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The lack of correlation between the incidence of Lyme

disease and deaths due to Alzheimers disease cannot
reflect the lack of involvement of Borrelia burgdorferi in
Alzheimers dementia

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!On 13 Aug, 2014

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I am writing this letter in reference to the recent paper by Danton and Catalano [1]. I have read with interest
their investigation based on the anticipation that If the biological agent Borrelia burgdorferi that causes LD
(Lyme disease) also causes AD (Alzheimers disease), then areas with the highest levels of LD should have
significantly higher numbers of deaths due to AD compared to low LD areas.
To compare AD populations suffering from Lyme neuroborreliosis in endemic and non-endemic areas would be
the right approach to obtain an answer to the question raised by the authors.
From 1993 it was emphasized, that Borrelia burgdorferi alone cannot explain all AD cases, as the incidence of
Lyme disease, and particularly of Lyme dementia, compared to AD is very low. The authors noticed that various
types of spirochetes were suggested to play a role in AD and to consider this point in their investigation would
be critical [2,3]. These various spirochetes, including the highly prevalent periodontal pathogen Treponemes
were detected in more than 90% of AD cases [4,5]. It is therefore expected that in both endemic and nonendemic LD areas, AD caused by other spirochetes can strongly overlap the small proportion of AD cases caused
by Borrelia burgdorferi alone. Consequently, the present study cannot prove or exclude the involvement of
Borrelia burgdorferi in AD.
It is also important to consider that only about 10-15% of Lyme patients and generally only those who are
untreated or insufficiently treated will develop dementia caused by Borrelia burgdorferi. Therefore, to simply
compare the incidence of Lyme disease with that of AD may further render the interpretation of the results
difficult.
The authors also state that The relationship between LD and AD has also been supported by analysis of existing
data using Kochs and Hills Postulates [8]. What is lacking to fulfill these postulates is the isolation of functional
entities (e.g., B. burgdorferi) followed by proof of their ability to induce AD-related events in tissue culture
cells.
The isolation of spirochetes from AD brains [1,6,7] and exposure of mammalian primary cell and organotypic
cultures to spirochetes were shown to reproduce lesions similar to the pathological and biological hallmarks of
AD [8]. The re-isolation of spirochetes (Borrelia burgdorferi) from cell cultures infected by B31 reference strain
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and those cultivated from AD brains, all induced lesions similar to AD, they revealed to be virulent, invaded
neurons and glial cells, and caused nuclear fragmentation, which were all previously documented [9]. But
independently of these observations, it is noteworthy that Koch himself acknowledged that the application of
his four postulates to establish causality should be used as guidelines and not as definite postulates [10].
Indeed, like Treponema pallidum, several other bacteria and viruses cannot be grown in pure culture and
consequently cannot be re-isolated. Despite of this, the causal relationship between Treponema pallidum and
syphilitic dementia is established. In order to address the limitations of Kochs postulates, Hill introduced his
new criteria for causality [11]. Hills nine postulates do not require the isolation of the microorganisms in pure
culture or their re-isolation from infected cell cultures.
This letter is guided with the best intention to openly discuss this newly emerging field of AD research in order
not to stop but to help and encourage further investigations in this direction. An infectious etiology of AD was
first proposed a century ago and it was never discarded. Leading AD researchers [12,13] about three decades
ago claimed that an infectious etiology of AD is a real possibility and cannot be disregarded. To further consider
the involvement of various types of spirochetes and co-infections with various bacteria, including Chlamydia
pneumoniae [14], Porphyromonas gingivalis [15], and various viruses, like herpes simplex virus type 1 (HSV-1)
[16], in AD is critical, particularly as these microorganisms were also detected in various other chronic
inflammatory disorders, which are associated with AD.
We do not possess a targeted therapy for AD. If AD is caused by spirochetal infection associated with other
bacteria and viruses, this might bring new hope for all patients who are suffering from AD and for all those who
have concerns about the relationship between LD, periodontal pathogen spirochetes, and AD, as syphilitic
dementia was almost eradicated by the use of penicillin. As we have an example in the history of medicine that
chronic spirochetal infection can cause dementia and reproduce the pathological hallmarks of AD, including
amyloid-! deposition [17], prompt action is needed to promote this research not only by the neuroscience
community but also by governmental health authorities as AD might be prevented.
Judith Miklossy, Director, Prevention Alzheimer International Foundation, International Alzheimer Research
Center, Martigny-Croix, Switzerland
References:
[1] ODay DH, Catalano A (2014) A lack of correlation between the incidence of Lyme disease and deaths due to
Alzheimers disease. J Alzheimers Dis 42, 115-118.
[2] Miklossy J (1993) Alzheimer's disease--a spirochetosis? Neuroreport 4, 841-848.
[3] 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.
[4] Miklossy J (2011) Alzheimer's disease - a neurospirochetosis. Analysis of the evidence following Koch's and
Hill's criteria. J Neuroinflammation 8, 90. Ref [8] of the authors.
[5] Miklossy J (2011) Emerging roles of pathogens in Alzheimer disease. Expert Rev Mol Med 13, e30.
[6] MacDonald AB, Miranda JM (1987) Concurrent neocortical borreliosis and Alzheimer's disease. Hum Pathol
18, 759-761.
[7] 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, 1-11.
[8] 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 Alzheimers type changes induced by Borrelia spirochetes. Neurobiol
Aging 27, 228-236.
[9] Miklossy J, Kasas S, Zurn AD, McCall S, Yu S, McGeer PL (2008) Persisting atypical and cystic forms of Borrelia
burgdorferi and local inflammation in Lyme neuroborreliosis. J Neuroinflammation 5, 40.
[10] Koch R (1893) Ueber den augenblicklichen Stand der bakteriologischen Cholera Diagnose. J Hyg Inf 14, 319333.
[11] Hill AB (1965) The environment and disease: association or causation? Proc R Soc Med 58, 295-300.
[12] Wisniewsky HM (1978) Possible viral etiology of neurofibrillary changes and neuritic plaques. In
Alzheimers Disease: Senile Dementia and Related Disorders (Aging, Vol 7), Katzman R, Terry RD, Bick KL, eds.
Raven Press, New York, pp. 555-557.
[13] Khachaturian ZS (1985) Diagnosis of Alzheimers disease. Arch Neurol 42, 1097-1105.
[14] Balin BJ, Hudson AP (2014) Etiology and pathogenesis of late-onset Alzheimer's disease. Curr Allergy
Asthma Rep 14, 417.

