Curmudgeon’s Corner
By Jacob Schor, ND, FABNO
Back in November 2020, a federal panel of medical experts refused to endorse a new drug for Alzheimer’s disease, saying that the evidence wasn’t persuasive enough. However, half a year later, in June 2021, the FDA went ahead and approved this same drug, aducanumab. Even if you pay little attention to pharmaceutical current events, you may have heard the uproar over this decision and how members of the expert committee have resigned as a result. Even if you aren’t prone to believing conspiracy theories, it’s hard not to wonder what motivated the FDA to make this choice that goes strongly against both expert opinions and common sense.
Treatment with aducanumab is expected to cost patients over $50,000 a year. In theory the drug will slow progression of Alzheimer’s disease by clearing amyloid plaques from the brain. For years, the accepted theory has been that these plaques disrupt cognition. Prior drugs developed to clear amyloid plaque have not improved symptoms or slowed the disease and have not been approved by the FDA. Biogen, the company behind aducanumab, claims that the drug was useful in high doses for late-stage disease. Biogen reworked data from previously discounted studies in which the drug was ineffective to show slight possible improvements. “The average degree of improvement on a 0-18 point cognitive scale was just 0.39 points relative to placebo, far smaller than the 1 or 2 point threshold typically used to define a clinically important difference…”[1]
The commotion questioning why the FDA has taken this step to approve an expensive drug with considerable side effects while there are grave doubts whether it is helpful at all have obscured news coverage of several recent studies on Alzheimer’s disease that really do deserve our attention. These studies question whether the amyloid plaque theory of AD is true and should have weakened enthusiasm for Biogen’s drug further.
Let’s back up to 2016 and recall a paper by Mark Ide et al published in March of that year on periodontitis and Alzheimer’s disease.[2] Ide and colleagues at Guy’s Hospital in London followed sixty non-smokers, who had not been treated for periodontitis in the prior six months and who had mild to moderate dementia. The goal was to see if there was an association between disease symptoms, chronic inflammation, and rate of cognitive decline. The study participants diagnosed with periodontitis at the start of the study declined more rapidly than those without this disease; periodontitis was associated with a six-fold increase in the rate of cognitive decline.
Ide’s results supported a new theory that AD is an immune response to infection. Up to this point the association between periodontal disease and cognitive decline was known but the assumption was that it was a case of inverse causation, that AD caused periodontitis because people who can’t remember things don’t remember to brush their teeth.[3],[4],[5] Ide et al was the first study to correlate the rate of cognitive decline with poor dental health and suggested the association went the other way, that poor dental health causes mental decline.
In May 2016, Deepak Kumar and colleagues at Harvard suggested that the amyloid proteins, which are the hallmark sign of AD, serve an antimicrobial function protecting the brain against infection. Kumar suggested that some form of chronic infection triggers an over response by this defense system triggering excessive amounts of amyloid plaque to be generated. Amyloid-Beta might be made by the brain for a good reason. It helps fight infection; Kumar described amyloid as “… primary effector molecules of innate immunity, antimicrobial peptides (AMPs).”[6] When bacteria or viruses slip across the blood brain barrier, the brain generates amyloid-Beta to trap the invaders. Amyloid literally cages the bacteria, surrounding them in a matrix, preventing further invasion. The problem is that the plaque remains after the bacteria die, forming long lasting deposits. While Kumar demonstrated this process in Petri dishes, Mark Ide’s periodontitis study was the first study involving humans to support this idea.
Over the last two years several significant studies have been published that lend further support to this idea that periodontal disease is causatively associated with AD. A significant study by May Beydoun and a team of researchers from the National Institute on Aging (NIA) was published in 2020. They examined whether gum disease and infections with oral bacteria were linked to dementia diagnoses by using data from the third National Health and Nutrition Examination Surveys (NHANES III) that was linked with National Death Index and Medicare data. The team compared different age groups at baseline, with up to 26 years of follow-up, for more than 6,000 participants.
The NHANES participants had received a dental exam for signs of gum disease. In addition, the participants received blood tests for antibodies against causative bacteria. The team analyzed antibodies against 19 oral bacteria seeking an association with Alzheimer’s, any kind of dementia, or death from Alzheimer’s.
The data revealed that older adults with signs of gum disease and mouth infections were more likely to develop Alzheimer’s disease in the future. Both Alzheimer’s diagnoses and deaths were associated with antibodies against the oral bacterium P. gingivalis, which is the most common cause of periodontal disease.[7]
A second important study, one by Schwahn et al, looking at the association between these two diseases was published in May 2021.[8]
Schwahn’s team simulated a controlled clinical trial by utilizing recently developed statistical models that allowed them to combine data from treated and untreated patients from two different population cohorts. They shuffled data from 409 untreated participants in the Study of Health in Pomerania (SHIP), a cohort recruited in 1997 to track the effect of dental disease on general health, together with data from 177 patients who underwent periodontal treatment in the Greifswald GANI-MED study. Magnetic resonance imaging (MRI) was used to stage onset of Alzheimer’s disease. All patients were younger than 60 at the time of their MRI examination that occurred a mean of 7.3 years after periodontal treatment.
Treatment of periodontal disease years prior to AD onset was associated with a significant reduction in loss of brain matter. Brain atrophy in treated patients was lower, (-0.41; 95% CI: -0.70 to -0.12; P = .0051), a shift from the 50th to the 37th percentile of the outcome distribution.
