int J Biol Macromol. 2015;74:530–540. pmid:25583021
  108. 108. Wozniak MA, Frost AL, Preston CM, Itzhaki RF. Antivirals reduce the formation of key Alzheimer’s disease molecules in cell cultures acutely infected with Herpes simplex virus type 1. PLoS ONE. 2011;6:e25152. pmid:22003387
  109. 109. Wozniak MA, Itzhaki RF. Intravenous immunoglobulin reduces beta amyloid and abnormal tau formation caused by Herpes simplex virus type 1. J Neuroimmunol. 2013;257:7–12. pmid:23385080
  110. 110. Devanand DP. Viral hypothesis and antiviral treatment in Alzheimer’s disease. Curr Neurol Neurosci Rep. 2018;18:55. pmid:30008124
  111. 111. Devanand DP, Andrews H, Kreisl WC, Razlighi Q, Gershon A, Stern Y, et al. Antiviral therapy: Valacyclovir treatment of Alzheimer’s disease (VALAD) trial: protocol for a randomised, double-blind, placebo-controlled, treatment trial. BMJ Open. 2020;10:e032112. pmid:32034019
  112. 112. Lindblom N, Lindquist L, Westman J, Åström M, Bullock R, Hendrix S, et al. Potential virus involvement in Alzheimer’s disease: Results from a phase IIa trial evaluating Apovir, an antiviral drug combination. J Alzheimers Dis Rep. 2021;5:413–431. pmid:34189413
  113. 113. Hemmingsson E-S, Hjelmare E, Weidung B, Olsson J, Josefsson M, Adolfsson R, et al. Antiviral treatment associated with reduced risk of clinical Alzheimer’s disease—A nested case-control study. Alzheimers Dement Transl Res Clin Interv. 2021;7:e12187. pmid:34136638
  114. 114. Itzhaki RF. Corroboration of a major role for Herpes simplex virus type 1 in Alzheimer’s disease. Front Aging Neurosci. 2018;10:324. pmid:30405395
  115. 115. Lin W-R, Wozniak MA, Cooper RJ, Wilcock GK, Itzhaki RF. Herpesviruses in brain and Alzheimer’s disease. J Pathol. 2002;197:395–402. pmid:12115887
  116. 116. Rizzo R, Bortolotti D, Gentili V, Rotola A, Bolzani S, Caselli E, et al. KIR2DS2/KIR2DL2/HLA-C1 haplotype is associated with Alzheimer’s disease: Implication for the role of herpesvirus infections. J Alzheimers Dis. 2019;67:1379–1389. pmid:30689576
  117. 117. Carbone I, Lazzarotto T, Ianni M, Porcellini E, Forti P, Masliah E, et al. Herpes virus in Alzheimer’s disease: Relation to progression of the disease. Neurobiol Aging. 2014;35:122–129. pmid:23916950
  118. 118. Bae S, Yun S-C, Kim M-C, Yoon W, Lim JS, Lee S-O, et al. Association of herpes zoster with dementia and effect of antiviral therapy on dementia: A population-based cohort study. Eur Arch Psychiatry Clin Neurosci. 2021;271:987–997. pmid:32613564
  119. 119. Chen C-H, Wu S-I, Huang K-Y, Yang Y-H, Kuo T-Y, Liang H-Y, et al. Herpes zoster and dementia: A nationwide population-based cohort study. J Clin Psychiatry. 2018;79:8164. pmid:29244265
  120. 120. Lopatko Lindman K, Hemmingsson E, Weidung B, Brännström J, Josefsson M, Olsson J, et al. Herpesvirus infections, antiviral treatment, and the risk of dementia—a registry-based cohort study in Sweden. Alzheimers Dement Transl Res Clin Interv. 2021;7:e12119. pmid:33614892
  121. 121. Cairns DM, Itzhaki RF, Kaplan DL. Potential Involvement of Varicella zoster virus in Alzheimer’s disease via reactivation of quiescent Herpes simplex virus type 1. J Alzheimers Dis. 2022;88:1189–1200. pmid:35754275
  122. 122. Lurain NS, Hanson BA, Martinson J, Leurgans SE, Landay AL, Bennett DA, et al. Virological and immunological characteristics of human Cytomegalovirus infection associated with Alzheimer disease. J Infect Dis. 2013;208:564–572. pmid:23661800
  123. 123. Lövheim H, Olsson J, Weidung B, Johansson A, Eriksson S, Hallmans G, et al. Interaction between Cytomegalovirus and Herpes simplex virus type 1 associated with the risk of Alzheimer’s disease development. J Alzheimers Dis. 2018;61:939–945. pmid:29254081
  124. 124. Caruso C, Buffa S, Candore G, Colonna-Romano G, Dunn-Walters D, Kipling D, et al. Mechanisms of immunosenescence. Immun Ageing. 2009;6:1–4.