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[15] Poole S, Singhrao SK, Chukkapalli S, Rivera M, Velsko I, Kesavalu L, Crean S (2014) Active invasion of
Porphyromonas gingivalis and infection-induced complement activation in ApoE-/- mice brains. J Alzheimers
Dis, doi: 10.3233/JAD-140315.
[16] Itzhaki RF, Dobson CB, Shipley SJ, Wozniak MA (2004) The role of viruses and of APOE in dementia. Ann N Y
Acad Sci 1019, 15-18.
[17] Miklossy J, Rosemberg S, McGeer PL (2006) Beta amyloid deposition in the atrophic form of general paresis.
In Alzheimers Disease: New advances. Proceedings of the 10th International Congress on Alzheimers Disease
(ICAD). Iqbal K, Winblad B, Avila J, eds. Medimond, International Proceedings, pp. 429-433.
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admin
Wed, 08/13/2014 - 06:11
Permalink

Letter to the Editor Response

Letter to the Editor Response
In their paper, ODay and Catalano discuss both the existence of spirochaete-induced dementia and the
extensive work by Miklossy and others on the potential role of Borrelia burgforerithe bacterial perpetrator in
Lyme disease (LD)in Alzheimers disease (AD) [1]. That said, it is clear that the incidence of deaths due to AD is
in fact lower, not higher, in areas of high LD compared to those areas where LD occurrence is low or essentially
non-existent. While extensive circumstantial evidence has suggested the opposite, the results of ODay and
Catalano thus argue strongly that the two diseases, LD and AD, are not linked. In the long run, we hope that
improved reporting of both LD and AD cases, including deaths due to AD, will allow others to validate this
conclusion.
Danton H. ODaya,b,* and Andrew Catalano c
a Department

