The Microbes of Periodontitis as a Contributing Cause of Alzheimer's Disease

The open access review paper I'll point out today is good overview of current thinking on the microbial contribution to Alzheimer's disease, with a particular focus on the microorganisms involved in gum disease, or periodontitis. The past century has seen huge strides in our control over the worst of the microbial life that caused so much suffering and death to our ancestors. Nowadays, of that worst, what is left uncontrolled are those microbes whose impact is more subtle and slow, or where it is inherently challenging to intervene. Tooth decay and gum disease remain widespread because these problems typically do not kill people rapidly, and because none of the simple approaches to unwanted microbes work when it comes to removing problem bacteria from the mouth.

In Alzheimer's disease, the dominant theme for research is the aggregation of harmful proteins in the brain, and how exactly it is that these aggregates and their consequences kill cells. The dominant theme for the development of therapies is a focus on removing protein aggregates. This is a good thing for the field of medicine as a whole, as it is the case that protein aggregation is one of the causes of aging, and success in for any one such unwanted protein should eventually lead to technologies to address them all. Unfortunately, large-scale investment in this plan for Alzheimer's disease has produced only very limited positive outcomes over the last decade: many clinical trials have launched and failed. This may well be because it is intrinsically challenging to safely intervene in the brain, since our understand is still very incomplete, and the primary choice of approach, meaning forms of immunotherapy, is still a comparatively young and developing technology.

As protein aggregate clearance has progressed without any attempt reaching the clinic, a great deal of reexamination of assumptions and theorizing has taken place. In the course of this, newfound support has emerged for the role of microbes in the development of Alzheimer's. There is a solid foundation of evidence to support the view that lingering infection by microbial life capable of disrupting the biochemistry of the brain is one of the important causes of this and other neurodegenerative conditions. The bacteria of the mouth, those involved in gum disease, are a good candidate. This is particularly true given the range of evidence gathered over the years to link periodontitis to chronic inflammation, heart disease, and neurodegenerative conditions such as Alzheimer's.

Periodontitis, Microbiomes and their Role in Alzheimer's Disease

As far back as the eighteenth and early nineteenth centuries, microbial infections were responsible for vast numbers of deaths. The trend reversed with the introduction of antibiotics coinciding with longer life. Increased life expectancy, however, accompanied the emergence of age related chronic inflammatory states including the sporadic form of Alzheimer's disease (AD). Taken together, the true challenge of retaining health into later years of life now appears to lie in delaying and/or preventing the progression of chronic inflammatory diseases, through identifying and influencing modifiable risk factors.

Diverse pathogens, including periodontal bacteria have been associated with AD brains. Amyloid-beta (Aβ) hallmark protein of AD may be a consequence of infection, called upon due to its antimicrobial properties. Up to this moment in time, a lack of understanding and knowledge of a microbiome associated with AD brain has ensured that the role pathogens may play in this neurodegenerative disease remains unresolved. The oral microbiome embraces a range of diverse bacterial phylotypes, which especially in vulnerable individuals, will excite and perpetuate a range of inflammatory conditions, to a wide range of extra-oral body tissues and organs specific to their developing pathophysiology, including the brain.

This offers the tantalizing opportunity that by controlling the oral-specific microbiome; clinicians may treat or prevent a range of chronic inflammatory diseases orally. Evolution has equipped the human host to combat infection/disease by providing an immune system, but Porphyromonas gingivalis and selective spirochetes, have developed immune avoidance strategies threatening the host-microbe homeostasis. It is clear from longitudinal monitoring of patients that chronic periodontitis contributes to declining cognition.

Undoubtedly, a complex etiology underlies the clinical manifestations seen in AD. Candidate microbes conforming to the AD microbiome would be those that induce immunosuppression, are pathogenic, are able to evade the innate and adaptive immune recognition, incite local inflammation and are incapable of allowing entry of activated peripheral blood myeloid cells in the brain. The periodontal microbiome does concur with the type of expected bacteria in AD brains. As an analogy to the dysbiotic periodontal microbial communities driving periodontal disease, the AD microbiome may reflect similar traits.

One such example is the keystone periodontal pathogen P. gingivalis, which is a master immune evader and an immunosuppressor of the host through IL-2 suppression. Although P. gingivalis lacks the curli gene, it has alternative inflammatory mechanisms to indirectly activate β secretases and contribute to host derived Aβ as well as correlate with loss of mental function. A recent systematic review and a 16-year follow-up retrospective cohort study significantly link 10-year exposure to chronic periodontitis as a risk factor for AD. These reports, together with effort from other researchers firmly places periodontitis as a risk factor for AD.

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