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