Lyme disease is a tick-borne illness that results when a tick carrying several species of bacteria, most notably the spirochete Borrelia burgdorferi, takes a bloodmeal from a human. The bacteria enter the human, and it is known to disseminate throughout the body to cause the pathological and clinical symptoms of Lyme disease. Although Lyme disease can be treated with antimicrobials when recognized before dissemination, when left untreated, the infection can spread to other organs, including the brain, where it can cause the patient to exhibit neurological symptoms [55]. Late Lyme disease is characterized by inflammatory arthritis, resulting from pro-inflammatory factors, such as TNF-α [55]. Additionally, B. burgdorferi has been associated with the development of psychiatric disorders, including depression, bipolar disorder, and anxiety disorders [56]. Due to the inflammation seen in late Lyme disease, neurological symptom presentation, and the spirochete’s ability to disseminate to other organs, it has been suspected that Borrelia burgdorferi infections may be involved in AD.

Lyme neuroborreliosis (LNB) is caused by B. burgdorferi and can result in meningoencephalomyelitis and altered motor functions associated with the peripheral nervous system [57]. Early studies indicated that antigens specific for B. burgdorferi are detectable in the brains of AD patients with Lyme neuroborreliosis, and bacterial DNA based on PCR analysis was also present [27]. One of the hypotheses linking AD to B. burgdorferi is that infection with the bacterium could induce Aβ deposition in the brain. When neurons, astrocytes, and mammalian microglial cells are infected with B. burgdorferi, Aβ precursor protein and Aβ plaque aggregation and deposition are observed to increase with time, demonstrating that the bacterium could induce this pathological feature of AD as Lyme disease progresses [58]. It is also thought that AβPP is the cause of the Aβ plaque formation due to B. burgdorferi infection, and higher levels of AβPP were seen in Borrelia-infected cells [58]. Therefore, it can be assumed that infection with B. burgdorferi induces the Aβ plaque deposition in neuronal cells through increased AβPP. Hyperphosphorylation of tau is also seen in these infected cells, further suggesting that B. burgdorferi infection may induce AD pathology [30]. Evidence has indicated that one of the components of B. burgdorferi, lipopolysaccharide (LPS), could have a role in causing AD pathology, specifically tau hyperphosphorylation [58]. When cells were exposed to LPS, AβPP levels increased as time increased, coinciding with an increase in tau hyperphosphorylation [30]. This suggests that the LPS component of B. burgdorferi could be the cause of AD pathology. The observation that Lyme disease is often a co-infection with several other pathogens— such as the previously described C. pneumoniae, HSV-1, and H. pylori—further suggests that B. burgdorferi might act similarly to these pathogens in reference to AD development, or that their co-infection contributes to AD pathology [27].

While studies have shown an association between AD pathology and B. burgdorferi, exactly how the bacterium can induce it is unclear. One hypothesis is that biofilm formation creates the Aβ plaques characteristic of AD. This hypothesis stems from the observation that B. burgdorferi forms biofilms in vitro and in the joints of individuals with Lyme disease, an area affected by the disease [59]. Studies have also shown that Aβ plaques are composed of biofilms and their constituents, and spirochetes can express AβPP, suggesting that spirochetes themselves could induce the plaque formation characteristic of AD [59]. In an in vitro culture, it was confirmed that B. burgdorferi forms biofilms and aggregations that increase over time, and these biofilms contained Aβ and AβPP when analyzed with immunostaining [59]. When examining senile plaques harvested from the brains of patients diagnosed with AD, B. burgdorferi peptidoglycan-specific antigens, B. burgdorferi-specific antigens, and B. burgdorferi DNA were discovered [59]. It was also seen that these biofilms react to anti-AβPP and anti-Aβ antibodies [59]. These results indicate that biofilms formed by B. burgdorferi exhibit similar pathology to one of the hallmarks of AD, Aβ plaque deposition. Upon direct examination of cortical sections of AD patients, biofilms formed by B. burgdorferi were present in the brain samples, as shown by immunoreaction of anti-B. burgdorferi antibodies and anti-Aβ antibodies [59]. Overall, these observations indicate that senile plaques contain bacterial amyloid, potentially due to biofilm formation by the spirochete B. burgdorferi. Therefore, it can be hypothesized that B. burgdorferi infection may cause AD pathology and induce AD symptoms.

For many years, there has been evidence that treponemes are present in the oral cavity. Given previously described observations that oral bacteria in chronic periodontitis can travel to and infect the brain, it was hypothesized that Treponema spp. can do the same. When examining the possibility that oral treponema species can travel to the brain and induce AD pathology, Riviere et al. demonstrated that AD brains were positive for at least one treponeme species, and some AD patients had multiple species present [60]. It is noted that control subjects without AD were negative for most Treponema species in the brain samples, but the presence of treponemes in the oral cavities of control and AD patients did not differ significantly [60]. Therefore, it is suggested that several oral treponemes may invade the central nervous system and lead to AD pathology, although the mechanism remains unclear.

It is now known that treponemes, specifically T. pallidum, can invade the brain by way of penetration of endothelial cell tight junctions, presenting evidence that infection with T. pallidum can cause disseminated infections in other areas of the body, including the brain [61]. The spirochete Treponema pallidum is the causative agent of syphilis, a progressive sexually transmitted infection that can infect the brain when left untreated, resulting in neurosyphilis. When the disease reaches this stage, the bacterium has been known to induce dementia with a persistent brain infection, potentially decades after primary infection [31]. For many years, T. pallidum and its effects on the brain have been studied. It is known that the spirochete can persist in the brain and lead to general paresis, characterized by brain inflammation and muscular weakness, and early studies indicated that spirochetes gathered in the cortexes and neuronal cells of patients with neurosyphilis [31]. Additional early evidence described neurofibrillary tangles in patients with neurosyphilis, leading to the hypothesis that there is a relationship between T. pallidum and AD. Via direct examination of the brain, spirochetes, specifically T. pallidum, can form masses or aggregates in the brain, which highly resemble Aβ senile plaques in individuals with AD [31]. Upon central nervous system invasion, T. pallidum can cause inflammation and amyloid plaque formation [50]. It is noted that the Aβ plaques formed by T. pallidum highly resemble the Aβ plaques observed in AD, indicating that spirochetes, specifically T. pallidum, may contribute to AD development [31]. However, several cases have been presented that demonstrate Alzheimer’s dementia can be mimicked by neurosyphilis, and neurosyphilis may be mistaken for early-onset AD. For example, in 2012, a Bulgarian man presented with signs typical of early AD, including memory loss [62]. When scored with the Mini-Mental State Examination (MMSE) cognitive functioning scale, the man presented with low ability to retain new information, verbal impairment, and disorientation [62]. These clinical symptoms closely mimic some of the cognitive impairments seen with AD, but hemagglutination assays showed a positive result for T. pallidum [62]. In a similar case, a 40-year-old man presented with cognitive decline and behavioral changes, prompting clinicians to suspect AD [63]. An MRI showed significant atrophy of the medial temporal lobe, again signaling AD [63]. However, hemagglutination assay performed on the patient’s CSF indicated the presence of T. pallidum [63]. These presented cases prompted further examination after the initial diagnosis of early-onset AD because of the patients’ ages. These cases beg the question if older patients diagnosed with AD may be misdiagnosed with the disease when they have neurosyphilis. Given the findings that T. pallidum may induce AD pathology, and the presented cases, it might be of interest to examine if patients diagnosed with AD by the presence of Aβ plaques and NFTs are positive for T. pallidum with a hemagglutination assay.