Dr. Oskar Fischer’s Mysterious Little Alzheimer’s Germ

by Lawrence Broxmeyer, MD on 3 November 2017

Alois Alzheimer might have mentioned plaques and tangles in a single short paper on pre-senile dementia in 1907, but it was the co-discover of Alzheimer’s disease (AD), Oskar Fischer, who in that same year far more extensively reported neuritic plaque in 12 cases of senile dementia, a condition which he and many others refused to differentiate from Alzheimer’s “pre-senile” dementia. Fischer, Alzheimer’s great rival, speculated that for the most part these plaques, found only in senile demented patients, caused their dementia. Moreover, Fischer felt such cerebral plaque to be the result of an infection and was very specific as to the sort of infection that might be involved. He felt that he had spotted, throughout his brain autopsies, a tubercular-like Actinobacteria then called Streptothrix (Actinomycosis), often and repeatedly confused with the filamentous cell-wall-deficient forms of the tubercular bacilli. At this point for Fischer, this was the possible infectious cause of AD. To be sure, Oskar Fischer was the first on record to suggest that chronic infection might be causative for what we today call AD. Fischer’s infectious view never gained immediate popularity, although today, more than a century later, a volume of data supporting such an approach has begun to accumulate. But was Fischer’s specific microbe on the right track to discovering the cause of AD to begin with? Documents uncovered since then seem to suggest that he was considerably closer than anyone else—either then or since.

In June of 2017, a University of Bristol study in the UK found a 5 to 10-fold increase in Actinobacteria (order Actinomycetales) population in postmortem AD brains compared with controls [1]. Oskar Fischer’s Steptothrix was an Actinobacteria as well, as was the filamentous tuberculosis that Streptothrix was so often mistaken for. But specifically, the Bristol group found an Actinobactor called Propionibacterium acnes (P. Acnes) in autopsied AD brains—a common organism, traditional felt to be non-pathogenic and commonly found on our skin which can cause, among other things, acne. Yet since much of the present pathology attributed to P. Acnes places it in a category of an opportunistic organism which secondarily infects tissue already damaged through surgery (craniotomy) or secondary to a previous primary infection, the Bristol investigators added this: “Additionally, any infection, which initiates the neuropathology of AD, may occur 15–20 years pre-mortem; therefore the bacteria identified here may be due to secondary infection after BBB [blood-brain barrier] breakdown.” [ibid 1 p. 10]

And although Streptothrix had always been identified as a rare central nervous system pathogen, its lookalike, tuberculosis, is extremely neurotropic and fully capable of breaching and then entering the brain parenchyma or meninges at the level of this same blood-brain barrier (BBB) [2]. Furthermore, P. acnes shares similarities with the genome of Mycobacterium tuberculosis (M. tuberculosis). And numerous homologues to virulence factors between these microbes have been found. [3] In fact a quick BLAST search of Propionibacterium acnes genes for 16S ribosomal RNA (GenBank: AB097215.1) against M. tuberculosis shows an 88% identity within the first 100 hits.

In addition, Mollerup’s 2016 Journal of Clinical Microbiology review regarding P. acnes, using similar next-generation sequencing as the Bristol group, cautioned: “Our results show that P. acnes can be detected in practically all sample types when molecular methods, such as next-generation sequencing, are employed. The possibility of contamination from the patient or other sources, including laboratory reagents or environment, should therefore always be considered carefully when P. acnes is detected in clinical samples” [4]. Rossen said this about species identification (such as the species P. acnes) using next generation sequencing: “when one gets down to the species level such molecular methods need “a priori” knowledge of the likely pathogenic species that could be present in the sample" [5]. This presents the problem of whether candidates such as cell-wall-deficient filamentous forms of a microbe like those of M. tuberculosis would or could through existing known sequences even be considered. They certainly were not in the Bristol University Alzheimer’s brain study.

Nevertheless, if the actual species behind the AD germ could be questioned, the fact that Bristol authors Emery et al. had detected 5 to 10 times increase in the amount of an Actinobacter of the same class as Oskar Fischer’s Streptothrix could not.

Probably the most influential paper to date on this topic is Mawanda and Wallace’s 2013 review entitled “Can Infections Cause Alzheimer’s Disease?” [6]. In that paper, having struck down some of the current commonly entertained pathogens for AD such as herpes simplex virus type 1, Chlamydia pneumoniae, and several types of spirochetes, Mawanda and colleague again suspected a microbe of the same order (Actinomycetales) that Emery and Fischer had probed. Mawanda and Wallace pointed to two prime suspects for Alzheimer’s amyloid-beta deposition, concluding: “especially chronic infections like tuberculosis and leprosy”. Their suggestion seemed within the realm of possibility, with the understanding that leprosy could not be behind most AD.

The history of those investigators/events which supported Oskar Fisher’s finding through related Actinobacteria as a possible cause of AD is an interesting one, available for review [7].

The Alzheimer's Germ: Alzheimer's Disease-How Its Bacterial Cause Was Found and Then Discarded, 2016, by Lawrence Broxmeyer, MD

REFERENCES
[1] Emery DC, Shoemark DK, Batstone TE, Waterfall CM, Coghill JA, Cerajewska TL, Davies M, West NX and Allen SJ (2017) 16S rRNA next generation sequencing analysis shows bacteria in Alzheimer’s post-mortem brain. Front Aging Neurosci 9, 195.
[2] Be NA, Kim KS, Bishai WR, Jain SK (2009) Pathogenesis of central nervous system tuberculosis. Curr Mol Med 9, 94-99.
[3] Bhatia A, Maisonneuve JF, Persing DH (2004) Propionibacterium acnes and chronic diseases. In Institute of Medicine (US) Forum on Microbial Threats, Knobler SL, O'Connor S, Lemon SM, et al., editors. The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects: Workshop Summary. Washington (DC): National Academies Press (US). Available from: https://www.ncbi.nlm.nih.gov/books/NBK83685/
[4] Mollerup S, Friis-Nielsen J, Vinner L, Hansen TA, Richter SR, Fridholm H, Herrera JAR, Lund O, Brunak S, Izarzugaza JMG, Mourier T, Nielsen LP, Hansen AJ (2016) Propionibacterium acnes: disease-causing agent or common contaminant? Detection in diverse patient samples by next-generation sequencing. J Clin Microbiol 54, 980-987.
[5] Deurenberg RH, Bathoorn E, Chlebowicz MA, Couto N, Ferdous M, García-Cobos S, Kooistra-Smid AM, Raangs EC, Rosema S, Veloo AC, Zhou K, Friedrich AW, Rossen JW (2017) Application of next generation sequencing in clinical microbiology and infection prevention. J Biotechnol 243, 16-24.
[6] Mawanda F, Wallace R (2013) Can infections cause Alzheimer's disease? Epidemiol Rev 35, 161-180.
[7] Broxmeyer L (2017) Dr. Oskar Fischer’s Curious Little Alzheimer’s Germ. Curr Opin Neurol Sci 1, 160-178. https://scientiaricerca.com/srcons/SRCONS-01-00026.php

Last comment on 26 September 2024 by Lawrence Broxmeyer, MD

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Broxmeyer's blog is useful in that it describes the work of Fischer, whose contribution to the understanding of AD is rarely mentioned, and his suggestion that a new type of bacterium might be added to the list of microbes possibly involved in AD is interesting but perhaps no great surprise. However, his contention that HSV1 is not involved in AD (he maintains that it has been “struck down”, along with Chlamydia pneumoniae, and several types of spirochetes) seems to be based solely on a single assumption in a review by Mawanda and Wallace [1]. Unfortunately for all three authors though, the assumption is totally fallacious: it states that if the frequency of infection with a microbe in brain is similar in AD patients and normal subjects (as we and others have shown is the case with HSV1), that microbe cannot be a factor in the disease. Broxmeyer, and Mawanda and Wallace, need to recall that many people can be infected by a microbe yet are asymptomatic, and so are classed as “controls” (i.e., they appear to be uninfected). The most striking example of this is the TB bacterium—Mycobacter tuberculosis, which infects approximately one-third of the world's population yet only some 10% actually develop TB. Similarly with HSV1, the usual cause of cold sores, only about 25% of the many who are infected with the virus display any sores, despite the frequency of reactivation of the virus. Surprisingly on this theme, Mawanda and Wallace state elsewhere in the review, referring to a study by Deatly et al. [2]: “Notably, in situ hybridization of postmortem brain tissue samples from 21 patients with AD and 19 controls detected HSV-1 DNA in a significantly higher proportion of AD samples (81%) than controls (47.4%)”, but Mawanda and Wallace do not even intimate if this supports or undermines their case. However, Deatly et al. found these percentages not for the brain but for the trigeminal ganglion, and what was sought was “latent HSV1 RNA” because of its presumed much higher level, not HSV1 DNA! In fact, Deatly et al. found “no evidence of viral RNA in the central nervous system”.

