The Impact of Biofilms in Alzheimer’s disease compared to Other Diseases in Which They Play a Role

Allen HB, Cusack CA and Joshi SG

Published on: 2019-12-26


Herein we present the findings related to biofilms in Alzheimer’s disease and compare them to known findings related to biofilms in other chronic diseases. Similarities include microbes making the biofilms both intra and extracellularly, the interaction of the innate immune system in many instances, the devastating impact of the adaptive immune system, and the devastating impact resulting from the various genes involved. Differences include location, the production of beta amyloid, neurofibrillary tangles, and hyperphosphorylated tau protein. The diseases compared include atopic dermatitis, psoriasis, tinea versicolor, leprosy, gout, rheumatoid arthritis and other arthritides.


Alzheimer’s disease; Abeta; extracellularly


We have recently shown that biofilms created by Lyme and dental spirochetes play an etiologic role in Alzheimer’s disease [1]. In affected brains, spirochetes have been seen with bright field microscopy and identified by culture and/or polymerase chain reaction [2,3]. In pure culture, Borrelia burgdorferi from the affected brains have been shown to make beta amyloid (Abeta) and beta amyloid precursor protein at the same time they create biofilms [4]. This has been demonstrated in vivo as well [5]. The in vivo observation was made with biofilms found both intracellularly and extracellularly. Further, it has been shown that biofilms and Abeta found intracellularly lead to neurofibrillary tangles because Abeta together with ordinary tau protein leads to the production of hyperphosphorylated tau (p-tau) [6]. The p-tau is unable to stabilize dendrites as does ordinary tau [7]. The affected dendrites subsequently degenerate, and this leads to neurofibrillary tangles and neuronal cell death [8]. The extracellular biofilms are present in the senile plaques which are made up of biofilms that are coated with Abeta [9]. These extracellular biofilms are made not only by spirochetes that are in the extracellular space, but also by those that are extruded when the neuronal dendrites disintegrate, and the intracellular organisms are now found extracellularly.

Consequently, the extracellular Abeta derives not only from that which was once intracellular, but also from the impact of the innate immune system molecule Toll-like receptor 2 (TLR2) that has been shown to be upregulated by biofilm [10]. Utilizing known pathways, TLR 2 leads to nuclear factor kappa B (NFkB) which catalyzes Abeta converting enzyme that, in turn, catalyzes beta and gamma secretase that convert beta amyloid precursor protein to Abeta [11]. Thus, the Abeta is made by the microbes when they make biofilms and by the reaction of the immune system to the biofilm. The same pathological findings found in Alzheimer’s disease are also present in syphilitic dementia, general paresis (GP) [12]. Thus, the two diseases, Alzheimer’s disease and GP, are similar both clinically and pathologically. The only difference is different spirochetes in each disease. Presumably, Alzheimer’s disease would respond similarly to the administration of penicillin as in GP if given before the onset of tertiary spirochetosis [13].

