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Alzheimer’s Disease and Spirochetosis: A Causal Relationship

The World Health Organization [1] 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 [2]. 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 [5]. 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 [5]. 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 [7]. Oral treponemes are predominant periodontal pathogens, and were present in more than 90% of AD patients analyzed [12]. 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 [13].

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 [14] 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 [18], Proprionibacterium acne [19], Helicobacter pylori [20, 21] and other bacterial taxa were found to be associated with AD. Viruses, including Herpes simplex virus type 1 (HSV-1) [22] and fungi [23] 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 [24]. 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 [25] 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.

References
[1] World Health Organization (WHO), ISBN 978 92 4 156445 8; NLM classification: WM 200; www.who.int
[2] Fischer O (1910) Die presbyophrene demenz, deren anatomische grundlage und klinische abgrenzung. Z Gesamte Neurol Psychiatr 3, 371–471.
[3] Wisniewsky HM (1978) Possible viral etiology of neurofibrillary changes and neuritic plaques. In Alzheimer’s Disease: Senile Dementia and Related Disorders (Aging, Vol. 7), Katzman R, Terry RD, Bick KL, eds. Raven Press, New York, pp. 555-557.
[4] Khachaturian ZS (1985) Diagnosis of Alzheimer’s disease. Arch Neurol 42, 1097-1105.
[5] Miklossy J (2015) Historic evidence to support a causal relationship between spirochetal infections and Alzheimer’s disease. Front Aging Neurosci 7, 46.
[6] Miklossy J (1993) Alzheimer’s disease - A spirochetosis? Neuroreport 4, 841-848.
[7] Miklossy J (2011) Alzheimer's disease - a neurospirochetosis. Analysis of the evidence following Koch's and Hill's criteria. J Neuroinflammation 8, 90.
[8] Miklossy J (2011) Emerging roles of pathogens in Alzheimer disease. Expert Rev Mol Med 13, e30.
[9] MacDonald AB, Miranda JM (1987) Concurrent neocortical borreliosis and Alzheimer’s disease. Hum Pathol 18, 759–761.
[10] MacDonald AB (1988) Concurrent neocortical borreliosis and Alzheimer’s disease: Demonstration of a spirochetal cyst form. Ann N Y Acad Sci 539, 468-470.
[11] Miklossy J, Khalili K, Gern L, Ericson RL, Darekar P, Bolle L, Hurlimann J, Paster BJ (2004) Borrelia burgdorferi persists in the brain in chronic Lyme neuroborreliosis and may be associated with Alzheimer disease. J Alzheimers Dis 6, 639-649.
[12] Riviere GR, Riviere KH, Smith KS (2002) Molecular and immunological evidence of oral Treponema in the human brain and their association with Alzheimer’s disease. Oral Microbiol Immunol 17, 113-118.
[13] Miklossy J, Kis A, Radenovic A, Miller L, Forro L, Martins R, Reiss K, Darbinian N, Darekar P, Mihaly L, Khalili K (2006) Beta-amyloid deposition and Alzheimer’s type changes induced by Borrelia spirochetes. Neurobiol Aging 27, 228-236.
[14] Dewhirst FE, Tamer MA, Ericson RE, Lau CN, Levanos VA, Boches SK, Galvin JL, Paster BJ (2000) The diversity of periodontal spirochetes by 16S rRNA analysis. Oral Microbiol Immunol 15, 196-202.
[15] Riviere GR, Weisz SK, Adams DF, Thomas DD (1991) Pathogen-related oral spirochetes from dental plaque are invasive. Infect Immun 59, 3377–3380.
[16] Balin BJ, Gerard HC, Arking EJ, Appelt DM, Branigan PJ, Abrams JT, Whittum-Hudson JA, Hudson AP (1998) Identification and localization of Chlamydia pneumoniae in the Alzheimer’s brain. Med Microbiol Immunol 187, 23-42.
[17] Little CS, Joyce TA, Hammond CJ, Matta H, Cahn D, Appelt DM, Balin BJ (2014) 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 5, 304.
[18] Poole S, Singhrao SK, Kesavalu L, Curtis MA, Crean S (2013) Determining the presence of periodontopathic virulence factors in short-term postmortem Alzheimer’s disease brain tissue. J Alzheimers Dis 36, 665-677.
[19] Kornhuber HH (1995) Chronic anaerobic cortical infection in Alzheimer’s disease: Propionibacterium acnes. Neurol Psych Brain Res 3, 177-182.
[20] Malaguarnera M, Bella R, Alagona G, Ferri R, Carnemolla A, Pennisi G (2004) Helicobacter pylori and Alzheimer's disease: a possible link. Eur J Intern Med 15, 381-386.
[21] Kountouras J, Gavalas E, Polyzos SA, Deretzi G, Kouklakis G, Grigoriadis S, Grigoriadis N, Boziki M, Zavos C, Tzilves D, Katsinelos P (2014) Association between Helicobacter pylori burden and Alzheimer's disease. Eur J Neurol 21, e100.
[22] Jamieson GA, Maitland NJ, Wilcock GK, Craske J, Itzhaki RF (1991) Latent herpes simplex virus type 1 in normal and Alzheimer’s disease brains. J Med Virol 33, 224–227.
[23] Pisa D, Alonso R, Juarranz A, Rábano A, Carrasco L (2015) Direct visualization of fungal infection in brains from patients with Alzheimer's disease. J Alzheimers Dis 43, 613-624.
[24] Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson M, Hyman B, Burton MA, Goldstein LE, Duong S, Tanzi RE, Moir RD (2010) The Alzheimer’s disease-associated amyloid beta-protein is an antimicrobial peptide. PLoS One 5, e9505.
[25] de la Torre JC (2000) Impaired cerebromicrovascular perfusion: summary of evidence in support of its causality in Alzheimer’s disease. Ann N Y Acad Sci 924, 136–152.
[26] McGeer PL, Rogers J, McGeer EG (2016) Inflammation, antiinflammatory agents, and Alzheimer's disease: the last 22 years. J Alzheimers Dis 54, 853-857.
[27] Griffin WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ, White CL 3rd, Araoz C (1989) Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease, Proc Natl Acad Sci U S A 86, 7611–7615.