What is notable is that Deatly et al. [2] stated that the sensitivity of the in situ hybridisation method they used for detecting HSV1 RNA was one viral sequence per cell, which is vastly lower than that of DNA detectable by PCR (e.g., the sensitivity detected by my group in 1997 [3] was about one viral sequence per 104 cells). As for detection of serum antibodies to HSV1 which, anyway, in early publications, showed little consistency, two of the three older references cited by Mawanda and Wallace were published 27 and 30 years ago when, as with DNA, the sensitivity of antibody detection would have been much lower; their third reference, 125, cites instead my lab’s study (and definite detection) of intrathecal antibodies to HSV1! However, referring elsewhere to recent studies, they state that “Serologic analysis .... has also linked HSV-1 to increased AD risk”. Mawanda and Wallace do acknowledge in the case of DNA, though, that usage of PCR has increased the detection sensitivity of specific sequences. Nonetheless, their case, and hence that of Broxmeyer, is fatally undermined by these fallacies and factual errors. Real errors and fallacies need to be struck down, not phantom ones; tilting at windmills has never been a wise pursuit.

References
[1] Mawanda F, Wallace R (2013) Can infections cause Alzheimer's disease? Epidemiol Rev 35, 161-180.
[2] Deatly MA, Haase AT, Fewsters PH, Lewis E, Ball MJ (1990) Human herpes virus infections and Alzheimer’s disease. Neuropathol Appl Neurohiol 16, 213-223.
[3] Itzhaki RF, Lin W-R, Shang D, Wilcock GK, Faragher B, Jamieson GA (1997) Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. Lancet 349, 241-244.

Dr. Lawrence Broxmeyer’s blog suggests that Dr. Oskar Fischer’s identification of tubercular-like Actinobacteria should still be considered as the principal infectious organism(s) suspected to cause Alzheimer’s disease (AD). He suggests that recent identification of another Actinobacteria organism, Propionibacterium acnes, by Emery et al., 2017 also could be indicative of another organism in the same order of Actinomycetales, namely Mycobacterium tuberculosis. Broxmeyer infers that this organism should also be considered as the cell-wall deficient form of this organism and its extremely neurotropic nature make it highly more likely to be in the nervous system as compared to Oskar Fischer’s Streptothrix or Emery et al.’s Propionibacterium acnes, both of which are rarely associated with primary brain infections. Further, he cites a review by Mollerup et al., 2016 that suggests Propionibacterium acnes should be cautiously considered, as this organism may be a contaminant of clinical samples. He continues on to indicate that regardless of the specific organism, the findings by Emery et al. of 5-10 times the amount of Actinobacteria in AD brains as compared to controls supports Oskar Fischer’s initial findings.

Dr. Broxmeyer continues on to suggest that an influential review article by Mawanda and Wallace, 2013 also supports Oskar Fischer’s initial findings and those of Emery et al. of involvement of Actinomycetales in AD. Unfortunately, this is not the case.

Mawanda and Wallace simply cite that “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 (51-58).” There is no suggestion by these authors that either tuberculosis or leprosy is directly involved in AD.

Further, stating that the review by Mawanda and Wallace has “struck down some of the current commonly entertained pathogens for AD such as herpes simplex virus type 1, Chlamydia pneumoniae, and several types of spirochetes” is not accurate.The fact is that the authors conclude at the end of each section discussing the findings for these organisms with the following: “Thus, lack of consistency leaves studies linking HSV-1 to the causation of AD inconclusive”; “Again, ambiguous study findings leave the exact role of C. pneumoniae in the pathogenesis of AD unclear”; “Because of these mixed findings, the role of B. burgdorferi in the etiology of AD remains unresolved.” The Mawanda and Wallace review article concludes with “In conclusion, the particular role infections play in pathogenesis of AD remains undetermined, but substantial evidence suggests an association.” This is the perspective that we who are studying infection in AD are taking, with insight into the varied mechanisms by which different organisms may play primary or secondary roles in AD pathogenesis.

The historical perspective of infection in AD as noted by this blog is well-appreciated by those of us currently studying infection in AD knowing full-well that this concept is not new but is ever evolving. Furthermore, this perspective brings to bear issues for which Oskar Fischer was confronting and for which many of us confront in 2017.

The most important concept is that infectious agents have been and are being identified in AD brains and we need to determine if they are causative for the disease. The nature of these infections have led us to evaluate issues such as (1) contamination of clinical specimens, (2) technological issues for identification including molecular approaches, immunohistochemical labeling, ultrastructural (EM and IEM) evaluation, and culturing, (3) mimicry of cellular components, e.g., elementary bodies of Chlamydia and lysosomes, or filamentous curli fibers and amyloids, and (4) entry into the nervous system, e.g., blood-brain barrier versus cranial nerve involvement (olfaction). All of these issues, and more, need to be and are being considered in shifting the paradigm back to infection as a major feature in AD.

“Mawanda and Wallace simply cite that “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 (51-58).” There is no suggestion by these authors that either tuberculosis or leprosy is directly involved in AD.”

Nor was it suggested otherwise. As stated, Mahwanda and Wallace pointed to two prime suspects for Alzheimer’s amyloid-beta deposition: tuberculosis or leprosy. When looking for an infectious cause for Alzheimer’s I think it prudent to look for an organism that can cause amyloidopathy and related Tau protein. What about you?

“Further, stating that the review by Mawanda and Wallace has “struck down some of the current commonly entertained pathogens for AD such as herpes simplex virus type 1, Chlamydia pneumoniae, and several types of spirochetes” is not accurate.”

Mawanda and Wallace’s [“Can Infections Cause Alzheimer’s Disease”] 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, that these results have, however, not been replicated.

Mawanda F, Wallace R (2013) Can infections cause Alzheimer's disease? Epidemiol
Rev 35, 161-180.

“Mawanda and Wallace do acknowledge in the case of DNA, though, that usage of PCR has increased the detection sensitivity of specific sequences. Nonetheless, their case, and hence that of Broxmeyer, is fatally undermined by these fallacies and factual errors. Real errors and fallacies need to be struck down, not phantom ones; tilting at windmills has never been a wise pursuit.”

Depends upon which “windmills” you are talking about. There are also viral windmills.

