The World Health Organization  has declared dementia as public health priority. Alzheimer’s disease (AD) is the most frequent cause of dementia. The challenges to governments to respond to the growing number of people with dementia are substantial. Tremendous efforts have been made in research during the last four decades highlighting important aspects of the pathogenesis of AD, but if the cause of AD is not defined, and treatments to prevent the disease are not provided, the world will face an unprecedented health-care problem by the middle of the century.
The idea that infectious agents might be involved in AD is not new. In 1910, Oskar Fischer suggested that senile plaques are reminiscent of bacterial colonies but the cultivation of microorganisms remained unsuccessful . The concept that a slow-acting unconventional infectious agent acquired at an early age and requiring decades to become active might be involved in AD, was never discarded. Renowned AD researchers encouraged research in this direction [3,4]. Spirochetes are such unconventional infectious agents with these capabilities.
The occurrence of dementia in late stage syphilis demonstrates that chronic spirochetal infection can cause dementia. The strongest evidence that spirochetes play a causal role in the etiology of AD is derived from observations and illustrations made by hundreds of scientists during the last century . Treponema pallidum, the causative agent of syphilitic dementia, reproduces all the clinical and pathological hallmarks, which are necessary for the definite diagnosis of AD, including amyloid-β (Aβ) deposition . Individual spirochetes and spirochetal colonies accumulating in the cerebral cortex in syphilitic dementia cannot be distinguished from curly fibers and senile plaques. Each curly fiber corresponds to a single spirochete and each senile plaque to a spirochetal colony. These historic observations clearly indicate that it is our obligation to explore this path as it might bring cutting-edge solutions to help the patients and prevent AD.
Recent observations also demonstrate the proliferation of spirochetes in the brain, cerebrospinal fluid, and blood of neuropathologically-confirmed definite AD patients, and in the blood of living patients with clinically diagnosed probable AD [6-8]. We have detected spirochetes in 100% of AD patients, and they were absent in controls without any AD-type changes. Spirochetes were also present in moderate number, in preclinical stages of AD. Borrelia burgdorferi, the causative agent of Lyme disease, was detected and cultivated from the AD brain by several authors [9-11] and was 14 times more frequent in AD than in controls . Oral treponemes are predominant periodontal pathogens, and were present in more than 90% of AD patients analyzed . Spirochetes induced AD-type lesions, and increased APP, Aβ, and phosphorylated tau levels were also observed in vitro in primary mammalian neuronal and glial cells and organotypic cultures .
Why spirochetes? The “curly” pathological filaments accumulating in the brain in AD indicates that the main invading pathogen should be helically shaped, in order to reproduce the filamentous pathology of AD. There are many spirochetes in the human body and they are strongly neurotropic. Various species of Borrelia and Treponema can infect the human. Oral treponeme spirochetes are predominant periodontal pathogens, and various intestinal and urogenital spirochetes also occur in the human body. The majority of these spirochetes were previously considered as commensal, however, 8 of the 60 oral Treponema species  revealed to be invasive [12,15], including Treponema denticola, which was first likely discovered by Leuwenhook 300 years ago.
Reports of an association between infection and AD are not confined to spirochetes. Chlamydophila (Chlamydia) pneumoniae [16, 17], Porphyromonas gingivalis , Proprionibacterium acne , Helicobacter pylori [20, 21] and other bacterial taxa were found to be associated with AD. Viruses, including Herpes simplex virus type 1 (HSV-1)  and fungi  were also detected in the brain in AD. It is noteworthy that spirochetes frequently co-infect with other bacteria, Herpes viruses, and fungi, as also observed in the case of syphilis.
Recent data indicate that bacterial and host derived amyloid both contribute to amyloid deposition in AD. This is in harmony with the observations showing that Aβ has properties of antimicrobial peptides . Disseminated spirochetes preferentially reach the brain crossing the capillary network of the cerebral cortex. Cerebral infarcts also occur in various spirochetal infections secondary to Heubner’s arteritis. These data underline the importance of those observations, which highlight the role of vascular involvement in AD  and with the pioneering work of McGeer, Rogers, and Griffin showing that cellular and molecular components of immune system reactions are associated with AD lesions [26, 27].
In conclusion, more attention and support is needed for this emerging field of research. Infection occurs long before the diagnosis of dementia is made. An adequate treatment should start early in the course of infection to achieve prevention and eradication, as it occurred in the case of syphilis. The resulting effect on the suffering of patients and on the reduction of healthcare costs would be substantial.
Some important points recommended for future research in order to avoid controversies:
Borrelia burgdorferi alone cannot explain the occurrence of all AD cases. The involvement of various other spirochetes should be also considered. In neuropathological studies, brains without any AD-type changes should be used as controls. It is also critical to consider that the infectious and neurodegenerative process start years or decades before the onset of clinical dementia.
It is time to intensively investigate the role of pathogens in AD. In such devastating diseases, everything which may help the patients must be considered. Why are adequate funds for this vital effort not forthcoming? We cannot wait another century and we all want to achieve the same objective, to solve the problem of patients who are suffering from AD.
 World Health Organization (WHO), ISBN 978 92 4 156445 8; NLM classification: WM 200; www.who.int
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