Last comment on 23 May 2017 by Lawrence Broxmeyer, MD

Comments

Submitted by Sim Singhrao on

Professor Miklossy raises an interesting discussion around a cause and effect relationship of Alzheimer’s disease (AD) with specific types of bacterial infections [1]. Indeed Osker Fischer (1910) proposed the infection theory for the development of AD and the very observation of peripheral bacterial infectious agents entering the brains supports this concept to date. However, the late-onset AD lacks direct evidence as to which one of many oral and non-oral microorganisms may predominate, and/or whether there is a synergistic effect among multiple-species. A comprehensive list of candidate microbes that appear to be associated with, and survive the highly inflammophilic environment of the AD brain is given by Olsen and Singhrao [2]. In 2013, Mawanda and Wallace [3] asked the question “can infections cause Alzheimer’s disease?” and attempted to answer it using a systematic review of the literature. Mawanda and Wallace [3] were unsuccessful in finding a clear outcome but acknowledged the associations were strong. Four years later, Maheswari and Eslick [4] conducted a meta-analysis. They found a strong statistical association between spirochetal and Chlamydia pneumoniae bacterial infections with AD. For now, the infection theory of the late-onset AD will continue to uncover candidate bacteria from peripheral organ sources that together will play a role in the pathogenesis of late-onset AD.

References
[1] Miklossy J (2011) Alzheimer's disease - a neurospirochetosis. Analysis of the evidence following Koch's and Hill's criteria. J Neuroinflammation 8, 90.
[2] Olsen I, Singhrao SK (2015) Can oral infection be a risk factor for Alzheimer’s disease? J Oral Microbiol 7, 29143.
[3] Mawanda F, Wallace R (2013) Can infections cause Alzheimer’s disease? Epidemiol Rev 35, 161-180.
[4] Maheshwari P, Eslick GD (2017) Bacterial infection increases the risk of Alzheimer’s disease: An evidence-based assessment. In Handbook of Infection and Alzheimer’s Disease, Miklossy J, ed. IOS Press, Amsterdam, in press.

Submitted by Kilmer McCully on

Altered homocysteine metabolism and oxidative metabolism caused by microbial infection in Alzheimer's dementia and atherosclerosis: a strategy for prevention

As demonstrated by the important studies of Miklossy, oral spirochetes have been identified in plaques and tangles in the brain in cases of Alzheimer’s dementia, and the historic evidence supports a causal relationship between spirochetal infections and the pathogenesis of Alzheimer’s disease (AD) [1]. Chronic infections by Herpes Simplex Virus, Cytomegalovirus, other Herpesviridae, Chlamydophilia pneumoniae, spirochetes, Helicobacter pylori, and several peri-odontal pathogens have been implicated in the pathogenesis of AD for a number of years [2]. According to this view, the deposition of amyloid-β (Aβ) in plaques and tangles in AD, hyperphosphorylation of tau protein, neuronal injury, and apoptosis of neurons are reactive processes caused by chronic microbial infection.

Chronic infection by many of the same pathogens which are observed in AD is causally implicated in the pathogenesis of atherosclerotic plaques [3]. These pathogens form aggregates with homocysteinylated low-density lipoprotein (LDL) and LDL autoantibodies which obstruct the vasa vasorum, leading to ischemia and necrosis of arterial wall and rupture into intima to form a micro-abscess, the vulnerable plaque [4].

After eight years of observation of participants, the Framingham Heart Study determined that an elevated plasma level of homocysteine is a prospective risk factor for development of AD [5]. Earlier studies showed that reduced blood levels of folate and cobalamin are associated with hyperhomocysteinemia in AD patients, and an interventional study with these B vitamins and pyridoxal demonstrated reduction of cerebral atrophy in gray matter regions vulnerable to the AD process in elderly subjects with mild cognitive impairment [6]. Since introduction of the homocysteine theory of arteriosclerosis in 1969, multiple studies have shown that elevated plasma homocysteine is also a strong, independent risk factor for atherosclerosis [7].