  125. 125. Fulop T, Witkowski JM, Larbi A, Khalil A, Herbein G, Frost EH. Does HIV infection contribute to increased beta-amyloid synthesis and plaque formation leading to neurodegeneration and Alzheimer’s disease? J Neuro-Oncol. 2019;25:634–647. pmid:30868421
  126. 126. Corder EH, Robertson K, Lannfelt L, Bogdanovic N, Eggertsen G, Wilkins J, et al. HIV-infected subjects with the E4 allele for APOE have excess dementia and peripheral neuropathy. Nat Med. 1998;4:1182–1184. pmid:9771753
  127. 127. Letendre SL, Ellis RJ, Ances BM, McCutchan JA. Neurologic complications of HIV disease and their treatment. Top HIV Med. 2010;18:45–55. pmid:20516524
  128. 128. Wu Y, Du S, Johnson JL, Tung H-Y, Landers CT, Liu Y, et al. Microglia and amyloid precursor protein coordinate control of transient Candida cerebritis with memory deficits. Nat Commun. 2019;10:58. pmid:30610193
  129. 129. Alonso R, Pisa D, Marina AI, Morato E, Rábano A, Carrasco L. Fungal infection in patients with Alzheimer’s disease. J Alzheimers Dis. 2014;41:301–311. pmid:24614898
  130. 130. Alonso R, Pisa D, Rábano A, Rodal I, Carrasco L. Cerebrospinal fluid from Alzheimer’s disease patients contains fungal proteins and DNA. J Alzheimers Dis. 2015;47:873–876. pmid:26401766
  131. 131. Alonso R, Pisa D, Aguado B, Carrasco L. Identification of fungal species in brain tissue from Alzheimer’s disease by next-generation sequencing. J Alzheimers Dis. 2017;58:55–67. pmid:28387676
  132. 132. Alonso R, Pisa D, Fernández-Fernández AM, Carrasco L. Infection of fungi and bacteria in brain tissue from elderly persons and patients with Alzheimer’s disease. Front Aging Neurosci. 2018;10:159. pmid:29881346
  133. 133. Pisa D, Alonso R, Juarranz A, Rábano A, Carrasco L. Direct visualization of fungal infection in brains from patients with Alzheimer’s disease. J Alzheimers Dis. 2015a;43:613–624. pmid:25125470
  134. 134. Pisa D, Alonso R, Rábano A, Rodal I, Carrasco L. Different brain regions are infected with fungi in Alzheimer’s disease. Sci Rep. 2015b;5:15015. pmid:26468932
  135. 135. Bedarf JR, Beraza N, Khazneh H, Özkurt E, Baker D, Borger V, et al. Much ado about nothing? Off-target amplification can lead to false-positive bacterial brain microbiome detection in healthy and Parkinson’s disease individuals. Microbiome. 2021;9:75. pmid:33771222
  136. 136. Le Govic Y, Demey B, Cassereau J, Bahn Y-S, Papon N. Pathogens infecting the central nervous system. PLoS Pathog. 2022;18:e1010234. pmid:35202445
  137. 137. Janecek E, Wilk E, Schughart K, Geffers R, Strube C. Microarray gene expression analysis reveals major differences between Toxocara canis and Toxocara cati neurotoxocarosis and involvement of T. canis in lipid biosynthetic processes. Int J Parasitol. 2015;45:495–503. pmid:25843806
  138. 138. Waindok P, Strube C. Neuroinvasion of Toxocara canis- and T. cati-larvae mediates dynamic changes in brain cytokine and chemokine profile. J Neuroinflammation. 2019;16:147. pmid:31315623
  139. 139. Janecek E, Waindok P, Bankstahl M, Strube C. Abnormal neurobehaviour and impaired memory function as a consequence of Toxocara canis- as well as Toxocara cati-induced neurotoxocarosis. PLoS Negl Trop Dis. 2017;11:e0005594. pmid:28481889
  140. 140. Chou C-M, Lee Y-L, Liao C-W, Huang Y-C, Fan C-K. Enhanced expressions of neurodegeneration-associated factors, UPS impairment, and excess Aβ accumulation in the hippocampus of mice with persistent cerebral toxocariasis. Parasit Vectors. 2017;10:620. pmid:29273062