Some say that Herpes simplex virus type 1 in conjunction with APOE-epsilon 4 allele is a strong risk factor for AD, though either of these features alone do not increase the risk of AD. People who have symptoms of late onset Alzheimer disease (AD) and have one or more APOE e4 copies are more likely to have AD. However, APOE e4 is not diagnostic of AD and should not be used to screen people or their family members. Furthermore, many of those who have e4 alleles will never develop AD. And even in symptomatic people, only about 60% of those with late onset AD will have APOE e4 alleles. [1,2]

Furthermore in the case of herpes simplex virus type 1 ― an estimated 80 percent of the U.S. population has HSV-1. To Alzheimer’s specialist Jagan Pillae of the Cleveland Clinic, the connection between HSV-1 and Alzheimer’s is still murky and “The research does not say, nor does it tell us if herpes simplex 1 virus caused Alzheimer’s. The studies show that for some as-yet unclear reason, immune changes related to herpes simplex 1 appear to be more common in older individuals (meaning older than age 60) with Alzheimer’s. The research does not say, nor does it tell us, if the herpes simplex 1 virus caused Alzheimer’s. It could be that immune changes related to Alzheimer’s disease simply cause more reactivations of the virus.”

Pillae goes on to say that besides, HSV-1 studies rely on the clinical diagnosis of Alzheimer’s ― and not the actual examination of the brain at autopsy ― pointing out that the clinical diagnosis of Alzheimer’s is accurate only about 70 percent of the time. [3]

1. Goldman JS et al. American College of Medical Genetics and the National Society of Genetic Counselors. Genetic counseling and testing for Alzheimer disease: joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors. Genet Med. 2011; 13(6): 597-605.]

2. Mayeux et al. Utility of the Apolipoprotein E Genotype in the Diagnosis of Alzheimer’s disease. NEJM. 1998; 338(8):506-511.

3. Cleveland Clinic Brain and Spine Team. Does Your Cold Sore Mean You’ll Get Alzheimer’s Disease? November 3, 2014. Cleveland Clinic Health Essentials https://health.clevelandclinic.org/2014/11/does-your-cold-sore-mean-youl...

The points raised by Broxmeyer are new but can be answered very easily:

1. Unfortunately, Broxmeyer has again repeated a misleading statement by Mawanda and Wallace [1]: that in our first HSV1-APOE study [2],"APOE genotype was not independently associated with AD". Our data showed a marginal risk of AD from APOE-e4 alone (i.e., for subjects not harbouring HSV1 in brain). In contrast, AD patients with HSV1 in brain had very high e4 allele frequencies: values for AD patients, HSV1-positive or HSV1-negative in brain were, respectively, 52.8% and 10%. The overall APOE-e4 allele frequencies for all AD patients and all age-matched controls, irrespective of HSV1 presence, were 43.4% and 4.5%. (Our low control values perhaps reflected the fact that most subjects had been born in the first decades of the 20th century, so that many e4 carriers might have died in middle age, through, say, heart disease.) Incidentally, it is very probably significant that we found that APOE-e4 is a risk for cold sores - caused usually by HSV1.

2) The suggestion of Pillae that "The research does not say, nor does it tell us if herpes simplex 1 virus caused Alzheimer’s. It could be that immune changes related to Alzheimer’s disease simply cause more reactivations of the virus.” In fact a major action of HSV1 is via the inflammation it causes, and our papers have always stressed that. Also, we have never suggested that HSV1 is the cause of AD, but instead that it is a (major) cause. It would indeed be useful to know what Pillae proposes as the cause of the immune changes related to AD. Further, re cause and effect, HSV1 presence in brain cannot be attributed to a greater susceptibility of AD patients, or of e4 carriers, to HSV1 infection, because we found that the frequency of HSV1 presence in brain was quite similar in AD patients and controls. Thus, a causal relationship of virus (with an e4 allele) to AD is very plausible. However, the only way to prove definite cause and effect in the case of HSV1-APOE-e4 and AD - a non-contagious human disease - would be successful vaccination against HSV1 and/or successful antiviral treatment.

3) Pillae's assertion that "HSV-1 studies rely on the clinical diagnosis of Alzheimer’s ― and not the actual examination of the brain at autopsy" is strange, as autopsy specimens are precisely those that were used for seeking the presence of HSV1 DNA [3] (and that of other herpesviruses [4]). And in most cases, HSV1 DNA and also HHV6 DNA were found. Of course, many subsequent studies implicating HSV1, such as its causing accumulation of beta amyloid and AD-like-tau, and its localisation within amyloid plaques, have since been done in vitro.

4) As a non-clinician I can't argue with Pillae's statement that "the clinical diagnosis of Alzheimer’s is accurate only about 70 percent of the time" but if correct, it does weaken all data that are obtained from studies in vivo.

Happily, Broxmeyer and I totally agree on one point: that carriage of an APOE-e4 allele should not - and I believe is not - taken as diagnostic or predictive of the disease.

References
[1] Mawanda F, Wallace R (2013) Can infections cause Alzheimer's disease? <em">Epidemiol Rev 35, 161-180.
[2] Itzhaki RF, Lin W-R, Shang D, Wilcock GK, Faragher B, Jamieson GA (1997) Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. Lancet 349, 241-244.
[3] 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, 224–27.

Thank you for your valued response. It is refreshing to understand that we share at least one point of agreement. And the fact still remains that no specific pathogen has been linked conclusively to the causation of late-onset AD in humans. That might just be our second point of agreement –or at least I would hope.

Dr. Contini and associates 2010 study [1] reminds us that several groups have investigated an association between various infectious agents and AD, “but none of these has been accepted as either etiological for disease development, or worsening of neuropathology.” Although “interesting perspectives”, he admits, came from one study which identified herpes simplex virus type1 (HSV-1) infection as a risk factor for development of AD in subjects expressing APOE ε4 allele [2, 3], but that this viral quest, including measles virus, adenovirus, lentiviruses, and several other others were also initially considered for AD but later discarded. [4, 5].

In the meantime, Nimgaonkar et al. [6], in a 2016 study published in the journal Alzheimer's Disease and Associated Disorders, from the University of Pittsburgh School of Medicine in Pennsylvania clarified that HSV-1, which is the type of herpes associated with cold sores - and which an estimated 3.7 billion people under the age of 50 have worldwide –is not associated nor linked to greater temporal cognitive decline. Clinically, Herpes Simplex encephalopathy is a rare disorder.

Dr. Sam Gandy, director of the Center for Cognitive Health at Mount Sinai Hospital in New York City, doubts that herpes and Alzheimer's disease are connected: "From time to time data such as these appear in the literature, but they do not address causality or mechanism. The new data are likewise not definitive, and they do not say anything new about the association," he said. "I do not disbelieve the data. I simply do not know whether the association has anything to do with the cause of Alzheimer's disease," Gandy added. In addition, Greg Cole, the associate director of the Geriatric Research and Clinical Center at the UCLA Alzheimer Disease Research Center in Los Angeles, isn't totally convinced: "More than 90 percent of the population has antibodies to herpes, and they are not all destined to develop Alzheimer's disease," he said.

There are several more specific reasons that the role of HSV-1 in the causation of AD could be considered as remaining questionable. Several studies of post-mortem brain tissues found no evidence linking HSV-1 to AD [7-13]. For example, Taylor et al. [8] used in situ hybridization to analyze postmortem brain samples (55 from 8 patients with AD and 57 from 9 non-neurologic control patients), as well as samples from HSV-1-infected mice; with this technique, none of the samples revealed detectable levels HSV-1 DNA. In another in situ hybridization study, Roberts et al. [9] examined postmortem brain specimens from 25 patients with AD and 32 controls, but none hybridized to HSV-1 DNA probes. Similarly, HSV-1 DNA was not detected by Southern blotting in any postmortem brain tissue samples or peripheral blood cells obtained from 5 patients with AD and 5 normal controls [12]. These negative findings, however, could be due in part to differences in methodology because in situ hybridization and Southern blotting are less sensitive than PCR in detecting DNA. Consistently, the majority of studies reporting positive findings used PCR. Nevertheless, most PCR-based studies show no significant difference in the frequency of AD versus control brain tissue samples that contain HSV-1 DNA [14-21]. Several serology-based studies also found no evidence to link HSV-1 infection to AD [22-24]. For example, Renvoize et al. [23] analyzed serum from 33 patients with clinical diagnosis of AD and 28 controls suffering from psychiatric disorders but without evidence of comorbid dementia. They found that serum from the 2 groups did not differ significantly in the levels of antibody titers to various viral pathogens, including HSV-1, but this result is not surprising given the high prevalence of HSV-1 among older adults. Moreover, Ounanian et al. [22] found that controls, rather than patients with AD, showed higher levels of anti-HSV-1 antibody titers. Thus, lack of consistency leaves studies linking HSV-1 to the causation of AD inconclusive.