By contrast, the chronic skin disease tinea versicolor caused by Malassezia furfur/ovale is a biofilm disease that creates no symptoms, only color change and skin peeling [14]. This is because the biofilms form in the stratum corneum of the epidermis that is devoid of live cells, and consequently cannot generate an immune response. Tinea versicolor becomes a superb control as a biofilm that has no immune interaction. Atopic dermatitis (eczema), on the other hand, is a chronic skin disease in which extracellular biofilms made by normal flora staphylococci form in the eccrine sweat glands, upregulate TLR 2, activate PAR 2 (a potent pruritogen), and create the typical rash[15]. Eczema has been termed “the itch that rashes.” This disease is a double-hit phenomenon with the gene being filaggrin (or similar) and the environmental component being the staphylococcal biofilms occluding the sweat ducts [16]. Without the genetic component, the patients get “miliaria” from the sweat duct occlusion. All the various forms of eczema (flexural, facial-extensor, dyshidrotic, etc.) show the same pathological and microbiological findings [16]. Diseases thought to have an eczema component such as Doucas Kapetanakis disease and Meyerson’s nevus also have similar pathology [16]. Certain skin diseases not thought to be eczema, such as seborrheic dermatitis, granular parakeratosis, and tinea pedis also have the same pathology and the same microbiology (occluded sweat ducts filled with staphylococcal created biofilms). In these disorders, the derangement of the stratum corneum from Malassezia yeasts in seborrheic dermatitis, and minute granules in granular parakeratosis, and fungal hyphae in tinea pedis causes similar changes in the stratum corneum as does the filaggrin gene that creates a faulty outer layer of the integument [17]. The innate immune response leading to the intense itching is followed by the adaptive response once the basement membrane is breached. This is similar to the situation in Alzheimer’s disease when the blood brain barrier is breached as in stroke, and the adaptive immune system floods the brain [18]. This leads to dementia in 1-3 years as opposed to the 20-30 years with the ordinary progression of Alzheimer’s disease [18]. Psoriasis differs from eczema in that the biofilms are made by Streptococci and are located in the tonsils and not the skin [19]. The biofilms are found both intra and extracellularly. Further, both arms of the immune system (innate and adaptive) are involved [20,21]. Psoriasis is also a double-hit disease with the genetic factor being one of the PSORS genes (or others) and the environmental component the streptococcal-created biofilms [19]. Without the gene, patients can have an elevated circulating anti streptococcal IgG and no psoriatic lesions unlike their counterparts with plaque psoriasis (cf controls in El Rachkidy’s monumental work).

An important comparison with psoriasis and Alzheimer’s disease is the comparison of treatment with biologics such as adalimumab with the various molecules that attempted to limit the production of Abeta. The adalimumab inhibits tumor necrosis factor alpha (TNFa), a late appearing cytokine in the pathway generated by the immune system; this biologic is extraordinarily effective in eliminating the symptoms and signs of psoriasis. However, the skin can restore and regenerate itself whereas the molecules attempting to diminish Abeta, by acting similarly late in the cascade of events, are “doomed” to failure because the neurons cannot regenerate or be restored. Further, only the extracellular material could be addressed and no intracellular biofilms or Abeta could be targeted. This is problematic because the intracellular biofilms and Abeta likely play the leading role in Alzheimer’s disease [22]. Leprosy is a chronic cutaneous biofilm disease caused by Mycobacterium leprae; the biofilms are situated extracellularly in the lever, spleen, and kidneys and not in the skin until late in lepromatous leprosy. At this stage, very large histiocytes (globi) are present in the dermis and are filled with acid fast microbes and biofilms [23]. The immune system is activated and leads too much of the damage to much of the peripheral nerve system damage noted in this biblical disease [24]. Leprosy has nearly disappeared over the past 40 years (incidence of 15 million in 1975 vs 800,000 in 2015). This is largely due to the addition of rifampin, a biofilm disperser (“buster”), to the therapeutic regimen. It was added because the organisms were becoming resistant to Dapsone, and, consequenty, this was added simply as another antibiotic. This was a fortuitous choice because rifampin clearly offered more; but, only recently, has its true nature been revealed [25].