A pioneering study of oxidative metabolism in AD patients by positron emission spectroscopy revealed down-regulation of oxidative phosphorylation and decreased energy utilization in areas of brain most affected by the AD process [8]. Thioretinaco ozonide (TR2CoO3) is a complex composed of thioretinamide, cobalamin, and ozone which is proposed to be the active site which catalyzes adenosine triphosphate (ATP) synthesis from nicotinamide adenine dinucleotide (NAD+) and inorganic phosphate during oxidative phosphorylation [9]. The allosteric regulator of methionine metabolism is the sulfonium derivative of methionine, adenosyl methionine, which is produced from thioretinaco ozonide and ATP. The hyperhomocysteinemia and decreased oxidative phosphorylation observed in AD are attributable to loss of thioretinaco ozonide from mitochondria and dysregulation of methionine metabolism because of decreased biosynthesis of adenosyl methionine [9].

The pathogenic microbes, which are demonstrated in AD brain and in atherosclerotic plaques, synthesize polyamines that mediate genetic translation, genetic regulation, resistance to stress, cell proliferation and differentiation. Polyamines are synthesized from adenosyl methionine, and infections by pathogenic microbes cause depletion of cellular adenosyl methionine [10]. In a study of Chlamydia trachomatis, the infectious agent of trachoma and venereal disease, infection of cultured human mesenchymal stem cells caused down-regulation of inducible nitric oxide (NO) synthase (iNOS) and up-regulation of ornithine transcarboxylase, the rate-limiting enzyme in the polyamine biosynthetic pathway [11]. The resulting inhibition of NO biosynthesis potentially decreases the powerful anti-microbial activity of NO because of reduced formation of peroxynitrite (OONOO-). Similar studies are needed to determine whether the spirochetes, viruses and bacteria that are implicated in the pathogenesis of AD and atherosclerosis also produce decreased NO biosynthesis in infected cells.

As pointed out by Miklossy and other authorities in the field of the infectious origin of AD, understanding of the microbial etiology of the disease is essential for design of an effective preventive and therapeutic strategy. The indolent and chronic nature of AD requires early detection by proven methods, followed by effective anti-microbial and metabolic therapy, to achieve elimination of dementia from increased prevalence in aging populations. A proposed homocysteine-lowering strategy, comprised of thioretinamide, B complex vitamins, including methyl cobalamin, methyl folate, pyridoxal phosphate, and nicotinamide riboside, ascorbate, co-enzyme Q10, adenosyl methionine, menoquinone, amygdalin, vitamin D3, pancreatic enzymes, cod liver oil, and dietary improvement to eliminate processed foods and to prevent subclinical protein energy malnutrition may be effective in delaying or preventing progression of cognitive impairment to dementia. In addition, meticulous oral hygiene, consumption of dietary monolaurin and other nutrients with anti-microbial activity, consumption of adequate dietary protein, and avoidance of neurotoxins from foods or environmental contaminants are essential components of an effective preventive strategy against progression of dementia [7,10]. A properly designed clinical trial is needed to provide validation of this preventive strategy.

References
[1] Miklossy J (2015) Historic evidence to support a causal relationship between spirochetal infections and Alzheimer’s disease. Front Aging Neurosci 7, 1-12.
[2] Harris SA, Harris EA (2015) Herpes Simplex Virus Type 1 and other pathogens are key causative factors in sporadic Alzheimer’s disease. J Alzheimers Dis 48, 319-353.
[3] Ravnskov U, McCully KS (2012) Infections may be causal in the pathogenesis of atherosclerosis. Am J Med Sci 344, 391-394.
[4] Ravnskov U, McCully KS. (2009) Vulnerable plaque formation from obstruction of vasa vasorum by homocysteinylated and oxidized lipoprotein aggregates complexed with microbial remnants and LDL autoantibodies. Ann Clin Lab Sci 39, 3-16.
[5] Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D’Agostino RB, Wilson PWF, Wolf PA (2002) Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. New Engl J Med 346, 476-483.
[6] Duoad G, Refsum H, de Jager CA, Jacoby R, Nichols TE, Smith SM, Smith AD (2013) Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment. Proc Natl Acad Sci U S A 110, 9523-9528.
[7] McCully KS (2015) Homocysteine and the pathogenesis of atherosclerosis. Exp Rev Clin Pharmacol 8, 211-219.
[8] Chandrasekaran K, Hatanpaa K, Brady DR, Rapoport SI (1996) Evidence for physiological down-regulation of brain oxidative phosphorylation in Alzheimer’s disease. Exp Neurol 142, 80-88.
[9] McCully KS (2015) The active site of oxidative phosphorylation and the origin of hyperhomocysteinemia in aging and dementia. Ann Clin Lab Sci 45, 222-225.
[10] McCully KS (2016) Homocysteine, infections, polyamines, oxidative metabolism and the pathogenesis of dementia and atherosclerosis. J Alzheimers Dis 54, 1283-1290.
[11] Abu-Lubad M, Meyer TF, Al-Zeer MA (2014) Chlamydia trachomatis inhibits inducible NO synthase in human mesenchymal stem cells by stimulating polyamine synthesis. J Immunol 193, 2941-2951.