Also, in Potgieter’s review of The dormant blood microbiome in chronic, inflammatory diseases [25], which I believe you are familiar with, in Figure 5 on page 579 you will see the coccus-shaped bacteria associated with Alzheimer’s (AD). Is this, in any ways related to Herpes Simplex Virus, type 1?

1. Contini C, Seraceni S, Cultrera R, Castellazzi M, Granieri E, Fainardi E (2010) Chlamydophila pneumoniae Infection and Its Role in Neurological Disorders,” Interdiscip Perspect Infect Dis 2010, Article ID 273573, 18 pages.
2. Itzhaki RF, Lin WR, Shang D, Wilcock GK, Faragher B, Jamieson GA (1997) Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. The Lancet 349, 241–244.
3. Itzhaki RF, Dobson CB, Lin WR, Wozniak MA (2001) Association of HSV1 and apolipoprotein E-ε4 in Alzheimer’s disease. J Neurovirol 7, 570–571.
4. Pogo BG, Casals J, Elizan TS (1987) A study of viral genomes and antigens in brains of patients with Alzheimer’s disease Brain 110, 907–915.
5. Friedland RP, May C, Dahlberg J (1990) The viral hypothesis of Alzheimer’s disease: absence of antibodies to lentiviruses. Arch Neurol 47, 177–178.
6. Nimgaonkar VL, Yolken RH, Wang T, Chang C-CH, McClain L, McDade E, Snitz BE, Ganguli M (2016) Temporal cognitive decline associated with exposure to infectious agents in a population-based, aging cohort. Alzheimer Dis Assoc Disord 30, 216–222.
7. Middleton PJ, Petric M, Kozak M, Rewcastle NB, McLachlan DR (1980) Herpes-simplex viral genome and senile and presenile dementias of Alzheimer and Pick [letter]. Lancet 1, 1038.
8. Taylor GR, Crow TJ, Markakis DA, Lofthouse R, Neeley S, Carter GI (1984) Herpes simplex virus and Alzheimer’s disease: a search for virus DNA by spot hybridization. J Neurol Neurosurg Psychiatry 47, 1061–1065.
9. Roberts GW, Taylor GR, Carter GI, Johnson JA, Bloxham C, Brown R, Crow TJ (1986) Herpes simplex virus: a role in the etiology of Alzheimer’s disease? [letter]. J Neurol Neurosurg Psychiatry 49, 216.
10. Pogo BG, Casals J, Elizan TS (1987) A study of viral genomes and antigens in brains of patients with Alzheimer’s disease. Brain 110, 907–915.
11. Walker DG, O’Kusky JR, McGeer PL (1989) In situ hybridization analysis for herpes simplex virus nucleic acids in Alzheimer disease. Alzheimer Dis Assoc Disord 3, 123–131.
12. Kittur SD, Hoh JH, Kawas CH, Hayward GS, Endo H, Adler WH (1992) A molecular hybridization study for the presence of herpes simplex, cytomegalovirus and Epstein-Barr virus in brain and blood of Alzheimer’s disease patients. Arch Gerontol Geriatr 15, 35–41.
13. Mann DM, Tinkler AM, Yates PO (1983) Neurological disease and herpes simplex virus. An immunohistochemical study. Acta Neuropathol 60, 24–28.
14. Beffert U, Bertrand P, Champagne D, Gauthier S, Poirier J (1998) HSV-1 in brain and risk of Alzheimer’s disease [letter]. Lancet 351, 1330.
15. Wozniak MA, Mee AP, Itzhaki RF (2009) Herpes simplex virus type 1 DNA is located within Alzheimer’s disease amyloid plaques. J Pathol 217, 131–138.
16. 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.
17. Jamieson GA, Maitland NJ, Craske J, Wilcock GK, Itzhaki RF (1991) Detection of herpes simplex virus type 1 DNA sequences in normal and Alzheimer’s disease brain using polymerase chain reaction. Biochem Soc Trans 19, 122S.
18. Lin WR, Casas I, Wilcock GK, Itzhaki RF (1997) Neurotropic viruses and Alzheimer’s disease: a search for varicella zoster virus DNA by the polymerase chain reaction. J Neurol NeurosurgPsychiatry 62, 586–589.
19. Itabashi S, Arai H, Matsui T, Higuchi S, Sasaki H (1997) Herpes simplex virus and risk of Alzheimer’s disease [letter]. Lancet 349, 1102.
20. Cheon MS, Bajo M, Gulesserian T, Cairns N, Lubec G (2001) Evidence for the relation of herpes simplex virus type 1 to Down syndromeand Alzheimer’s disease. Electrophoresis 22, 445–448.
21. Lin W, Graham J, MacGowan S, Wilcock GK, Itzhaki RF (1998) Alzheimer’s disease, herpes virus in brain, apolipoprotein E4 and herpes labialis. Alzheimers Rep 1, 173–178.
22. Ounanian A, Guilbert B, Renversez JC, Seigneurin JM, Avrameas S (1990) Antibodies to viral antigens, xenoantigens, and autoantigens in Alzheimer’s disease. J Clin Lab Anal 4, 367–375.
23. Renvoize EB, Awad IO, Hambling MH (1987) A seroepidemiological study of conventional infectious agents in Alzheimer’s disease. Age Ageing 16, 311–314.
24. Wozniak MA, Shipley SJ, Combrinck M, Wilcock GK, Itzhaki RF (2005) Productive herpes simplex virus in brain of elderly normal subjects and Alzheimer’s disease patients. J Med Virol 75, 300–306.
25. Potgieter M, Bester J, Kell DB, Pretorius E (2015) The dormant blood microbiome in chronic, inflammatory diseases. FEMS Microbiol Rev 39, 567-591.

To answer each point:
1. Bhatia et al. [1] now state that “significant dysfunction was observed among HSV-1 infected participants in three of eight cognitive domains, consistent with prior cross-sectional studies.........The relatively high prevalence of HSV-1 infection increases its potential public health impact. The temporal change in cognitive dysfunction could contribute to cognitive aging (Nimgaonkar et al., 2016), a process that is arousing public health concern.” Sensitivity of detection is again the issue: Paul Klapper and I [2] pointed out that a previous study implicating CMV but not HSV1in AD [3] used a far less sensitive assay for HSV, detecting only a single viral glycoprotein for HSV1, whereas for CMV, all of its many proteins were detectable. The same assay was used by Nimgaonkar et al. in 2016 [4] - but gratifyingly, they alluded to the lack of sensitivity of their assays for HSV1! Obviously, such differences in sensitivity to various viruses should be taken into account when comparing different viruses or estimating infectious burden.

2. A propos the non-detection of HSV1 DNA by the 7 pre-PCR studies cited - published between 1976 and 1992, it's good that Broxmeyer acknowledges that hybridisation techniques are "less sensitive" than PCR; in fact PCR sensitivity is several orders of magnitude greater.

3. Gandy's point re cause and effect was dealt with in my previous comments.

4. Cole seems unaware that HSV1-AD proponents refer to HSV1 presence in brain, not to serum antibodies to HSV1, which are present in the vast majority of older people. As for HSV1-seropositivity not being associated with AD, it should be recalled that seropositivity reflects HSV1 presence in the periphery. Of the references on serum antibodies that Broxmeyer cites (22-24), 24 describes a study from my lab, but it was not on serum antibodies; instead we investigated intrathecal antibodies which, we found, were present in many aged people and AD patients, consistent with our PCR results.