  141. 141. Liao C-W, Fan C-K, Kao T-C, Ji D-D, Su K-E, Lin Y-H, et al. Brain injury-associated biomarkers of TGF-beta1, S100B, GFAP, NF-L, tTG, AbetaPP, and tau were concomitantly enhanced and the UPS was impaired during acute brain injury caused by Toxocara canis in mice. BMC Infect Dis. 2008;8:84. pmid:18573219
  142. 142. Heuer L, Beyerbach M, Lühder F, Beineke A, Strube C. Neurotoxocarosis alters myelin protein gene transcription and expression. Parasitol Res. 2015;114:2175–2186. pmid:25773181
  143. 143. Springer A, Heuer L, Janecek-Erfurth E, Beineke A, Strube C. Histopathological characterization of Toxocara canis- and T. cati-induced neurotoxocarosis in the mouse model. Parasitol Res. 2019;118:2591–2600. pmid:31350619
  144. 144. Dobolyi A, Vincze C, Pál G, Lovas G. The neuroprotective functions of transforming growth factor beta proteins. Int J Mol Sci. 2012;13:8219–8258. pmid:22942700
  145. 145. Lesné S, Docagne F, Gabriel C, Liot G, Lahiri DK, Buée L, et al. Transforming growth factor-β1 potentiates amyloid-β generation in astrocytes and in transgenic mice. J Biol Chem. 2003;278:18408–18418. pmid:12626500
  146. 146. Wyss-Coray T, Masliah E, Mallory M, McConlogue L, Johnson-Wood K, Lin C, et al. Amyloidogenic role of cytokine TGF-β1 in transgenic mice and in Alzheimer’s disease. Nature. 1997;389:603–606. pmid:9335500
  147. 147. Fan C-K, Holland CV, Loxton K, Barghouth U. Cerebral toxocariasis: Silent progression to neurodegenerative disorders? Clin Microbiol Rev. 2015;28:663–686. pmid:26062575
  148. 148. Flegr J. How and why Toxoplasma makes us crazy. Trends Parasitol. 2013a;29:156–163. pmid:23433494
  149. 149. Flegr J. Influence of latent Toxoplasma infection on human personality, physiology and morphology: pros and cons of the Toxoplasma–human model in studying the manipulation hypothesis. J Exp Biol. 2013b;216:127–133. pmid:23225875
  150. 150. Kusbeci OY, Miman O, Yaman M, Aktepe OC, Yazar S. Could Toxoplasma gondii have any role in Alzheimer disease? Alzheimer Dis Assoc Disord. 2011;25:1–3. pmid:20921875
  151. 151. Mahami-Oskouei M, Hamidi F, Talebi M, Farhoudi M, Taheraghdam AA, Kazemi T, et al. Toxoplasmosis and Alzheimer: Can Toxoplasma gondii really be introduced as a risk factor in etiology of Alzheimer? Parasitol Res. 2016;115:3169–3174. pmid:27106237
  152. 152. Perry CE, Gale SD, Erickson L, Wilson E, Nielsen B, Kauwe J, et al. Seroprevalence and serointensity of latent Toxoplasma gondii in a sample of elderly adults with and without Alzheimer disease. Alzheimer Dis Assoc Disord. 2016;30:123–126. pmid:26421353
  153. 153. Torniainen-Holm M, Suvisaari J, Lindgren M, Härkänen T, Dickerson F, Yolken RH. The lack of association between herpes simplex virus 1 or Toxoplasma gondii infection and cognitive decline in the general population: An 11-year follow-up study. Brain Behav Immun. 2019;76:159–164. pmid:30465879
  154. 154. Bayani M, Riahi SM, Bazrafshan N, Gamble HR, Rostami A. Toxoplasma gondii infection and risk of Parkinson and Alzheimer diseases: A systematic review and meta-analysis on observational studies. Acta Trop. 2019;196:165–171. pmid:31102579
  155. 155. Tooran NC, Sarvi S, Moosazadeh M, Sharif M, Aghayan SA, Amouei A, et al. Is Toxoplasma gondii a potential risk factor for Alzheimer’s disease? A systematic review and meta-analysis. Microb Pathog. 2019;137:103751. pmid:31536800
