Alzheimer's disease - a neurospirochetosis. Analysis of the evidence following Koch's and Hill's criteria

Abstract

It is established that chronic spirochetal infection can cause slowly progressive dementia, brain atrophy and amyloid deposition in late neurosyphilis. Recently it has been suggested that various types of spirochetes, in an analogous way to Treponema pallidum, could cause dementia and may be involved in the pathogenesis of Alzheimer's disease (AD). Here, we review all data available in the literature on the detection of spirochetes in AD and critically analyze the association and causal relationship between spirochetes and AD following established criteria of Koch and Hill. The results show a statistically significant association between spirochetes and AD (P = 1.5 × 10-17, OR = 20, 95% CI = 8-60, N = 247). When neutral techniques recognizing all types of spirochetes were used, or the highly prevalent periodontal pathogen Treponemas were analyzed, spirochetes were observed in the brain in more than 90% of AD cases. Borrelia burgdorferi was detected in the brain in 25.3% of AD cases analyzed and was 13 times more frequent in AD compared to controls. Periodontal pathogen Treponemas (T. pectinovorum, T. amylovorum, T. lecithinolyticum, T. maltophilum, T. medium, T. socranskii) and Borrelia burgdorferi were detected using species specific PCR and antibodies. Importantly, co-infection with several spirochetes occurs in AD. The pathological and biological hallmarks of AD were reproduced in vitro by exposure of mammalian cells to spirochetes. The analysis of reviewed data following Koch's and Hill's postulates shows a probable causal relationship between neurospirochetosis and AD. Persisting inflammation and amyloid deposition initiated and sustained by chronic spirochetal infection form together with the various hypotheses suggested to play a role in the pathogenesis of AD a comprehensive entity. As suggested by Hill, once the probability of a causal relationship is established prompt action is needed. Support and attention should be given to this field of AD research. Spirochetal infection occurs years or decades before the manifestation of dementia. As adequate antibiotic and anti-inflammatory therapies are available, as in syphilis, one might prevent and eradicate dementia.

Figure 1

Association of spirochetes with Alzheimer's disease. The frequency of spirochetes is significantly higher in the brains of Alzheimer patients compared to controls. The statistical analysis is based on the cumulative data of the literature entered in Table 1. The association is statistically significant in the four groups analyzed: in the group where all types of spirochetes were detected using neutral techniques (All spirochetes), in the group of oral periodontal pathogen spirochetes (Oral spirochetes), in the group where Borrelia burgdorferi was detected alone (B. burgdorferi) and in the group where all studies were considered (All studies)

Figure 2

Association of oral invasive periodontal Treponema (T.) spirochetes with Alzheimer's disease. Using species specific PCR and antibodies six of seven periodontal pathogen spirochetes analyzed were detected in the brains of AD patients [96], (Table 1). The association of oral Treponemas with Alzheimer's disease is statistically significant [96], (Table 1).

Figure 3

Schematic representation of spirochetal invasion of the cerebral cortex reproducing the pathological hallmarks of Alzheimer's disease. Spirochetes, in an analogous way to Treponema pallidum, form argyrophilic "plaques", colonies or masses along the cerebral cortex. Accumulation of spirochetes in masses reproduces the morphology of amorphous, immature and mature plaques. Agglutination of spirochetes in the center results in a homogeneous central core, which attract microglia. Spirochetes invading neurons lead to the formation of neurofibrillary tangles, and their pleomorphic granular form to granulovacuolar degeneration. Individual spirochetes disseminate along the cerebral cortex forming neuropil threads or curly fibers. Invasion of astrocytes by spirochetes can results in a similar granular pathology as in neurons. Spirochetes can also invade microglia, which may lead to their dysfunction and diminish their capacity to fight infection. Lesions similar to plaques, tangles and granulovacuolar degeneration were all reproduced by exposure of mammalian CNS cells and organotypic cultures to spirochetes [107].