Oh, if only people would actually read the original publication rather than quote other people's quotes, which are all too often misquotes, or which omit essential data, it would save so much time.

References
[1] Bhatia T, Wood J, Iyengar S, Narayanan SS, Beniwal RP, Prasad KM, Chen K, Yolken RH, Dickerson F, Gur RC, Gur RE, Deshpande SN, Nimgaonkar VL (2017) Emotion discrimination in humans: Its association with HSV-1 infection and its improvement with antiviral treatment. Schizophr Res, doi: 10.1016/j.schres.2017.08.001.
[2] Itzhaki RF, Klapper P (2015) Comment on cytomegalovirus infection and risk of Alzheimer disease in older black and white individuals. J Infect Dis 211, 2023-2024.
[3] Barnes LL, Capuano AW, Aiello AE, Turner AD, Yolken RH, Torrey EF, Bennett DA (2015) Cytomegalovirus infection and risk of Alzheimer disease in older black and white individuals. J Infect Dis 211, 230-237.
[4] Nimgaonkar VL, Yolken RH, Wang T, Chung-Chou HC, McClain L, McDade E, Snitz BE, Ganguli M (2016) Temporal cognitive decline associated with exposure to infectious agents in a population-based, aging cohort. Alzheimer Dis Assoc Disord 30, 216–222.

“…..it's good that Broxmeyer acknowledges that hybridisation techniques are "less sensitive" than PCR; in fact PCR sensitivity is several orders of magnitude greater.”

And it’s good that Itzhaki is here to emphasize the obvious. So let’s talk about PCR.

Kary Mullis, the inventor of that PCR, and as a result a Nobel Laureate, has been very clear, to this day, regarding what constitutes PCR’s valid uses. Mullis said that such tests cannot detect free, infectious viruses at all; they can only detect proteins that researchers believe, in some cases wrongly, are unique to the virus being tested for. The tests can detect genetic sequences of viruses, but not viruses themselves.

In her study Life-Threatening Herpes Simplex Virus Infections in the Normal and Immunocompromised Host, Birgit Sköldenberg, an Associate Professor of Infectious Diseases at the Karolinska Institute in Stockholm pointed out that other diseases can be confused with Herpes simplex encephalitis (HSE) “such as tuberculosis, brain abscess or tumor, and other viral infections” [1]. These are all in the differential diagnosis of Herpes simplex encephalitis and therefore must be considered.

Certainly this was the case in a September, 2016 case published by Oxford University press on behalf of the Infectious diseases Society of America (IDSA). The publication was entitled the “Delayed Diagnosis of Tuberculous Meningitis Misdiagnosed as Herpes Simplex Virus- 1 Encephalitis With the FilmArray Syndromic Polymerase Chain Reaction Panel” [2]. In October 2015, the FDA cleared the first multiplex, meningitis/encephalitis (ME) PCR panel (FilmArray ME panel; BioFire Diagnostics LLC, Salt Lake City, UT) for the diagnosis of most common infectious etiologies of acute central nervous system (CNS) infections. This fully automated, sample-to-answer, multiplex polymerase chain reaction (PCR) assay required <2 minutes of hands-on time, and in 1 hour it tests for 14 ME pathogens, including bacteria, fungi, and viruses [3]. Not included in the FilmArray Meningitis/Encephalitis (ME) Panel, however, was any means of detecting another prominent ME agents, M. tuberculosis. So below is a classic illustration of what you don’t look for, you don’t find.

One of the many patients to be subjected to this particular PCR panel was a 75-year-old Vietnamese man, who immigrated to California more than 40 years ago, and not unlike Auguste Deter, Alzheimer’s first patient, presented with confusion, disorientation to time and place, but with no focal neurologic deficits.

In this case, a spinal tap was negative for Gram and acid-fast stains but cerebrospinal fluid tested with the FilmArray ME PCR panel was positive for HSV-1, prompting the initiation of intravenous anti-viral acyclovir therapy for HSV encephalitis. It was because of failure, and worsening of this patient’s condition while on such anti-viral treatment that an Infectious Diseases (ID) consult was requested to expand the diagnostic workup for chronic meningitis. Per the ID recommendation, additional CSF testing by real-time PCR for HSV-1/HSV-2 (artus HSV-1/2 QS-RGQ Kit; QIAGEN, Germantown, MD), VZV, and CMV (also from QIAGEN), and cryptococcal antigen detection by lateral flow immunochromatography (IMMY, Norman, OK) all yielded negative results.

On hospital day 7, Mycobacterium tuberculosis nucleic acid testing on a CSF sample, using a laboratory-developed PCR assay [4], was positive and tuberculosis therapy with first-line drugs (isoniazid, rifampin, pyrazinamide, and ethambutol) and dexamethasone were initiated. Cerebrospinal fluid cultured in liquid medium (MGIT960 system; Becton Dickinson, Franklin Lakes, NJ) turned positive for M tuberculosis after 13 days. Phenotypic susceptibility testing with first-line drugs demonstrated a pan-susceptible isolate. Unfortunately, in large part due to the initial delay in proper diagnosis, over the following weeks, despite aggressive clinical management, the patient did not have meaningful neurologic recovery and eventually required a tracheostomy and gastric feeding tube for transition to a rehabilitation ward. At the time of the authors writing this report, he continued on tuberculosis therapy with severe neurological deficit.

So in this study, we have a case of tuberculous meningitis leading to severe neurological sequelae, in an immunocompromised patient whose diagnosis was delayed due to a false-positive herpes simplex virus (HSV)-1 result with the FilmArray ME panel PCR.

More importantly, no matter how sensitive and sophisticated your diagnostic tests and next-generation PCRs are it still does not address the concerns of Alzheimer’s specialist Jagan Pillae of the Cleveland Clinic, who feels the connection between HSV-1 and Alzheimer’s is still murky and that “The research does not say, nor does it tell us if herpes simplex 1 virus caused Alzheimer’s. The studies show that for some as-yet unclear reason, immune changes related to herpes simplex 1 appear to be more common in older individuals (meaning older than age 60) with Alzheimer’s. The research does not say, nor does it tell us, if the herpes simplex 1 virus caused Alzheimer’s. It could be that immune changes related to Alzheimer’s disease simply cause more reactivations of the virus.” [5] And, it is not inconceivable that such immune changes come as a result of an immunosuppressive primary infection, to this point, undetected.

Thank you for your kind response.

1. Sköldenberg B (1995) Life-threatening Herpes Simplex Virus infections in the normal and immunocompromised host. Chapter 7. In Clinical Management of Herpes Viruses, Sacks SL, ed. IOS Press, p. 117. https://tinyurl.com/ydchmdrv
2. Gomez CA, Pinsky BA, Liu A, Banaei N (2017) Delayed diagnosis of tuberculous meningitis misdiagnosed as Herpes Simplex Virus-1 encephalitis with the film array syndromic polymerase chain reaction panel. Open Forum Infect Dis 4, ofw24. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437853/
3. U.S. Food & Drug Administration. FDA News Release. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm466360.htm. Accessed 24 August 2016.
4. Luo RF, Scahill MD, Banaei N (2010) Comparison of single-copy and multicopy realtime PCR targets for detection of Mycobacterium tuberculosis in paraffin-embedded tissue. J Clin Microbiol 48, 2569–2570.
5. Cleveland Clinic Brain and Spine Team. Does Your Cold Sore Mean You’ll Get Alzheimer’s Disease? November 3, 2014. Cleveland Clinic Health Essentials https://health.clevelandclinic.org/2014/11/does-your-cold-sore-mean-youll-get-alzheimers-disease/ Accessed 6/11/2017.

