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The Impact of Diabetes on Alzheimer’s Disease

6 September 2016

Diabetes has been known to affect Alzheimer’s disease (AD) adversely [1, 2]. A recent article postulated that the mechanism for this occurrence was comprised of four underlying malfunctions. The first malfunction was described as inadequate protease production or activity secondary to severe insulin deficiency; second, that an underlying deficiency of essential proteases results in accumulation of excess amyloid; third, that high levels of insulin have been found to competitively inhibit amyloid-β (Aβ) degradation; and fourth, that processes contributing to excess production of amyloidogenic proteins are responsible for the accumulation of amyloid [3]. Here, we propose an alternate mechanism to explain the increased occurrence of AD in diabetes.

We have shown the presence of biofilms in AD brains. In fact, the pathological “plaques” that are characteristic of AD, have been shown to be comprised of biofilms [4]. Our work theorizes that these biofilms are produced by spirochetes (with 25% of those being Lyme spirochetes, and 75% dental spirochetes), which have also been shown to be present in the brains of AD patients [5,6]. In most instances, biofilm production is attributed to the phenomenon of quorum sensing, which occurs over an extended period of time (approximately 2 years), to produce one biofilm “plaque” [7]. Quorum sensing is a mechanism of signaling environmental population awareness that stimulates bacteria to exude extracellular polysaccharides that assemble into a protective and impenetrable slime. This slime functions to protect the group from noxious substances [8,9].

Although quorum sensing is believed to account for the majority of production of biofilms by bacteria in AD, there are many other methods of inducing biofilm production. We have previously demonstrated that salt and water induce biofilm production in atopic dermatitis and in tinea versicolor [10,11]. We have also postulated that sublethal doses of doxycycline allow biofilm production in Lyme disease [12]. Others have shown that acidosis both stimulates biofilm production and, interestingly, also promotes neurodegeneration in AD [3].

When accounting for co-existing diabetes, it is believed that serum hyperosmolality is the most likely largest contributing factor to biofilm production [13]. Normal blood glucose levels produced no increase in biofilm production is observed. Conversely, as the osmolality of the serum is increased, biofilm production was appreciated. These results indicate that serum hyperosmolality profoundly increases the likelihood of the process occurring, and promotes enhanced progression of these bacteria to form biofilms [13].

In such a setting, the spirochetes are not limited by the need to reach a quorum, and can immediately begin producing biofilms. Consequently, the time for plaque formation is not only markedly reduced, but larger and greater numbers of biofilms can be synthesized, without any factors limiting their progression. This mechanism would most definitely result in worsening neurodegeneration. The increased number and extent of these biofilms would promote increased activity of the innate immune system, which in turn results in increased production of Aβ [7]. Aβ accumulation and resulting neurodegeneration are what comprise AD. Thus, the entire pathogenesis of the disease is hastened, resulting in a more devastating and rapid clinical decline in cognitive function.

Just as increased biofilm formation is problematic, similarly, biofilm “breaking” (dispersing) poses many potential issues. Conceptually, the biggest problem would be the inability to clear the dispersed biofilms. The microglia may be inadequate to the task, likened to using a “shovel when a bulldozer is necessary.” Further, these organisms are all capable of making biofilms, so that, on dispersal, there is the potential for new foci of biofilm production. Even if biofilm dispersal is coupled with a bactericidal antibiotic, an overwhelming amount of biofilms, Aβ, and bacteria would still remain. This may be the process behind long-lasting Herxheimer-type reactions noted in neuroborreliosis.

Unfortunately, this dispersal process is already occurring. Donepezil, an anticholinesterase frequently prescribed in AD, is also a piperidine, which is known to cause biofilm dispersal [14]. Haloperidol, another piperidine, is not recommended in AD because it results in deterioration. Very likely, the biofilm dispersal caused by these agents is what accounts for the worsened clinical picture seen after long-term administration. Other compounds such as thiophenes, pyrroles, and furans, all have capabilities towards biofilm dispersal [15,16].

We theorize that worsening of AD cannot only be attributed to “making” biofilms, but also to “breaking” them after they already are present. Such is not the case in arthritis where biofilm dispersal coupled with bactericidal antibiotics has been shown to be useful in eliminating biofilms and eliminating clinical disease [17]. Potentially, the same approach is useful for psoriasis [18]. However, in arteriosclerosis, where biofilms have recently been shown in arteriosclerotic plaques, any rupture of the plaques could be debilitating or fatal [19].

Thus, we recommend an increased emphasis on blood glucose control and stability in order to avoid the potential for pre-existing diabetes to promote the development of AD. We have found that increased production of biofilms a well as dispersal of biofilms in an attempt to remove them, both exacerbate AD. It then becomes imperative to attempt to control for factors that promote AD prior to development of the disease. We have found that, after disease onset, even presumably effective treatment attempts may prove to be exacerbating once biofilm formation has occurred. Additionally, we recommend that the threshold for treating neurospirochetosis be greatly lowered, so as to treat before the spirochetes enter the brain and create irreversible damage via biofilm production [4].

Herbert B. Allen, Lina Husienzad, Suresh G. Joshi
Drexel University College of Medicine, Philadelphia, PA, USA. E-mail:

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