Submitted by Herbert Allen, MD on

We have recently written about how the ethics in Lyme disease are challenged [1]. Inasmuch as Lyme spirochetes (Borrelia burgdorferi) have been found in Alzheimer’s disease (AD) brains [2,3], similar bioethical inferences can be drawn between the two diseases. In Lyme disease, the continued presence of the spirochete has been disregarded, disparaged, overlooked or ignored. Yet, when the Lyme spirochetes can be cultured from affected brains, the denial of their presence seems spurious. The same may be said for AD where the prevalent hypothesis is centered on amyloid-β while the microbial pathogenesis has received little support [4]. Additionally, Lyme organisms make up 25% while dental spirochetes make up 75% of the AD cases [5].

We have also reported on how the organisms make biofilms and upregulate the innate immune system molecule Toll-like receptor 2 (TLR2) [6]. TLR2, by known pathways generates NFB and TNF which are largely responsible for the destruction of the neurocircuitry. Moreover, NFB, through known pathways, generates amyloid-β from amyloid-β protein precursor (AβPP) [7]. This precursor (AβPP) has actually been shown to be made by the microbes [3].

AD has been compared to general paresis of the insane (tertiary syphilis), and the neuropathology has been found to be exactly the same in both diseases [8]. Tertiary syphilis has been eradicated by treatment in the early stages of the diseases [9]. One would expect similar results with treatment of AD rendered before the organisms arrive at the brain or before they do damage. The spirochetes are all sensitive to penicillin; and, if this antibiotic is given before dental procedures and for early Lyme disease, similar results as in syphilis should be achievable [6]. Epistemic humility is the only requirement for this type of treatment.

In a forthcoming work, we will discuss other ethical challenges such as pursuing antidotes to amyloid-β in AD when that pursuit is directed late in the pathogenetic cascade of that disease.

Herbert B. Allen, MD and Erum Ilyas, MD
Drexel University College of Medicine Department of Dermatology

References
1. Jariwala N, Ilyas E, Allen HB (2016) Lyme disease: a bioethical morass. J Clin Res Bioeth 7, 5.
2. MacDonald AB (1988) Concurrent neocortical Borreliosis and Alzheimer's disease. Ann NY Acad Sci 539, 468-470.
3. Miklossy J (2016) Bacterial amyloid and DNA are important constituents of senile plaques: further evidence of the spirochetal and biofilm nature of senile plaques. J Alzheimers Dis 53, 1479-1473.
4. Miklossy J, Kis A, Radenovic A, Miller L, Forro L, Martins R, Reiss K, Darbinian N, Darekar P, Mihaly L, Khalili K (2006) Beta-amyloid deposition and Alzheimer's type changes induced by Borrelia spirochetes. Neurobiol Aging 27, 228-236.
5. Miklossy J (2011) Alzheimer’s disease – a neurospirochetosis- analysis of the evidence following Koch’s and Hill’s criteria. J Neuroinflammation 8, 90.
6. Allen HB (2016) Alzheimer’s disease: assessing the role of spirochetes, biofilms, the immune system, and beta amyloid with regard to potential treatment and prevention. J Alzheimers Dis 53, 1271-1276.
7. O’Brien RJ, Wong PC (2011) Amyloid precursor protein processing and Alzheimer’s disease. Annu Rev Neurosci 34, 185-204.
8. Miklossy J (2015) Historic evidence to support a causal relationship between spirochetal infections and Alzheimer’s disease. Front Aging Neurosci 7, 46.
9. Allen HB, Hannaway M, Joshi S (2015) Tertiary treponematosis. J Clin Exp Dermatol Res 6, 4.

Submitted by Bruce Paster on

I agree with Dr. Miklossy. There is significant evidence indicating the association of spirochetes and other bacteria in AD. The isolation of viable spirochetes from AD brains presents a powerful argument. Further research is certainly necessary to determine specific causal relationships and if antimicrobial therapy is at all possible for this devastating disease.

Submitted by Brian Balin, PhD on

Judith Miklossy should be commended for her continual efforts to bring long overdue attention to potential infectious causation of Alzheimer disease (AD). For the past 3 decades, as she has noted in her blog, reports have highlighted many different types of infectious agents associated with AD; many of these reports have identified direct brain infection and others systemic infection associated with disease [1-9]. In addition, polymicrobial involvement may be likely in many cases. Dr. Miklossy has laid out arguments as to why spirochetes including Borrelia and oral treponemes should be highly considered as causative agents for the development of the pathology as well as the symptomatology found in AD.  She has noted the nature of the filamentous pathology as it relates to both amyloids from both bacteria and eukaryotic cells and suggests that the curly fibers represent individual spirochetal forms while plaques represent spirochetal colonies.  This interpretation may have great importance for understanding the involvement of numerous infectious agents in the CNS as potentially the infectious morphologic forms could actually mimic the eukaryotic fibrils of amyloid and/or actually interact with eukaryotic beta amyloid.  Dr. Miklossy notes the possibility of amyloid from bacteria and eukaryotic cells may very well interact leading to amyloid deposition in AD. She also notes that spirochetes have been shown to induce AD-type lesions with increased APP, Aβ, and phosphorylated tau levels observed in vitro in primary mammalian neuronal and glial cells and organotypic cultures [10].