By February 9th, 2016 the Journal of Alzheimer’s Disease (JAD) accepted an enlightening Editorial entitled “Microbes and Alzheimer’s Disease” by Neurobiologist Ruth Itzhaki and others, signed-off on by 31 scientists from around the world [1].

Itzhaki et al. mention in their JAD editorial the abnormal microbiota: commensal, symbiotic and pathogenic microorganisms that literally share our body space were among the potential AD pathogens cited. Many of these microorganisms are helpful to us, and others, while not so helpful, cannot even be remotely tied to the subsequent development of Alzheimer’s disease ― but recently Potgieter et al (2015), in their review [2] of dormant, cell-wall-deficient (CWD) in chronic inflammatory disease referred to a study which found micro-pictographs of red blood cells (RBCs) with coccus-shaped bacteria from patients diagnosed with Alzheimer’s disease ("The dormant blood microbiome in chronic inflammatory diseases.") And although the precise identification of these microorganisms was yet to be made, their physical structure do not seem to differ from the “corynebacteria-like” coccoid microorganisms within RBCs developing in sick patients uncovered by Tedeschi [3] in 1978. Atlas mentioned [4] at the time that the differentiation between the corynebacteria, the mycobacteria, and various pleomorphic bacteria, including the filamentous Actinomycetes [Actinobacteria] was not easy, and that different observers might classify the same strain as belonging to the Corynebacteria or the mycobacteria. Tedeschi, for example, mentioned specifically in his study that the cocci he uncovered were from "microbial forms looking like corynebacteria" yet within the same culture he noted "very rare acid-fast cells", characteristic of the mycobacteria, a prominent form of the Actinobaccteria. Of all the pathogens, the dormand cell-wall-deficient or "L-forms" persist as, and are the most favored configuration of the mycobacteria such as tuberculosis―a survival strategy by the pathogen to endure harsh environmental conditions.

Very recently this author contacted some in the Potgieter group for an update [5], asking, with regard to both the coccoid-bacillus in the Figure 5 depicting AD and Figure 6, depicting bacterial forms of Parkinson's in their article [2] -had they done any further testing/studies to determine specifically which bacterial forms were present in these figures, such as the cocci found in the blood microbiome of Alzheimer's disease? The query was specifically aimed at finding out what family/species of bacteria they felt these bacteria, belonged to. The answer was that although they had nothing specific to report yet, that they were seeking to develop novel molecular methods to detect this. When asked if, specifically, the Actinobacteria including the mycobacteria, were a consideration in their AD/PD probes, the response was: "Actinobacteria (as they are nowadays called) are definitely among the prime candidates." 

[1] Itzhaki RF, Lathe R, Balin BJ, Ball MJ, Bearer EL, et al. (2016) Microbes and Alzheimer's disease. J Alzheimers Dis 51, 979-984.
[2] Potgieter M, Bester J, Kell DB, Pretorius E (2015) The dormant blood microbiome in chronic, inflammatory diseases. FEMS Microbiol Rev 39, 567-591.
[3] Tedeschi GG, Bondi A, Paparelli M, Sprovieri G (1978) Electron microscopical evidence of the evolution of corynebacteria-like Microorganisms within human erythrocytes. Experientia 34, 458–460.
[4] Atlas RM (1988) Microbiology: Fundamentals and Applications, 2nd Ed. Macmillan, New York, 807pp, p. 294.
[5] Personal communication 11/10/2017.

With regards to the fungal forms found in the Alzheimer’s brain mentioned in the JAD editorial, this has precedent, but its historical basis is poorly understood. Oskar Fischer [1], the co-discoverer of Alzheimer’s disease, saw such forms in 1907. But Fischer felt that they were related to Streptothrix, a germ with both bacterial and fungal properties–often and constantly confused with tuberculosis, which stained similarly and also had both bacterial and fungal forms. The disease Actinomycosis was at one time referred to interchangeably with its older bacterial name, the “Streptotriches” (the plural form of Streptothrix). Fischer used such older nomenclature in describing certain forms he saw under his microscope.

Pisa’s review relates that although she and her colleagues found “several fungal species” consistently in Alzheimer’s brains ― “it is quite possible” that one fungal infection may facilitate the colonization by other fungal species, “giving rise to mixed fungal infections”. She also admits that although “the existence of fungal infection in AD” may be because they are causal, “it could also be possible that, for reasons yet unknown, these patients are more prone to this type of infection.” [2].

This brings to mind patients prone to fungal infection such as Candida species co-infection with the very same bacterial/fungal microorganism that Oskar Fischer uncovered in 1907. Fungal infections are common secondary infections and the late sequelae of tuberculosis [3-6]. In addition tuberculosis itself can be mistaken for a fungus [7,8]. Mycobacterium is a genus of Actinobacteria, given its own family, the Mycobacteriaceae. The genus includes pathogens known to cause serious diseases in mammals, including tuberculosis (Mycobacterium tuberculosis) and leprosy (Mycobacterium leprae). The Greek prefix myco- means "fungus," alluding to the way mycobacteria are observed to grow in a mold-like fashion on the surface of cultures.

Streptothrix was also of the Actinobacteria and its colonies formed 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). Yadu [4] found that 49% of cases of pulmonary tuberculosis were positive for opportunistic fungi and cites Chadeganipour et al., who Yadu relates found 68.75% or 11 out of 16 with pulmonary fungal infection in addition to already diagnosed tuberculosis [5].

References
[1] Fischer O (1907) Miliary necrosis with nodular proliferation of the neurofibrils, a common change of the cerebral cortex in senile dementia. Monatsschrift Psychiatr Neurol XXII, Th. Ziehen, ed. S. Karger, Berlin, pp. 361–372.
[2] Pisa D, Alonso R, Rábano A, Rodal I, Carrasco L (2015) Different brain regions are infected with fungi in Alzheimer's disease. Sci Rep 5, 15015.
[3] Kali A, Charles MVP, Joseph NM, Umadevi S, Kumar S, Easow JM (2013) Prevalence of Candida co-infection in patients with pulmonary tuberculosis. Australas Med J 6, 387–391.
[4] Yadu R, Nawange SR, Singh SM, Gutch RS, Gumasta R, Nawange M, Kavishwar A (2015) Prevalence of opportunistic fungal infection in patients with pulmonary tuberculosis in Madhya Pradesh, Central India. Microbioz J J Microbiol Biomed Res 6, 1-12.
[5] Chadeganipour M, Shadzi S, Dehghan P, Bijary J (2000) The incidence of opportunistic fungi in patients suspected of tuberculosis. Mycoses 43, 269-272.
[6] Iwata H, Miwa T, Takagi K (1990) Tuberculosis sequelae: secondary fungal infections. Kekkaku 65, 867-871.
[7] Mellon RR, Fisher LW (1932) New studies on the filterability of pure cultures of the tubercle group of micro-organisms. J Infect Dis 51, 117–128.
[8] Mellon RR, Beinhauer LG (1937) The pathogenesis of noncaseating tuberculosis of the skin and lymph glands. Arch Dermatol Syph 36, 515-533.

Is the Antibiotic Rifampicin Protective against Alzheimer’s disease?

Certain ideas in medical research do not go away easily, and rather keep reappearing. One of these is the topic of the possible use of rifampicin in Alzheimer’s disease (AD).

By 1984, de Beer [1], studying the relationship between a major rise in serum amyloid and having tuberculosis, also saw a rapid descent in amyloid in patients treated with anti-tubercular drugs. As an offshoot of de Beer’s work, Tomiyama [2] dissolved amyloid-β plaque with rifampicin, a first-line drug in the treatment of TB, and one of the few agents, to this day, which is able to dissolve amyloid plaque. And so by 2004, Anthony L Fink et al., working out of the University of California, Santa Cruz concluded that rifampicin also inhibits α-Synuclein fibrillation and disaggregates fibrils. Government trials followed which used inadequate amounts of rifampicin for an inadequate time [3]. Yet such trials could not rule out a therapeutic role for its use in mild to moderate AD and the authors encouraged more research in this area.