  156. 156. Jung B-K, Pyo K-H, Shin KY, Hwang YS, Lim H, Lee SJ, et al. Toxoplasma gondii infection in the brain inhibits neuronal degeneration and learning and memory impairments in a murine model of Alzheimer’s disease. PLoS ONE. 2012;7:e33312. pmid:22470449
  157. 157. Möhle L, Israel N, Paarmann K, Krohn M, Pietkiewicz S, Müller A, et al. Chronic Toxoplasma gondii infection enhances β-amyloid phagocytosis and clearance by recruited monocytes. Acta Neuropathol Commun. 2016;4:25. pmid:26984535
  158. 158. Cabral CM, McGovern KE, MacDonald WR, Franco J, Koshy AA. Dissecting amyloid beta deposition using distinct strains of the neurotropic parasite Toxoplasma gondii as a novel tool. Am Soc Neurochem. 2017;9:1759091417724915. pmid:28817954
  159. 159. Torres L, Robinson S-A, Kim D-G, Yan A, Cleland TA, Bynoe MS. Toxoplasma gondii alters NMDAR signaling and induces signs of Alzheimer’s disease in wild-type, C57BL/6 mice. J Neuroinflammation. 2018;15:57. pmid:29471842
  160. 160. Li Y, Severance EG, Viscidi RP, Yolken RH, Xiao J. Persistent Toxoplasma infection of the brain induced neurodegeneration associated with activation of complement and microglia. Infect Immun. 2019;87:e00139–e00119. pmid:31182619
  161. 161. Eimer WA, Vijaya Kumar DK, Navalpur Shanmugam NK, Rodriguez AS, Mitchell T, Washicosky KJ, et al. Alzheimer’s disease-associated β-amyloid is rapidly seeded by herpesviridae to protect against brain infection. Neuron. 2018;99:56–63.e3. pmid:30001512
  162. 162. Moir RD, Lathe R, Tanzi RE. The antimicrobial protection hypothesis of Alzheimer’s disease. Alzheimers Dement. 2018;14:1602–1614. pmid:30314800
  163. 163. Kagan BL, Jang H, Capone R, Teran Arce F, Ramachandran S, Lal R, et al. Antimicrobial properties of amyloid peptides. Mol Pharm. 2012;9:708–717. pmid:22081976
  164. 164. Alam MM, Yang D, Li X-Q, Liu J, Back TC, Trivett A, et al. Alpha synuclein, the culprit in Parkinson disease, is required for normal immune function. Cell Rep. 2022;38:110090. pmid:35021075
  165. 165. Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson M, Hyman B, et al. The Alzheimer’s disease-associated amyloid β-protein is an antimicrobial peptide. PLoS ONE. 2010;5:e9505. pmid:20209079
  166. 166. Spitzer P, Condic M, Herrmann M, Oberstein TJ, Scharin-Mehlmann M, Gilbert DF, et al. Amyloidogenic amyloid-β-peptide variants induce microbial agglutination and exert antimicrobial activity. Sci Rep. 2016;6:32228. pmid:27624303
  167. 167. Javed I, Zhang Z, Adamcik J, Andrikopoulos N, Li Y, Otzen DE, et al. Accelerated amyloid beta pathogenesis by bacterial amyloid FapC. Adv Sci. 2020;7:2001299. pmid:32999841
  168. 168. Friedland RP, McMillan JD, Kurlawala Z. What are the molecular mechanisms by which functional bacterial amyloids influence amyloid beta deposition and neuroinflammation in neurodegenerative disorders? Int J Mol Sci. 2020;21:1652. pmid:32121263
  169. 169. Nizet V. Antimicrobial peptide resistance mechanisms of human bacterial pathogens. Curr Issues Mol Biol. 2006;8:11–26. pmid:16450883
  170. 170. Bourgade K, Garneau H, Giroux G, Le Page AY, Bocti C, Dupuis G, et al. β-Amyloid peptides display protective activity against the human Alzheimer’s disease-associated herpes simplex virus-1. Biogerontology. 2015;16:85–98. pmid:25376108
  171. 171. Lukiw WJ, Cui JG, Yuan LY, Bhattacharjee PS, Corkern M, Clement C, et al. Acyclovir and Aβ42 peptide attenuates HSV-1-induced miRNA-146a levels in human brain cells. Neuroreport. 2010;21:922–927. pmid:20683212