 

Historical and current evidence suggests that infection is associated with AD, and while association isn’t necessarily causation, we cannot dismiss this hypothesis without thorough investigation. For far too long, research in the AD field has focused on the pathological hallmarks of disease without considering “triggering events or insults” that actually start the pathogenic process. These events could very well be the interplay of infection along with other genetic and environmental factors. Intriguingly, infection may be involved with both forms of AD, possibly accelerating familial disease to arise in the 4th and 5th decades, and more slowly triggering the late-onset sporadic form of disease in the 6th decade and above. But how do we prove these occurrences?

 

Studies are needed to test both hypotheses given the high likelihood that infection may enter the nervous system as a primary infection but also as a secondary process following from the development of pathology due to prior damage.  Many of us believe (with evidence - see [3,4]) that direct primary infection could occur through the olfactory neuroepithelia as olfaction deficits arise early in the disease and innervation is direct from the olfactory bulbs into the lateral entorhinal cortex. As this region of the brain is affected very early in AD, infections using this route of entry into the brain (to circumvent the blood brain barrier) such as infection with Chlamydia pneumoniae, Herpes Simplex Virus 1 and possibly others including treponemes, could actually initiate inflammation, amyloid generation, synaptic damage, etc that could start AD pathogenesis. Secondarily, blood brain barrier insult could occur in the same region shortly after as there would be specific signaling from the entorhinal cortex. This could then lead to other insult that may involve systemic factors including other blood-borne infections as well as other chronic conditions predisposing to AD such as atherosclerosis, diabetes and traumatic brain injury. This scenario would certainly account for many of the associated findings in AD in contrast to the more conservative views often citing more conventional understanding of the individual conditions and diseases considered as risks for AD.    

 

Finally, I could not agree more with Dr. Miklossy that much more attention and support is required for this field of study. A focus on biological underpinnings of disease based on infection gives us many more biomarkers and targets for which we can attempt prevention and treatment. While most of us in this area of research realize much still needs to be accomplished in understanding the infection biology of AD, we cannot wait for the exhaustive clinical trial failures based on other hypotheses before something is done; we cannot continue to spend hundreds of millions of dollars in those futile approaches. We need to act now, and differently, as the lives of so many are in the balance!

 

1. Miklossy J (1993) Alzheimer’s disease - A spirochetosis? Neuroreport 4, 841-848. 

2. MacDonald AB, Miranda JM (1987) Concurrent neocortical borreliosis and Alzheimer’s disease. Hum Pathol 18, 759–761.

3. Balin BJ, Gerard HC, Arking EJ, Appelt DM, Branigan PJ, Abrams JT, Whittum-Hudson JA, Hudson AP (1998) Identification  localization of Chlamydia pneumoniae in the Alzheimer’s brain. Med Microbiol Immunol 187, 23-42. 

4. Little CS, Joyce TA, Hammond CJ, Matta H, Cahn D, Appelt DM, Balin BJ (2014) 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 5, 304. 

5. Poole S, Singhrao SK, Kesavalu L, Curtis MA, Crean S (2013) Determining the presence of periodontopathic virulence factors in short-term postmortem Alzheimer’s disease brain tissue. J Alzheimers Dis 36, 665-677

6. Kornhuber HH (1995) Chronic anaerobic cortical infection in Alzheimer’s disease: Propionibacterium acnes. Neurol Psych Brain Res 3, 177-182.

7. Malaguarnera M, Bella R, Alagona G, Ferri R, Carnemolla A, Pennisi G (2004) Helicobacter pylori and Alzheimer's disease: a possible link. Eur J Intern Med 15, 381-386.

8. Jamieson GA, Maitland NJ, Wilcock GK, Craske J, Itzhaki RF (1991) Latent herpes simplex virus type 1 in normal and Alzheimer’s disease brains. J Med Virol 33, 224–227.

9. Pisa D, Alonso R, Juarranz A, Rábano A, Carrasco L (2015) Direct visualization of fungal infection in brains from patients with Alzheimer's disease. J Alzheimers Dis 43, 613-624

10. Miklossy J, Kis A, Radenovic A, Miller L, Forro L, Martins R, Reiss K, Darbinian N, Darekar P, Mihaly L, Khalili K (2006) Beta-amyloid     deposition and Alzheimer’s type changes induced by Borrelia spirochetes. Neurobiol Aging 27, 228-236.

Submitted by Mayla Hsu, PhD on

Dr. Miklossy’s blog post documents historical findings that cumulatively suggest spirochete involvement in the development of AD, a hypothesis that urgently requires further study. Indeed, recent findings that the function of Ab peptides may be antimicrobial [1] and neuroprotective against brain infections [2] provide the rationale for further study in this field. Additionally, the development and functioning of the central nervous system may be heavily influenced by gut microbiota [3]. Approximately 10-20% of Lyme disease patients suffer from long-term health deficits that can include neurological sequelae [4,5], suggesting persistent infection and/or indirect immunologically-mediated neuropathology. We agree that well-controlled, rigorous studies will provide much-needed insight to examine a potential role of spirochete infection in AD development.

Mayla Hsu, PhD. Global Lyme Alliance, Greenwich, CT. http://www.globallymealliance.org 

[1] Spitzer P, Condic M, Herrmann M, Oberstein TJ, Scharin-Mehlmann M, Gilbert DF, Friedrich O, Gromer T, Kornhuber J, Lang R, Maler JM. (2016) Amyloidogenic amyloid-b-peptide variants induce microbial agglutination and exert antimicrobial activity. Sci Rep 6:32228. Doi: 10.1038/srep32228.