Similar treatment (penicillin/rifampin) for Alzheimer’s disease would be ineffective because, as with the biologics mentioned previously, it is too late in the course of the disease to be helpful. However, preventive treatment periodically with penicillin has been suggested as a rational measure. Penicillin crosses the blood brain barrier, travels intracellularly, and is bactericidal to sensitive microbes [26]. All spirochetes are such microbes, and where the comparator disease (GP) has been eliminated by penicillin, it seems both rational and ethical to consider similar treatment. Whether rifampin and penicillin might have a useful impact in very early disease would require a clinical trial with the penicillin/rifampin compared to one of the anticholinesterase drugs currently in use. The best known and studied biofilms are dental biofilms, and these generally have multiple organisms in the agglomerations. The main ones joining the dental spirochetes are Streptococcus mutans and porphyromonas [27]. The skin biofilms, in which there is definitive, microbiology show them to be monomorphous. It is likely that the biofilms in the Alzheimer’s brains are more similar to the dental biofilms rather than those in the skin. Chlamydia pneumoniae, herpes simplex, and porphyromonas gingivalis have all been shown to be present in Alzheimer’s brains along with the spirochetes [28-30]. It is likely that the spirochetes play a dominant role in these brains for many reasons. Among them is the pathology which is “helical” and not coccoid, rodlike, or viral [12]. Next, C. pneumoniae and HSV have never been shown to make biofilms and that is an important consideration because biofilms play an etiologic role in the disease. Third, C. pneumoniae and HSV are obligate intracellular microbes so they would not be able to form the extracellular biofilms that make up the senile plaques. Further, biofilms of one microbe have attachment sites for other organisms; this has been shown with 3-D confocal microscopy to be the case in Borrelial biofilms which encase C. pneumonia [31]. Further, with the pathology of GP and Alzheimer’s disease being the same, and with the brains teeming with spirochetes, it is likely that GP is an exceedingly good prototype for Alzheimer’s, and inasmuch as GP has been eradicated by penicillin, it is a very strong possibility that pre Alzheimer’s disease would respond similarly. Whether the multi-organism biofilm renders the process even more difficult to treat is unknown.

As mentioned previously HSV has not been shown to make biofilms, even though it is very likely it does. Other viruses have; Molluscum contagiosum virus and oncogenic human papilloma virus (HPV) have been shown to make biofilms in their skin lesions [32,33]. These are intracellular and the biofilm is present in the epidermal cells. Because of their intracellular location, they do not activate either arm of the immune system; this is corroborated by the lack of symptoms in the lesions of either disease. The HPV biofilms have been found in organ transplant patients of color in non-sun exposed skin. The lesions were pathologically determined to be squamous cell carcinoma in situ, and 6/9 of the lesions stained positive immunohistochemically for HPV [16,18] in the epidermal cells. No extracellular biofilm was noted in either disease. Consequently, in considering brain tissue, HSV is likely a co-conspirator at most in Alzheimer’s disease because it is unable to create extracellular biofilms. In the skin, Molluscum virus and HPV are thought to “hijack” the epidermal cell’s DNA to create biofilms [33]. Arthritis, in all its forms, has been shown to be a biofilm disease [34]. We recently have found biofilms in cutaneous gouty tophi and in rheumatoid arthritis nodules [35]. These biofilms were different in their nature because they had a more acidic biomass [35]. This milieu favors gram negative organisms, but the microbiology has not yet been done. The lesions clinically were asymptomatic which likely accounted for their not activating the innate immune system.

What we have attempted to show in this work is that Alzheimer’s disease is similar to other chronic diseases relating to the impact of biofilms on disease progression. The innate immune system is upregulated in Alzheimer’s disease and eczema; the adaptive immune system is activated in psoriasis and leprosy and in Alzheimer’s disease after stroke. Intracellular biofilms have been seen in MC, psoriasis, squamous cell carcinoma in situ, and Alzheimer’s disease. Extracellular biofilms have been seen in eczema, psoriasis, leprosy, tinea versicolor, rheumatoid arthritis nodules, gouty tophi and Alzheimer’s disease. The diseases evoked by the different organisms are different even though the microbes all make biofilms. Much of the difference is related to location, the organs involved, and which arm of the immune system is activated. Another factor is the presence (or lack) of a gene, especially in a double-hit disease. It is obvious that Alzheimer’s disease differs from the other chronic diseases in the production of Abeta, p-tau, and neurofibrillary tangles. It does not differ with regard to the adaptive immune system creating more destruction than the innate (cf stroke), and it does not differ in regard to the impact of a gene (cf AD 7) also creating destruction.


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