of Biology, University of Toronto at Mississauga, Mississauga, Ontario, Canada

bDepartment

of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada

cDepartment

of Chemistry, City College of New York, New York, New York, USA

*Correspondence to: Danton H ODay: danton.oday@utoronto.ca

Reference:
[1] ODay DH, Catalano A (2014) A lack of correlation between the incidence of Lyme disease and deaths due to
Alzheimers disease. J Alzheimers Dis 42, 115-118.
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admin
Sun, 08/17/2014 - 13:39
Permalink

Response
Response
I would like to thank the opportunity given by the editorial board of JAD for such open discussions. As I did not
get an answer with respect to a relevant comment of my letter, I felt that some further clarifications might be
helpful for future research.
In the study of ODay and Catalano [1], there is no evidence whether the AD patients analyzed had a positive
serology for LD or not. In addition, considering the number of deaths due to AD does not mean that all these

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patients suffered from definite AD, as neuropathological confirmation of definite AD is necessary. Furthermore,
there is no evidence whether the LD patients included in the study have dementia or not. Comparing in this way
the incidence of deaths due to AD, in areas of high or low LD cannot exclude the involvement of Borrelia
burgdorferi in AD, even if the number of AD cases is higher in non-endemic LD areas. AD populations suffering
from LD should be compared in LD endemic and non-endemic areas. Even in such conditions, other highly
prevalent spirochetes involved in AD may mask the results.
A recent European study by Blanc et al. [2], considering the positive serology of Borrelia burgdorferi in a large
demented population, obtained results that are opposite to those of ODay and Catalano. They found 20 among
1,594 demented patients with positive Borrelia burgdorferi antibody index (AI), indicating that these patients
suffered from Lyme neuroborreliosis. They concluded that Lyme dementia exists and that a small percentage of
neurodegenerative dementia is associated with Lyme neuroborreliosis. Seven cases with positive AI were
clinically diagnosed with AD (3 of them were associated with Lewy body dementia). Two AD cases (one with
AD/Lewy body dementia) were neuropathologically confirmed. As spirochetal infection can lead to dementia,
sometimes several decades following the primary infection, further prospective studies and pathological
confirmation might give important results.
These observations, taken together with all those previous observations showing that Borrelia burgdorferi was
cultivated from the brains of AD patients suffering from Lyme neuroborreliosis and that Borrelia specific
antigens and DNA were co-localized with AD-type lesions, clearly indicate that Borrelia burgdorferi is implicated
in a small percentage of AD cases. We have an example in the history of medicine that another chronic
spirochetal infection can cause dementia and reproduce the pathological and biological hallmarks defining AD,
including amyloid-! deposition. Therefore, it is important to follow research in this direction and consider that
various types of spirochetes and other co-infecting bacteria and viruses are involved in AD.
With respect to the analysis of the involvement of Borrelia burgdorferi in AD, improved reporting of LD cases
suffering from dementia and AD cases with positive serology for Borrelia burgdorferi will further help research
in this direction. For this, testing AD patients for Borrelia burgdorferi and considering dementia as one of the
tertiary manifestations of late Lyme neuroborreliosis is necessary. That AD-type dementia might be stopped
and/or prevented would only give hope to AD and LD patients and to all the medical and neuroscience
community.
Judith Miklossy, Director, Prevention Alzheimer International Foundation, International Alzheimer Research
Center, Martigny-Croix, Switzerland
References
[1] ODay DH, Catalano A (2014) A lack of correlation between the incidence of Lyme disease and deaths due to
Alzheimers disease. J Alzheimers Dis 42, 115-118.
[2] Blanc F, Philippi N, Cretin B, Kleitz C, Berly L, Jung B, Kremer S, Namer IJ, Sellal F, Jaulhac B, de Seze J (2014)
Lyme neuroborreliosis and dementia. J Alzheimers Dis 41, 1087-1093.
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