In the meanwhile, a 2012 Journal of Alzheimer’s disease study pointed also to the enhanced brain amyloid-β clearance by rifampicin and caffeine as a possible protective mechanism against AD [4]. The possible role of mycobacterial disease, a prominent genus of Actinobacteria, has been described for AD [5-7].

Takami Tomiyama revisited the preventative properties of rifampicin in AD, this time with Umeda and others in 2016, reporting that rifampicin inhibited amyloid-β oligomerization and tau hyperphosphorylation in mouse models and improved their memory in the Morris water maze [8]. The findings in mouse models indicated that rifampicin could serve as a promising available medicine for the prevention of AD. It therefore once again became of interest whether rifampicin had such preventive effects in humans. Thus by June of 2017, Iizuka et al. set out to determine this in a study using 40 patients with mycobacterial disease in which dementia had not yet set in and yet who showed AD-like hypometabolism patterns under stereotaxic statistical analysis [9]. As an important offshoot of this study, besides addressing whether rifampicin had preventative effects with AD, Iizuka’s raw data showed that in his two groups [Group A and Group B] of elderly patients with mycobacterial disease–approximately 46% of those in Group A showed Alzheimer-type hypometabolism while in Group B approximately 55% showed AD-like hypometabolism. This averages out to slightly over half of the patients with mycobacterial disease showing AD-like hypometabolism on FDG-PET.

To examine whether rifampicin has such preventive effects in humans, Iizuka retrospectively reviewed FDG-PET scan findings of elderly patients with mycobacterial infection treated with rifampicin. For over 20 years, FDG-PET [also known as 18F-FDG-PET] has been used to measure cerebral metabolic rates of glucose (CMRglc), as a proxy for neuronal activity in AD. Many studies have shown that CMRglc reductions occur early in AD, both correlating with disease progression, and predicting histopathological diagnosis [10].

In their introduction Iizuka et al. mention that AD is the most common cause of neurodegenerative dementia and is becoming increasingly common as the global population ages [11]. And that therefore, development of preventive therapy for the disease has been urgently needed. As both amyloid-β and tau were believed to play central roles in AD pathogenesis, they have been targets of disease-modifying therapy. However clinical studies of amyloid-β-targeting therapies in AD have revealed that the treatments after disease onset have little effect on the cognition of patients [12–14].

One presumable reason why rifampicin was not performing up to expectations in previous AD studies might be that the treatment of AD should have been started prior to the onset of clinical symptoms [15]. Also, rifampicin is an antibiotic, which is easy for mycobacterium to gain resistance to. To prevent the manifestation of resistance to rifampicin in mycobacterium, it should be administered with other anti-mycobacterial antibiotics as a combination therapy.

Rifampicin had been routinely administered at Iizuka’s hospital to treat mycobacterial infections such as tuberculosis (TB) and mycobacterium avium complex (MAC) for many years. Therefore, there had been accumulated data on patients treated with rifampicin, and almost half of the patients were elderly. In addition, a considerable number of the elderly patients had undergone 18F-FDG-PET including brain scans for various reasons since 2005 and since then investigators had occasionally encountered AD-type findings. Accordingly, the investigators retrospectively reviewed FDG-PET findings of elderly patients with mycobacterial infection that were treated with rifampicin and were not demented at the start of treatment to examine the preventive effects of rifampicin on the progression of AD.

Their results showed that before treatment, AD-type hypometabolism was observed in 12 patients. The FDG uptake in the posterior cingulate cortex (PCC) was improved or stabilized in 6 patients after 12-month therapy (450 mg/day), whereas another 6 patients with 6-month therapy showed a decreased FDG uptake in the PCC. In patients who underwent FDG-PET only after treatment, the metabolic decline in the PCC was significantly milder in patients with ≥12 months of rifampicin treatment than in those with 6 months of treatment. Multiple regression analysis revealed that the dose of rifampicin and treatment duration significantly influenced FDG uptake in the PCC.

Their conclusion was that the preventive effect of rifampicin depended on the dose and the treatment duration, and that the desired effect required at least 450 mg daily for 1 year.

By March 2018, still another rifampicin/AD study appeared on Medline, this one a multi-center probe, concluding, once again, that rifampicin exerts significant brain protective functions in multiple experimental AD models [16]. In this capacity rifampicin was found to have a neuroprotective and pro-cognitive effect that was mediated by its anti-inflammatory, anti-tau, and anti-amyloid effects. Beyond suggesting that rifampicin shows strong brain protective effects in preclinical models of AD, Yulug et al. also provided substantial clinical evidence for the neuroprotective and pro-cognitive effects of rifampicin. Again, further future neuroimaging studies combined with clinical assessment scores were suggested.

Just where such research dealing with anti-mycobacterial, anti-tubercular agents like rifampacin will go, no one can definitively predict. But its mere persistence suggests a continued interest on the part of more than a few.

Keywords: Alzheimer's disease, FDG-PET, Rifampicin, Amyloid-β, Oligomer, Preventive therapy

REFERENCES

[1] De Beer FC, Nel AE (1984) Serum Amyloid A-Protein and C - reactive protein Levels in Pulmonary Tuberculosis: Relationship to Amyloidosis. Thorax 30, 196–200.
[2] Tomiyama T, Asano S, Suwa Y, Morita T, Kataoka K, Mori H, Endo N (1994) Rifampicin prevents the aggregation and neurotoxicity of amyloid beta protein in vitro. Biochem Biophys Res Commun 204, 76-83.
[3] Loeb MB, Molloy, DW, Smieja M, Standish T, Goldsmith CH, Mahony J, Smith S, Borrie M, Decoteau E, Davidson W, Mcdougall A, Gnarpe J, O'donnell M, Chernesky M (2004) A Randomized, Controlled Trial of Doxycycline and Rifampin for Patients with Alzheimer's Disease. J Am Geriatr Soc 52, 381–387.
[4] Qosa H, Abuznait AH, Hill RA, Kaddoumi A (2012) Enhanced Brain Amyloid-β Clearance by Rifampicin and Caffeine as a Possible Protective Mechanism Against Alzheimer’s Disease. J Alzheimers Dis 31, 151-165.
[5] Broxmeyer L (2017) Are the Infectious Roots of Alzheimer’s Buried Deep in the Past? J MPE Mol Pathol Epidemiol 3, 2. http://molecular-pathological-epidemiology.imedpub.com/are-the-infectious-roots-of-alzheimersburied-deep-in-the-past.pdf
[6] Broxmeyer L (2017) Dr. Oskar Fischer’s Curious Little Alzheimer’s Germ. Curr Opin Neurol Sci 1, 160-178. https://scientiaricerca.com/srcons/SRCONS-01-00026.php
[7] Broxmeyer L (2016) Alzheimer's Disease–How Its Bacterial Cause Was Found and Then Discarded. CreateSpace Independent Publishing Platform (August 3, 2016). 190 pages. ISBN-10: 1491287357; ISBN-13: 978-1491287354.
[8] Umeda T, Ono K, Sakai A, Yamashita M, Mizuguchi M, Klein WL, Yamada M, Mori H, Tomiyama T (2016) Rifampicin is a candidate preventive medicine against amyloid-β and tau oligomers. Brain 139, 1568–1586.
[9] Iizuka T, Morimoto K, Sasaki Y, Kameyama M, Kurashima A, Hayasaka K, Ogata H, Goto H (2017) Preventive Effect of Rifampicin on Alzheimer Disease Needs at Least 450 mg Daily for 1 Year: An FDG-PET Follow-Up Study. Dement Geriatr Cogn Disord Extra 7, 204-214. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5498941/
[10] Mosconi L, Berti V, Glodzik L, Pupi A, De Santi S, de Leon MJ (2010) Pre-Clinical Detection of Alzheimer’s Disease Using FDG-PET, with or without Amyloid Imaging. J Alzheimers Dis 20, 843-854.
[11] Alzheimer’s Association (2016) 2016 Alzheimer’s disease facts and figures. Alzheimers Dement 12, 459–509.
[12] Iizuka T, Kameyama M (2017) Cholinergic enhancement increases regional cerebral blood flow to the posterior cingulate cortex in mild Alzheimer’s disease. Geriatr Gerontol Int 17, 951-958.
[13] Iizuka T, Kameyama M (2016) Cingulate island sign on FDG-PET is associated with medial temporal lobe atrophy in dementia with Lewy bodies. Ann Nucl Med 30, 421–429.
[14] Molloy DW, Standish TI, Zhou Q, Guyatt G; DARAD Study Group (2013) A multicenter, blinded, randomized, factorial controlled trial of doxycycline and rifampin for treatment of Alzheimer’s disease: the DARAD trial. Int J Geriatr Psychiatry 28, 463–470.
[15] Sperling RA, Jack CR Jr, Aisen PS (2011) Testing the right target and right drug at the right stage. Sci Transl Med 3, 111cm33.
[16] Yulug B, Hanoglu L, Ozansoy M, Isık D, Kilic U, Kilic E, Schabitz WR (2018) Therapeutic role of rifampicin in Alzheimer's disease. Psychiatry Clin Neurosci. 72, 152-159.