  172. 172. Bigley TM, Xiong M, Ali M, Chen Y, Wang C, Serrano JR, et al. Murine roseolovirus does not accelerate amyloid-β pathology and human roseoloviruses are not over-represented in Alzheimer disease brains. Mol Neurodegener. 2022;17:10. pmid:35033173
  173. 173. Bocharova O, Pandit NP, Molesworth K, Fisher A, Mychko O, Makarava N, et al. Alzheimer’s disease-associated β-amyloid does not protect against herpes simplex virus 1 infection in the mouse brain. J Biol Chem. 2021;297:100845. pmid:34052228
  174. 174. White MR, Kandel R, Tripathi S, Condon D, Qi L, Taubenberger J, et al. Alzheimer’s associated β-amyloid protein inhibits influenza A virus and modulates viral interactions with phagocytes. PLoS ONE. 2014;9:e101364. pmid:24988208
  175. 175. Di Domizio J, Dorta-Estremera S, Gagea M, Ganguly D, Meller S, Li P, et al. Nucleic acid-containing amyloid fibrils potently induce type I interferon and stimulate systemic autoimmunity. Proc Natl Acad Sci U S A. 2012;109:14550–14555. pmid:22904191
  176. 176. Roy ER, Wang B, Wan Y, Chiu G, Cole A, Yin Z, et al. Type I interferon response drives neuroinflammation and synapse loss in Alzheimer disease. J Clin Invest. 2020;130:1912–1930. pmid:31917687
  177. 177. Sainz B, Halford WP. Alpha/beta interferon and gamma interferon synergize to inhibit the replication of Herpes simplex virus type 1. J Virol. 2002;76:11541–11550.
  178. 178. Vollstedt S, Arnold S, Schwerdel C, Franchini M, Alber G, Di Santo JP, et al. Interplay between alpha/beta and gamma interferons with B, T, and Natural Killer cells in the defense against Herpes simplex virus type 1. J Virol. 2004;78:3846–3850.
  179. 179. Kumar DKV, Eimer WA, Tanzi RE, Moir RD. Alzheimer’s disease: the potential therapeutic role of the natural antibiotic amyloid-β peptide. Neurodegener Dis Manag. 2016;6:345–348. pmid:27599536
  180. 180. Butterfield SM, Lashuel HA. Amyloidogenic protein–membrane interactions: Mechanistic insight from model systems. Angew Chem Int Ed. 2010;49:5628–5654. pmid:20623810
  181. 181. Choi SH, Kim YH, Hebisch M, Sliwinski C, Lee S, D’Avanzo C, et al. A three-dimensional human neural cell culture model of Alzheimer’s disease. Nature. 2014;515:274–278. pmid:25307057
  182. 182. Tarasoff-Conway JM, Carare RO, Osorio RS, Glodzik L, Butler T, Fieremans E, et al. Clearance systems in the brain—implications for Alzheimer disease. Nat Rev Neurol. 2015;11:457–470. pmid:26195256
  183. 183. Silva I, Silva J, Ferreira R, Trigo D. Glymphatic system, AQP4, and their implications in Alzheimer’s disease. Neurol Res Pract. 2021;3:1–9. pmid:33499944
  184. 184. Ishida K, Yamada K, Nishiyama R, Hashimoto T, Nishida I, Abe Y, et al. Glymphatic system clears extracellular tau and protects from tau aggregation and neurodegeneration. J Exp Med. 2022;219:e20211275. pmid:35212707
  185. 185. Proukakis C. Somatic mutations in neurodegeneration: An update. Neurobiol Dis. 2020;144:105021. pmid:32712267
  186. 186. Miller MB, Reed HC, Walsh CA. Brain somatic mutation in aging and Alzheimer’s disease. Annu Rev Genomics Hum Genet. 2021;22:239–256. pmid:33979534
  187. 187. Bushman DM, Kaeser GE, Siddoway B, Westra JW, Rivera RR, Rehen SK, et al. Genomic mosaicism with increased amyloid precursor protein (APP) gene copy number in single neurons from sporadic Alzheimer’s disease brains. Elife. 2015;4:e05116. pmid:25650802
  188. 188. Lee M-H, Siddoway B, Kaeser GE, Segota I, Rivera R, Romanow WJ, et al. Somatic APP gene recombination in Alzheimer’s disease and normal neurons. Nature. 2018;563:639–645. pmid:30464338