 

[2] Kumar DKV, Choi SH, Washicosky KJ, Eimer WA, Tucker S, Ghofrani J, Lefkowitz A, McColl G, Goldstein LE, Tanzi RE, Moir RD. (2017) Amyloid-b peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Sci Transl Med 8(340):340ra72. Doi:10.1126/scitranslmed.aaf1059.

 

[3] Sharon G, Sampson TR, Geschwind DH, Mazmanian SK. (2016) The central nervous system and the gut microbiome. Cell 167:915-932. Doi:10.1016/j.cell.2016.10.027.

 

[4] Aucott JN. (2015) Posttreatment Lyme disease syndrome. Inf Dis Clin N Am 29:309-323.

 

[5] Cairns V, Godwin J. (2005) Post-Lyme borreliosis syndrome: a meta-analysis of reported symptoms. Int J Epidemiol 34:1340-5.

 

Submitted by Thomas Lewis, Ph.D. on

Dr. Miklossy takes the clear lead when it comes to linking Alzheimer's disease and infection. It is critical that she and researchers like Dr. de la Torre and Balin continue their fine work. Others should indeed take the baton and drive this research forward. But the question becomes why more research? Yes, we need more research - but we desperately need more "translators" like Dr. Clement Trempe who, for decades has been testing glaucoma and dementia patients for infection and the underlying reason why these individuals have become vulnerable to the proliferation of pathogens in their systems leading to inflammation and neuroinflammation - then to brain-impacting diseases.

Dr. Trempe "does no harm" in treating his patients. Again, yes, research must continue and that is the job of researchers – that’s what the do. But doctors must not be afraid of the consequences (lawyers) of treating patients well even if it goes against the conventional wisdom or standard of care. There is simply not enough knowledgeable physicians willing to go the extra mile for their patients.

And you can successfully treat Alzheimer's, dementias, cognitive impairment and glaucoma without treating these diseases by name! It's simple, perform and in depth, broad and deep differential diagnosis and find those diagnostic "suspects" like poor gut health, mold, toxicity, spirochetes, and other pathogens. Once found, treat for them and see your patients get better. What is wrong with this model?

Yes, we must have brilliant people like Dr. Miklossy doing more research. It a requirement of the doubting clinicians and all the entrenchment surrounding medicine. But we see responses like "need to do more research" end the end of too many research articles because there are NOT ENOUGH audacious clinicians willing to go beyond their comfort zone and try something new.

Thank God the high tech industry doesn't use the same discovery/develop principles of medicine or we would all still be using an abacus!

(Anticipating the comments from researchers and scared doctors: What Dr. Trempe and functional doctors do is NO HARM first. It is much more harmful and UNETHICAL NOT to treat a disease that has addressable and treatable causes. Doctors – test for spirochetes and other pathogens. Dare to prescribe vitamin D and cod liver oil – and appropriate anti-infectives – your patients will thank you.)

Submitted by Herbert Allen, MD on

Herbert B. Allen, MD and Erum Ilyas MD, Drexel University College of Medicine, Department of Dermatology

Dr. McCully mentions that homocysteine is a risk factor for Alzheimer’s disease (AD); and, further, it has been shown to be a risk factor for arteriosclerotic heart disease. Homocysteine has been observed to encourage organisms to “make” biofilms [1]. Inasmuch as we have found biofilms in the plaques of arteriosclerosis [2], and, we and others have also found them in AD, it seems plausible to implicate the biofilm-forming effect of homocysteine in both the worsening of AD and in arteriosclerosis. This is similar to the effect of diabetes on AD where the hyperosmolality in diabetes leads to the creation of more biofilms, and that leads to deterioration in AD [3].

Drs. Singhrao, Balin, and Poster mention other organisms (in addition to spirochetes) in AD. Again, considered in the light of microbes making biofilms, it has been well documented that biofilms of one species have receptors for organisms of other species (and vice versa). This allows many different organisms to take up residence in the biofilm [4]. The biofilm, in this instance, is more comparable to a “hotel” than a “single family home”.

References
[1] Belval SC, Gal L, Margiewes S, Garmyn D, Piveteau P, Guzzo J (2006) Assessment of the roles of LuxS, S-Ribosyl Homocysteine, and Autoinducer 2 in cell attachment during biofilm formation by Listeria monocytogenes EGF-e. Appl Environ Microbiol 72, 2644-2650.
[2] Allen HB, Boles J, Morales D, Ballal S, Joshi SG (2016) Arteriosclerosis: the novel finding of biofilms and innate immune system activity within the plaques. J Med Surg Pathol 1, 135.
[3] Allen HB, Husienzad L Joshi SG (2016) Letter-to-the-Editor: The impact of diabetes on Alzheimer’s disease. J Alzheimers Dis, http://www.j-alz.com/content/impact-diabetes-alzheimers-disease.
[4] Rickard AH, Gilbert P, High NJ, Kolenbrander PE, Handley PS (2003) Bacterial coaggregation: an integral process in the development of multi-species biofilms. Trends Microbiol 11, 94-100.