It is always of critical importance to scrutinize biomedical studies for accuracy, especially those even suggesting benefits of novel applications for widely used medications. An example is a 2018 retrospective Taiwanese study in which Tzeng claims that patients with HSV infections ‘may have’ a 2.56-fold increased risk of developing dementia. Furthermore, and more appropriate to the title of his paper (Anti-herpetic Medications and Reduced Risk of Dementia in Patients with Herpes Simplex Virus Infections-a Nationwide, Population-Based Cohort Study in Taiwan), Tzeng claimed that the usage of anti-herpetic medications was associated with a decreased risk of dementia. However imperfections in the study suggest the need for a more controlled study. For example, in the HSV-group merely 13.7% (1147 in 8362) did not receive anti-herpetic medications.

Also, in January of 2006, Catherine Helmer first published a similar study: Herpes simplex virus, anti-herpetic medication, and dementia: Results from the three-city population-based cohort. But Helmer et al. concluded that their results regarding anti-herpetic medications were “not significant” for lessening dementia. Helmer presented this paper once again, this time for Alzheimer’s & Dementia in July, 2015.

Reference:
Broxmeyer L, Perry G. Alzheimer’s: Do Anti-Herpetics Reduce the Risk of Dementia and if so, Why? Current Opinions in Neurological Science. 2:6 (2018):594-598. http://scientiaricerca.com/srcons/SRCONS-02-00082.php https://scientiaricerca.com/srcons/pdf/SRCONS-02-00082.pdf

A 2018 study by Tricco et al. ranking the safety and effectiveness of the four leading drugs now taken to enhance concentration, memory, alertness and moods in, found that donepezil (Aricept®) was most likely to effectively improve cognition in patients with Alzheimer’s dementia. However, patients who took donepezil were more likely to experience side effects including nausea, vomiting and diarrhea than those who received a placebo, according to the study, published online in the Journal of the American Geriatrics Society [1]. And an earlier study showed that almost 19% of patients in an Aricept 23 mg daily group discontinued treatment due to side effects [2]. The fact is that as for all conventional drugs used in Alzheimer’s treatment –only a small percentage of AD victims are helped by them. Yet, in both the case of FDA approved and alternative treatments presently available, much can be gleaned by scrutinizing which pathogen or pathogens the bulk of their activity is directed towards. It seems that several compounds said to have effects upon the neuronal systems in Alzheimer’s may also exert influence through other mechanisms, such as antimicrobial actions.

Reference: Broxmeyer L. “Alzheimer’s FDA Approved Drugs & Alternatives: What are They Really Treating?” Current Opinions in Neurological Science 3.1 (2018): 613-623. DOI: 10.5281/zenodo.2247890. https://scientiaricerca.com/srcons/pdf/SRCONS-03-00085.pdf   https://scientiaricerca.com/srcons/SRCONS-03-00085.php

Dr. Lawrence Broxmeyer MD1* and Dr. George Perry PhD2

1 Chief Scientist of the New York Institute of Medical Research, USA
2 Professor and Chief Scientist of the Brain Health Consortium. Semmes Foundation Distinguished University Chair in Neurobiology, the University of Texas at San Antonio (UTSA)

As in the case of other CNS infectious agents claimed to cause Alzheimer’s disease (AD), the theory that Herpes Simplex Virus or any other herpes virus causes AD is still controversial. In their 2013 review, Mawanda and Wallace’s Can Infections Cause Alzheimer’s Disease [1] gave seven annotated references as to why HSV-1 “remains questionable” as a cause for Alzheimer’s. Some say that Herpes simplex virus type 1 in conjunction with APOE-epsilon 4 allele is a strong risk factor for AD, though either of these features alone do not increase the risk for AD. It is claimed that people who have symptoms of late onset AD and have one or more APOE-ε4 gene copies are more likely to have AD. However, APOE-ε4 is not diagnostic of AD and should not be used to screen people or their family members. Furthermore, many of those who have e4 alleles will never develop AD. And even in symptomatic people, only about 60% of those with late onset AD will have APOE-ε4 alleles [2,3]. Not only is the APOE gene not a clinical diagnosis, but just as importantly, “negative” results do not confer later protection. Beyond APOE, there are at least 20 other genetic factors which have been shown to have a small but significant role in determining Alzheimer risk [4]. And true understanding of genetic test results also requires attention to potential inaccurate results. For example, APOE-ε4 alleles themselves are known to show a distinct increase in tuberculosis [5]. Before widespread institution of anti-herpetics is unleashed on the general population, this is an area which requires further research. 

Citation: Lawrence Broxmeyer and George Perry. “Alzheimer’s Disease: Questions Raised by a Herpes Virus Origin”. Current Opinions in Neurological Science 3:2 (2019): 652-660. DOI: 10.5281/zenodo.2592845.

PDF available at: https://zenodo.org/record/2592845

Recently, several mentions on the internet have been made that early 20th century Czech physician Oskar Fischer — who, along with his German contemporary Dr. Alois Alzheimer, was integral in first describing the condition — noted a possible connection between the newly identified dementia and tuberculosis. 

Actually, this is historically inaccurate:

Dr. Oskar Fischer1 linked Alzheimer's to the germ called Streptothrix, an older designation for the disease Actinomycosis, although an association between Fischer's Streptothrix and tuberculosis has recently been implied.2

References
1. Fischer O, “Miliare Nekrosen Mit Drusigen Wucherungen der Neurofibrillen, eine Regelmassige Veranderung der Hirnrinde bei Seniler Demenz,” Monatsschr f Psychiat Neurol 22 (1907): 372; O. Fischer, “Miliary Necrosis with Nodular Proliferation of the Neurofibrils: A Common Change of the Cerebral Cortex in Senile Dementia,” Monatsschrift fur Psychiatrie und Neurologie, vol. XXII, Th. Ziehen (ed). (Berlin: Karger, 1907), 361–72; In The Early Story of Alzheimer’s Disease, edited by Katherine Bick, Luigi Amaducci, and Giancarlo Pepeu (Padova: Liviana Press, 1987), 5–18.

2. Broxmeyer L. Alzheimer's Disease –How Its Bacterial Cause Was Found and Then Discarded. CreateSpace Independent Publishing Platform (August 3, 2016). 190 pages. ISBN-10: 1491287357 ISBN-13: 978-1491287354. https://www.academia.edu/25443297/THE_ALZHEIMERS_GERM_A_BOOK_ENTITLED_AL...

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