The lack of correlation between the incidence of Lyme disease and deaths due to Alzheimer’s disease cannot reflect the lack of involvement of Borrelia burgdorferi in Alzheimer’s dementia

13 August 2014

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 (Alzheimer’s 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 non-endemic 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 Koch’s and Hill’s 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 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 Koch’s postulates, Hill introduced his new criteria for causality [11]. Hill’s 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-β 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


[1] O’Day DH, Catalano A (2014) A lack of correlation between the incidence of Lyme disease and deaths due to Alzheimer’s 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 Alzheimer’s 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, 319-333.
[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 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.
[13] Khachaturian ZS (1985) Diagnosis of Alzheimer’s 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.
[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 Alzheimer’s Disease: New advances. Proceedings of the 10th International Congress on Alzheimer’s Disease (ICAD). Iqbal K, Winblad B, Avila J, eds. Medimond, International Proceedings, pp. 429-433.


Letter to the Editor Response

In their paper, O’Day and Catalano discuss both the existence of spirochaete-induced dementia and the extensive work by Miklossy and others on the potential role of Borrelia burgforeri—the bacterial perpetrator in Lyme disease (LD)—in Alzheimer’s 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 O’Day 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. O’Daya,b,* and Andrew Catalanoc

aDepartment 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 O’Day:


[1] O’Day DH, Catalano A (2014) A lack of correlation between the incidence of Lyme disease and deaths due to Alzheimer’s disease. J Alzheimers Dis 42, 115-118.


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 O’Day 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 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 O’Day 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-β 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


[1] O’Day DH, Catalano A (2014) A lack of correlation between the incidence of Lyme disease and deaths due to Alzheimer’s 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.