Submitted by Lawrence Broxmeyer, MD on

Dr. Judith Miklossy has certainly presented a valid and provocative presentation towards a conceivable causal relationship between an infectious agent and Alzheimer’s and is to be deeply commended for doing so.

With regards to Oskar Fischer’s suggestion that senile plaques are reminiscent of bacterial colonies and his inability to cultivate them - by 1907, Oskar Fischer went to the extent of saying that many of the senile plaques he found “resemble more closely the central cell-free part of a tubercle.”[1] Thus, by 1911 Alzheimer wrote the following:

"Hitherto opinions about the nature of the plaques have been very divergent. Fischer pointed out their similarity to bacterial colonies and reported that he had undertaken cultivation experiments and complement-fixation tests which however produced negative results."[2]

At the time Fischer undertook cultivation and compliment fixation tests to validate his germ, negative results were the rule, not the exception. Thus, the fact that Fischer’s cultivation experiments and complement fixations were negative did not rule out the existence of Fischer’s brain microbe, which to him resembled a Strepothrix. For example, in the same year that Alzheimer made his 1911 statement, Harbitz and Grondahl reported repeatedly negative attempts at running complement-fixation tests in all cases using the serum of patients with known Streptothrix (actinomycosis) patients.[3] Before that, Woodhead, Director of Laboratories at the Royal College of Physicians, pointed out that any attempted failure to cultivate Streptothrix could easily occur when trying to cultivate the well-developed club-shaped form of the organism that Fischer repeatedly documented. Woodhead wrote this about such experiments:

It is interesting to note that most of the experiments that have been made on the cultivation of this organism [Streptothrix] have been attended with complete failure—a failure that in some measure, at any rate, appears to be due to the fact that almost all experimenters have used for their inoculating material only those colonies in which the club-shaped [Streptothrix] organisms have become well developed. The first attempt that was at all successful was made by Bostrom, who, throwing aside the club-like processes, took for his inoculating material the central network, selecting as far as possible young growing colonies for his seed material.”[4]

But even Bostrom succeeded in getting only eleven positive growths out of several hundred planted. [5] And when German investigator Fritzsche [6] addressed this same topic three years before Alzheimer challenged Fischer’s microorganism, Fritzsche found not only a limited number of cases in which complement fixation for Streptothrix proved positive, but, in addition, there were frequent cross-reactions in his meager positive test samples for Streptothrix with tuberculosis. He added that Streptothrix was further confused with TB because they both could stain with tubercular acid-fast dyes, and both could have filamentous as well as club-like forms. But Bolton [7] later pointed out that unlike TB, Fischer’s Streptothrix rarely involved the central nervous system. Furthermore, although the first case of Streptothrix involving the CNS was reported by Ponfick [8] in 1882, Harz never succeeded in cultivating the organism from there. [9] Most of this literature was readily available to the Alzheimer group. And, even in the case of using complement-fixation tests to detect the far, far more prevalent tuberculosis, Corper [10] reported as late as 1916 that such tests were positive in only 30 percent of already-proven cases of tuberculosis—whether active or inactive.

Just ten years before Oskar Fischer found Actinomycosis-like Streptothrix in Alzheimer’s cerebral plaque, Babèş and immunologist Levaditi reported in On the Actinomycotic Shape of the Tuberculous Bacilli that typical Actinomyces-like clusters [Drüsen] with clubs appeared in the tissue of rabbits inoculated with tubercle bacilli beneath the dura mater of their brains. Once introduced into the brain this way, reported Babes, TB bacilli not only branched out like the Actinomycosis such as Streptothrix, but showed filamentous fungal forms – and as they developed rosettes that were identical to the "drüsen" that Oskar Fischer spotted in Alzheimer’s plaque. [11]

Also, with regard to the Mawanda and Wallace’s Can Infections Cause Alzheimer’s Disease mentioned here, Mawanda and Wallace’s12 2013 review gave seven annotated references as to why HSV-1 “remains questionable” as a cause for Alzheimer’s; nine studies referenced as to why there was “no evidence to suggest an association between Chlamydia pneumoniae infection and AD pathogenesis”; and six “rigorous studies which found no evidence to suggest that spirochetal B. Burgdorferi, is “causally linked to AD.” Wallace also mentioned that although Riviere et al. found oral spirochetal Treponema, including T. denticola, T. pectinovorum, T. vincentii, T. amylovorum, T. maltophilum, T. medium, and T. socranskii in a significantly higher proportion of postmortem brain specimens from AD cases than controls,13 that these results have, however, not been replicated. Also, Oskar Fischer, the discoverer of Alzheimer’s plaque, failed to observe Alzheimer’s neuritic plaque in the brains of 45 cases with neurosyphilis.14

What Mawanda and Wallace did maintain however was the emerging evidence that supported an infectious pathogen and what to them were two prime suspects for Amyloid beta deposition to the extent that it was going on in Alzheimer’s. They said this:

In addition, amyloidopathy—a condition characterized by elevated levels of serum amyloid and by amyloid deposition and aggregation in tissues—is a frequent occurrence in several acute and chronic systemic inflammatory conditions, especially chronic infections like tuberculosis and leprosy.” IBID p.162

Mawanda and Wallace seemed to have no dearth of referenced studies to substantiate this mycobacterial  assertion. [15-21] Streptothrix was of the Actinobacteria and its colonies form fungus-like branched networks of hyphae. The aspect of these colonies initially led to the incorrect assumption that the organism was a fungus and to the name Actinomyces, "ray fungus" (from Greek actis, ray, beam and mykes, fungus).

