Alzheimer’s disease (AD) is the most frequent cause of dementia. All efforts made in AD research during the last four decades provided important insights into the pathogenesis of AD but the cause of the disease is still unclear and the treatment unresolved.
The clinical manifestations of AD begin with subtle short-term memory deficit and anxio-depressive symptoms followed by orientation and language difficulties. The intellectual functions progressively disappear and the patients become entirely dependent. They may survive in this devastating state for more than a decade. Death generally occurs from secondary infection, frequently from pneumonia or urinary infection. The duration of the disease from the appearance of the first symptoms and the manifestation of dementia varies between 5 and 20 years.
The fact that AD usually develops in later life suggested that a slow-acting unconventional infectious agent acquired at an early age and requiring decades to become active may be involved in its etiology (Wisniewski, 1978; Khachaturian, 1985). Spirochetes are such unconventional infectious agents. In the long-standing, stationary or atrophic form of general paresis, Treponema pallidum (T. pallidum) persists in the brain, sustains chronic infection and inflammation and causes slowly progressive dementia. It is established that T. pallidum is responsible for the various neuropsychiatric manifestations of chronic neurosyphilis. Dementia develops years or decades following the primary syphilitic infection (Merritt et al., 1946). As spirochetes are strongly neurotropic, a series of investigations were undertaken showing that following a long latent stage various types of spirochetes in similar way to T. pallidum can cause dementia (Miklossy, 1993, 1994; Miklossy et al., 1994, 1995). It is noteworthy, that the human oral cavity harbors more than 60 different Treponema species (Dewhirst et al., 2000). These were previously considered as commensal spirochetes, but several of them revealed to be predominant and invasive periodontal pathogens (Riviere et al., 1991; Miklossy, 2011b). T. pectinovorum, T. amylovorum, T. lecithinolyticum, T. maltophilum, T. medium and T. socranskii were all detected in the brains of AD patients (Riviere et al., 2002). Another spirochete, Borrelia burgdorferi (B. burgorferi), the causative agent of Lyme disease transmitted by infected tick bites to human (Burgdorfer et al., 1982), was also detected in the brain in a percentage of AD patients. The similarities of the clinical and pathological manifestations of syphilis and Lyme disease are well documented (e.g., Fallon and Nields, 1994). MacDonald and Miranda (1987) first reported the occurrence of B. burgdorferi in the brain of an AD patient. This was later confirmed by the same and by various other authors (MacDonald, 1988, 2006; Miklossy, 1993; Riviere et al., 2002; Miklossy et al., 2004). Exposure of primary neuronal and glial cells and brain cell aggregates to spirochetes induces plaque-, tangle- and granulovacuolar degeneration-like lesions, similar to those occurring in AD (Miklossy et al., 2006a). Spirochete specific antigens and DNA were co-localized with amyloid beta (Aβ). Several recent reviews concluded that there is a significant association between spirochetal infection and AD (Honjo et al., 2009; Miklossy, 2011a,b; De Chiara et al., 2012; Hill et al., 2014; Maheshwari and Eslick, 2015). That this strong association fulfills Hill’s nine criteria represented evidence in favor of a causal relationship (Miklossy, 2011b).
If AD is indeed caused by various chronic spirochetal infections, one should find AD-type lesions in syphilitic dementia as well. Therefore, the goal of the present study was to revisit the historic literature on the detection of spirochetes in the atrophic form of general paresis, which is known to be associated with slowly progressive dementia. The aim was to confirm that T. pallidum the causative agent of syphilitic dementia also reproduces the pathological hallmarks of AD. It is generally acknowledged that it is the invasion, the persistence and the accumulation of T. pallidum in the brain, which causes dementia in syphilis. Therefore, observations and illustrations on the detection of spirochetes in syphilitic dementia were compared to the characteristic pathology of AD. In order to ensure that the information presented is compliant to historic descriptions, particularly for strongly relevant subjects, citations from the original text or from published translations were sometimes used. Historic observations and illustrations indeed testify that the pathological hallmarks of AD also occur in the atrophic form of general paresis and indicate that persisting spirochetal infection can reproduce the clinical and pathological hallmarks of AD. These historic observations provide evidence in support of a causal relationship between various spirochetal infections and AD.