Observational study sheds light on the mechanisms driving Alzheimer’s disease progression. Can a relatively simple intervention help slow cognitive decline?
This is part of the October 2016 Special Issue on Immunology. Read the full issue or download it.
Ide M, Harris M, Stevens A, et al. Periodontitis and cognitive decline in Alzheimer's disease. PLoS One. 2016;11(3):e0151081.
Observational cohort study
Investigators recruited 60 nonsmoking adults with mild to moderate dementia from referrals to community memory assessment services in the United Kingdom. All participants had a minimum of 10 teeth and had not been treated for periodontitis in the 6 months prior to the study. Fifty-two participants completed the study.
To observe any associations between periodontitis and dementia severity, rate of cognitive decline, or chronic inflammation in adults with mild to moderate Alzheimer’s disease.
Cognitive status of participants was tested using both the Alzheimer’s Disease Assessment Scale (ADAS-cog) as the primary cognitive outcome and the standardized Mini-Mental State Examination (sMMSE) as a secondary cognitive outcome. At baseline, venous blood was tested for C-reactive protein (CRP), the pro-inflammatory cytokine tumor necrosis factor (TNF) α, the anti-inflammatory cytokine interleukin (IL)-10 and immunoglobulin G (IgG) antibodies to P. gingivalis. Dental health was assessed by a dental hygienist, blind to cognitive testing outcomes, to determine the presence or absence of periodontitis following established Centers for Disease Control and Prevention/American Academy of Periodontology (CDC/AAP) case definitions. All assessments were performed at baseline and repeated at 6 months.
The presence of periodontitis at baseline was not related to baseline cognitive state but was associated with a 6-fold increase in the rate of cognitive decline (P=0.005). There was no correlation between carriers and noncarriers of apolipoprotein E (ApoE) allele and baseline periodontitis or cognitive decline. Baseline antibody levels to P. gingivalis were not statistically associated with cognitive outcomes. Periodontitis at baseline was associated with a relative increase in the pro-inflammatory state (CRP, TNF-α) and decrease in the anti-inflammatory state (IL10) over the 6-month follow-up period. Periodontitis was associated with an increase in cognitive decline in Alzheimer's disease (AD), independent of baseline cognitive state, which may be related to systemic inflammation.
First, these data hold out the possibility that improving dental hygiene might slow the rate of cognitive decline in AD. Second, these data support a new theory that AD is in part an immune response to infection.
Several earlier studies have reported that AD patients have worse dental health than control subjects of similar ages and that the worse the dementia, the worse the dental health.1,2 The obvious assumption was that this was due to poorer self-care with advancing dementia, (ie, people were forgetting to brush their teeth).3
These data support a new theory that AD is in part an immune response to infection.
This study did not find a clear relationship between the dementia severity and periodontitis, but that may be because patients with severe dementia were not included in the cohort. This is the first study that correlates rates of declining cognitive function with poor dental health. Knowing that periodontitis was associated with faster cognitive decline during this study’s 6-month follow-up period suggests that we should be far more proactive with patients showing early signs of AD and insist on aggressive dental care.
While we may look for other explanations for this association, the most obvious one, that periodontitis drives Alzheimer’s disease progression, makes the most sense in light of other recent research and the newer hypothesis that suggests AD is an immune reaction to infection.
In May 2016, Science Translational Medicine published a paper by Harvard researcher Deepak Kumar and colleagues that suggested that the amyloid proteins that are the hallmark of AD normally serve an antimicrobial function, protecting the brain against infection. Their theory is that infections, in particular mild infections, combined with increased permeability of the blood brain barrier (BBB), elicit an over-response by the brain’s defensive mechanism that in its enthusiasm generates an overabundance of amyloid plaque. Amyloid beta, the substance that forms the plaque of Alzheimer’s disease, may in fact have a purpose in the brain. It is a defense mechanism against infection and is now described as “primary effector molecules of innate immunity, antimicrobial peptides (AMPs), also called host defense peptides.”4
When a virus, fungus or bacteria slips across the BBB, the brain generates amyloid material that surrounds and traps the invader. The amyloid cocoons the interloper into a cage. Even after the invader dies, the trap remains in place, forming permanent plaque deposits in the brain. The Harvard team has demonstrated this process occurring in vitro, to date. The study currently under review lends support to this theory, with its preliminary finding of an association between periodontitis and AD in humans.
There are several other examples of chronic infections associated with AD. In September 2016, Shim et al reported that elevated Epstein-Barr Virus (EBV) antibody levels are associated with cognitive decline, and went so far as to suggest EBV antibody levels might be used as a biomarker for assessing rate of disease progression.5 Herpes simplex virus-1 antibody titers also share a similar association with cognitive impairment.6
A similar association has been seen with bacterial infections in numerous studies. A meta-analysis of 25 separate studies, published in August 2016, found significant associations between both Chlamydia pneumoniae and spirochetal bacteria with AD. Spirochetal infections were associated with a 10-fold increased occurrence of AD (OR: 10.61; 95% CI: 3.38-33.29). A greater than 5-fold increase in risk of AD was seen with Chlamydia infection (OR: 5.66; 95% CI: 1.83-17.51).7
It may not be the type of infectious agent as much as the chronicity or persistence of the infection that provokes the AD triggering response in the brain. It may take continuous antigen exposure to trigger the amyloid response.8
Another paper published in August 2016 expands this hypothesis, suggesting that the chain of events that leads to AD starts in the gut with intestinal microbiota increasing intestinal permeability and in turn increasing permeability of the BBB. This in turn presents more antigenic material to the brain that triggers the amyloid beta producing reaction.9
Noting the many studies that have associated herpes antibody levels with AD, Ruth Itzhaki, writing in August 2016 in the Journal of Alzheimer’s Disease, suggested we consider “the usage of antiviral treatment to slow or halt the progression of AD.”10
Thus we could be fast entering a new era in how we view Alzheimer’s disease, one in which we both understand the underlying mechanisms and also have some simple interventions to offer our patients, starting with reminding them to brush their teeth.