  189. 189. Kaeser GE, Chun J. Mosaic somatic gene recombination as a potentially unifying hypothesis for Alzheimer’s disease. Front Genet. 2020;11:390. pmid:32457796
  190. 190. Shanbhag NM, Evans MD, Mao W, Nana AL, Seeley WW, Adame A, et al. Early neuronal accumulation of DNA double strand breaks in Alzheimer’s disease. Acta Neuropathol Commun. 2019;7:77. pmid:31101070
  191. 191. Zhu L-S, Wang D-Q, Cui K, Liu D, Zhu L-Q. Emerging perspectives on DNA double-strand breaks in neurodegenerative diseases. Curr Neuropharmacol. 2019;17:1146–1157. pmid:31362659
  192. 192. Thadathil N, Delotterie DF, Xiao J, Hori R, McDonald MP, Khan MM. DNA double-strand break accumulation in Alzheimer’s disease: Evidence from experimental models and postmortem human brains. Mol Neurobiol. 2021;58:118–131. pmid:32895786
  193. 193. Larek-Rąpała A, Żaba R, Kowalczyk MJ, Szramka-Pawlak B, Schwartz RA. Herpes simplex virus infection as a possible modulator of autoimmune diseases facilitated by human endogenous retroviruses. Postepy Dermatol Alergol. 2011;28:313–316.
  194. 194. Römer C. Viruses and endogenous retroviruses as roots for neuroinflammation and neurodegenerative diseases. Front Neurosci. 2021;15:648629. pmid:33776642
  195. 195. Gorbunova V, Seluanov A, Mita P, McKerrow W, Fenyö D, Boeke JD, et al. The role of retrotransposable elements in ageing and age-associated diseases. Nature. 2021;596:43–53. pmid:34349292
  196. 196. Ochoa Thomas E, Zuniga G, Sun W, Frost B. Awakening the dark side: retrotransposon activation in neurodegenerative disorders. Curr Opin Neurobiol. 2020;61:65–72. pmid:32092528
  197. 197. Kim J, Zhao B, Huang AY, Miller MB, Lodato MA, Walsh CA, et al. APP gene copy number changes reflect exogenous contamination. Nature. 2020;584:E20–E28. pmid:32814883
  198. 198. Lee M-H, Liu CS, Zhu Y, Kaeser GE, Rivera R, Romanow WJ, et al. Reply to: APP gene copy number changes reflect exogenous contamination. Nature. 2020;584:E29–E33. pmid:32814883
  199. 199. Park JS, Lee J, Jung ES, Kim M-H, Kim IB, Son H, et al. Brain somatic mutations observed in Alzheimer’s disease associated with aging and dysregulation of tau phosphorylation. Nat Commun. 2019;10:3090. pmid:31300647
  200. 200. Ivashko-Pachima Y, Hadar A, Grigg I, Korenková V, Kapitansky O, Karmon G, et al. Discovery of autism/intellectual disability somatic mutations in Alzheimer’s brains: Mutated ADNP cytoskeletal impairments and repair as a case study. Mol Psychiatry. 2021;26:1619–1633. pmid:31664177
  201. 201. Perez-Rodriguez D, Kalyva M, Leija-Salazar M, Lashley T, Tarabichi M, Chelban V, et al. Investigation of somatic CNVs in brains of synucleinopathy cases using targeted SNCA analysis and single cell sequencing. Acta Neuropathol Commun. 2019;7:219. pmid:31870437
  202. 202. Loeb MB, Molloy DW, Smieja M, Standish T, Goldsmith CH, Mahony J, et al. A randomized, controlled trial of doxycycline and rifampin for patients with Alzheimer’s disease. J Am Geriatr Soc. 2004;52:381–387. pmid:14962152
  203. 203. Allen HB. Alzheimer’s disease: assessing the role of spirochetes, biofilms, the immune system, and amyloid-β with regard to potential treatment and prevention. J Alzheimers Dis. 2016;53:1271–1276. pmid:27372648
  204. 204. Iqbal UH, Zeng E, Pasinetti GM. The use of antimicrobial and antiviral drugs in Alzheimer’s disease. Int J Mol Sci. 2020;21:4920. pmid:32664669