The Impact of Diabetes on Alzheimers Disease | Journal of Alzheimer's Disease Page 1 of 2

Share Us: Subscribe | Contact

Search

Welcome, Guest Join Log In

HOME JOURNAL INFO LATEST NEWS SUBMIT CONTENTS EDITORS' BLOG MEMBERS RANKINGS AND AWARDS FUNDING

Home

The Impact of Diabetes on Alzheimers Disease CURRENT ISSUE

6 September 2016

Diabetes has been known to affect Alzheimers 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- (A)
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 Volume 54, issue 2
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]. BOOKS

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. Handbook of Depression in
Consequently, the time for plaque formation is not only markedly reduced, but larger and greater numbers of biofilms can be Alzheimers Disease
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
OPEN POSITION
system, which in turn results in increased production of A [7]. A 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 Professor/Endowed Chair in Brain
function. Health at UTSA

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 ADVERTISE
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, Click here for more information
on advertising with JAD
an overwhelming amount of biofilms, A, 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: Herbert.Allen@drexelmed.edu

References
[1] Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM (1999) Diabetes mellitus and the risk of dementia: The
Rotterdam Study. Neurology 10, 1937-1942.
[2] Peila R, Rodriguez BL, Launer LJ (2002) Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The
Honolulu-Asia Aging Study. Diabetes 51, 1256-1262.
[3] Schilling MA (2016) Unraveling Alzheimers: making sense of the relationship between diabetes and Alzheimers disease. J
Alzheimers Dis 51, 961-977.

http://www.j-alz.com/content/impact-diabetes-alzheimers-disease 9/8/2016
The Impact of Diabetes on Alzheimers Disease | Journal of Alzheimer's Disease Page 2 of 2

[4] Allen HB, Morales D, Jones K, Joshi S (2016) Alzheimers disease: a novel hypothesis integrating spirochetes, biofilm, and the
immune system. J Neuroinfect Dis 7, 1.
[5] MacDonald AB (1988) Concurrent neocortical borreliosis and Alzheimers disease: demonstration of a spirochetal cyst form. Ann
NY Acad Sci 539, 468-470.
[6] Miklossy J (2016) Bacterial amyloid and DNA are important constituents of senile plaques: further evidence of the spirochetal
and biofilm nature of senile plaques. J Alzheimers Dis 53, 1459-1473.
[7] Allen HB (2016) Alzheimers disease: Assessing the role of spirochetes, biofilms, the immune system, and beta amyloid with
regard to potential treatment and prevention. J Alzheimers Dis 53, 1271-1276.
[8] Teschler JK, Zamorano-Snchez D, Utada AS, Warner CJA, Wong GCL, Linington RG, Yildiz FH (2015) Living in the matrix:
assembly and control of Vibrio cholerae biofilms, Box 2: Environmental signals controlling Vibrio cholerae biofilm formation. Nat Rev
Microbiol 13, 255268.
[9] Rutherford ST, Bassler BL (2012) Bacterial quorum sensing: its role in virulence and possibilities for its control. Cold Spring Harb
2, a012427.
[10] Allen HB, Vaze ND, Choi C, Hailu T, Tulbert BH, Cusack CA, Joshi SG (2014) The presence and impact of biofilm-producing
staphylococci in atopic dermatitis. JAMA Dermatol 150, 260-265.
[11] Allen HB, Goyal K, Ogrich L, Joshi S (2015) Biofilm formation by Malassezia Furfur/Ovale as a possible mechanism of
pathogenesis in Tinea Versicolor. J Clin Exp Dermatol Res 6, 311.
[12] Allen HB, Vin H, Warner C, Joshi S (2016) Lyme disease: beyond erythema migrans. J Clin Exp Dermatol 7, 330.
[13] Kavamura VN, Soares I (2014) Effects of different osmolarities on bacterial biofilm formation. Braz J Microbiol 45, 627-631.
[14] Kagan S, Jabbour A, Sianov E, Alguntar AA, Steinberg D, Srebnik M, Nir-Paz R, Weiss A, Polacheck I (2014) Anti-candida
albicans biofilm effect of novel heterocyclic compounds. J Antimicrob Chemother 69, 416-427.
[15] Baveja JK, Willcox MDP, Hume EBH, Kumar N, Odell R, Poole-Warren LA (2004) Furanoses as potential anti-bacterial
coatings no biomaterials. Biomaterials 25, 5003-5012.
[16] Liu H, Zhao Y, Shao D, Gong T, Wu Y, Han H Xu T, Peschel A, Han S, Qu D (2015) Antibacterial and anti-biofilm activities of
emerging microbes and thiazolidinone derivatives against clinical staphylococcus strains. Infections 4, e17.
[17] Richards JJ, Reed CS, Melendez C (2008) Effects of N-pyrrole substitution on the anti-biofilm activities of oroidin derivatives
against Acinetobacter baumannii. Bioorg Med Chem Lett 18, 4325-4327.
[18] Allen HB, Kim JY, Warner C, Joshi S (2015) Penicillin: the new/old wonder drug. J Drug Metab Toxicol 6, 4.
[19] Lanter BB, Sauer K, Davies DG (2014) Bacteria present in carotid arterial plaques are found as biofilm deposits which may
contribute to enhanced risk of plaque rupture. MBio 5, e01206-14.

Comment Bookmark Recommend Follow

JOURNAL INFO SUBMIT CONTENT RELATED LINKS SHARE

About the Journal For Authors Current Issue IOS Press Journals
Editorial Board Review Process All Issues Upcoming Meetings
Supplemental Issues Publication Fee Articles in Pre-Press Centers & Clinics
Advertising Submission Guidelines For Families Journal of Alzheimers
Subscribe Disease is published by
IOS Press
Copyright 2016

http://www.j-alz.com/content/impact-diabetes-alzheimers-disease 9/8/2016