So it becomes all but obvious that Fischer’s 1907 portrayal of Alzheimer plaque as often appearing like bacterial “Streptotriches” had to be weighed within the context that when Fischer found that nearly all brain plaque in the 60 to 80μ microscopic range had an appearance reminiscent of “glandular” actinomyces, that American bacteriologist Davis mentioned that Fischer’s “glandular” actinomycosis were among the most difficult to differentiate from tuberculosis: “the two are often all but indistinguishable.” [22]

 

References

[1] Fischer O. Miliary Necrosis with Nodular Proliferation of the Neurofibrils, a Common Change of the Cerebral Cortex in Senile Dementia, Monatsschrift fuer Psychiatrie und Neurologie, vol. XXII, edited by Th. Ziehen (Berlin: S. Karger, 1907), 361–72.

[2] Alzheimer A. H. Forstl, and R. Levy, an English translation of Alzheimer’s 1911 paper Uber Eigenartige Krankheitsfalle des Spateren Alters (“On Certain Peculiar Diseases of Old Age”), History of Psychiatry 2 (1991): 71–101.

[3] Harbitz F, Grondahl NB, Actinomycosis in Norway: Studies in the Etiology, Modes of Infection, and Treatment, American Journal of Medical Science 142 (1911): 386–95.

[4] Woodhead GS. Bacteria and Their Products (London and New York: Walter Scott, Ltd./Charles Scribner’s Sons, 1895), 258

[5] Cope VZ. Actinomycosis: The Actinomyces and Some Common Errors about the actinomyces and actinomycosis. Postgraduate Medical Journal 28 (1952): 572–4

[6] E. Fritzsche, “Experimentelle Untersuchungen Tiber Biologische Beziehungen des Tuberkelbazillus zu Einigen Anderen Saurefesten Mikroorganismen und Aktinomyzeten,” Archive for Hygiene 5 (1908): 181–220.

[7] Bolton CF, Ashenhurst EM. Review Article: Actinomycosis of the Brain. Canadian Medical Association Journal 90 (April 11, 1964): 922–8.

[8] Ponfick, Die Actinomykose des Menschen, Eine Neue Infectionskrankheit auf Vergleichend-Pathologischer und Experimenteller Grundlage Geschildert. Berlin: A. Hirschwald, 1882.

[9] Harz B, “Actinomyces Bovis, ein Neuer Schimmel in den Geweben des Rindes: Deutsche Zeitschr. f. their,” Med. und Vergl. Path. (1870): 125, Zweites Supplementheft.

[10] Corper HJ, “Complement-Fixation in Tuberculosis,” The Journal of Infectious Diseases 19, no. 3 (September 1916): 315–21.

[11] Babes V, Levaditi C. On the Actinomycotic Shape of the Tuberculosis Bacilli (Sur la Forme Actinomycosique du Bacilli de la Tuberculosis), In Arch. of Med. Exp. et D’anat, part 2, 9, no. 6 (1897): 1041–8.

[12] Mawanda F, Wallace R. Can infections cause Alzheimer's disease? Epidemiol Rev. 2013; 35:161-80.

[13] 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(2):113–118.

[14] Goedert M. Oskar Fischer and the study of dementia. Brain. 2009 Apr; 132(4): 1102–1111.

[15] De Beer FC, Nel AE, Gie RP, et al. Serum amyloid A protein and C-reactive protein levels in pulmonary tuberculosis: relationship to amyloidosis. Thorax. 1984; 39(3):196–200.

[16] Looi LM, Jayalakshim P, Lim KJ, et al. An immunohistochemical and morphological study of amyloidosis complicating leprosy in Malaysian patients. Ann Acad Med Singapore. 1988; 17(4):573–578.

[17] Looi LM. The pattern of amyloidosis in Malaysia. Malays J Pathol. 1994; 16(1):11–13.

[18] Röcken C, Radun D, Glasbrenner B, et al. Generalized AA-amyloidosis in a 58-year-old Caucasian woman with an 18-month history of gastrointestinal tuberculosis. Virchows Arch. 1999; 434(1):95–100.

[19] Wangel AG, Wegelius O, Dyrting AE. A family study of leprosy: subcutaneous amyloid deposits and humoral immune responses. Int J Lepr Other Mycobact Dis. 1982; 50(1):47–55.

[20] Tank SJ, Chima RS, Shah V, et al. Renal amyloidosis following tuberculosis. Indian J Pediatr. 2000; 67(9):679–681.

[21] Urban BA, Fishman EK, Goldman SM, et al. CT evaluation of amyloidosis: spectrum of disease. Radiographics.1993; 13(6):1295–1308.

[22] Davis DJ, Some Observations on Streptothrix Infections and Their Relation to Tuberculosis in the National Association for the Study and Prevention of Tuberculosis, Transactions of the Eleventh Annual Meeting, Seattle, Washington, June 14–16, 1915. Baltimore: Williams & Wilkins Company, 1935, 255–61

 

 

 

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