While the FDA is defending their approval of an expensive drug that probably won’t do patients any good, the theory of what causes AD is quietly shifting. The idea that treating the amyloid will cure the disease is now doubtful. This new hypothesis suggests chronic inflammation and microbial infection of the brain lead to Alzheimer’s disease. Instead these bacteria, P. gingivalis, which have been detected in the brain tissue of AD patients, should be the target for disease prevention. While recent experiments in mice suggest that P. gingivalis has a causative role,[9] these studies by Schwahn et al have brought us to the point that we can talk about treating periodontal disease to prevent AD.
Proving that this association is causative in humans is a challenge. Both diseases, AD and periodontitis, have many risk factors in common, including age, obesity, smoking, diabetes, alcohol, depression, stress and education. Cognitive decline, as mentioned, raises risk for poor oral hygiene so people with AD tend to have more periodontal disease.[10],[11] Sorting through this tangle of associations and relationships has made discerning causation difficult. The greatest challenge to clarifying the relationship though is ethical. One cannot ethically withhold a medical intervention, in this case dental care, when doing so may cause disease, in this case Alzheimer’s disease.
This ethical necessity has left us to rely on observational studies. That’s why Schwahn’s statistical manipulations have us paying attention; they simulate a clinical trial and may be as close as we get to a randomized clinical trial to test the hypothesis.
These findings strongly suggest that a timely intervention and treatment of periodontal disease may have a significant benefit in future years. It reinforces our understanding of whole-body medicine and reminds us that the etiology of disease may be complex and, in many circumstances, we need to act together with other healthcare providers. In this instance, actively getting our patients to see dentists and dental hygienists is good preventive medicine. Periodontal disease is caused by plaque formed by bacterial biofilms.
It may be more complicated. The chain of events that leads to AD may actually start in the gut with intestinal microbiota. An August 2016 paper hypothesized that gut dysbiosis increases intestinal permeability, which, in turn, increases blood brain barrier permeability that in turn bring more antigenic material to the brain and that this surge triggers the amyloid beta production.[12]
If the new hypothesis holds true, efforts to prevent AD should focus on preventing biofilm formation that develops into dental plaque rather than dissolving amyloid deposits. Our role as naturopathic doctors may be to suggest diets and supplements that decrease dental biofilm and to reduce periodontitis.[13]
While certain diets may reduce biofilm formation, they do not remove it. Biofilm adheres to the teeth tightly and cannot be rinsed away. Physical removal is required either with a toothbrush or those dental scraping tools that make me weak in the knees even thinking about them. Thus, no matter how compliant your patient is with diet and supplements, their good behaviors will not replace the need for dental treatment.
Rowinska and colleagues, in a comprehensive review of dental infections, suggest a diet that isn’t that different from what we generally consider a healthy diet that avoids simple sugars and refined carbohydrates while emphasizing vegetables and fresh fruit, and that is high in antioxidants, essential fats, fiber and collagen.[14],[15] As far as specific nutritional supplements, Rowinska suggests among other things, coenzyme Q-10, green tea, and quercetin.[16],[17]
While reducing P. gingivalis exposure remains key to controlling periodontal disease, reducing stress may be nearly as important.[18],[19] People with high levels of stress and poor coping skills have twice as many periodontal diseases as people with minimal stress and good coping skills. There is a relationship between cortisol levels and severity of periodontal disease. Oxidative stress may be just as important as emotional stress on degree of periodontal disease.[20] We were already aware that stress is associated with Alzheimer’s disease. Americans living under high psychological distress are nearly twice as likely to die of AD than those with lower stress levels.[21]
This reminds me of a 2010 paper that reported that individuals who were primary caretakers of a spouse with Alzheimer’s disease were at much higher risk to also suffer from eventual dementia.[22] The explanation tendered was this effect was due to stress. I recall wondering at the time whether it might be some sort of infectious etiology. The spousal risk was so high, about double or triple that of someone suffering from PTSD.
A Mediterranean diet and exercise may be helpful in preserving cognitive function.[23] The idea that such lifestyle interventions may also improve periodontal disease is quite plausible[24],[25] and has been examined but not definitively proven. Consuming olive oil may lower risk of periodontitis.[26] What we offer as naturopathic doctors certainly may be helpful,[27] but alone does not appear sufficient.
Schwahn et al strengthens the argument that periodontal disease contributes to development of Alzheimer’s disease and that early intervention to prevent periodontal disease can also decrease incidence of AD. A healthy diet, of course, helps, and certain supplements may be useful; but routine dental checkups and proper oral hygiene performed by the patient may be the foundation for prevention.
[1]. https://www.washingtonpost.com/outlook/2021/06/10/alzheimers-drug-patients-price/
[2]. Ide M, et al. Periodontitis and Cognitive Decline in Alzheimer’s Disease. PLoS One. 2016 Mar 10;11(3):e0151081.
[3]. Kamer AR, et al. Periodontal inflammation in relation to cognitive function in an older adult Danish population. J Alzheimers Dis. 2012; 28: 613–624.
[4]. Martande SS, et al. Periodontal health condition in patients with Alzheimer’s disease. Am J Alzheimers Dis Other Demen. 2014; 29: 498–502.
[5]. Syrjala AM, et al. Dementia and oral health among subjects aged 75 years or older. Gerodontology. 2012; 29: 36–42.
[6]. Kumar DK, et al. Alzheimer’s disease: the potential therapeutic role of the natural antibiotic amyloid-β peptide. Neurodegener Dis Manag. 2016 Oct;6(5):345-8.
[7]. Beydoun MA, et al. Clinical and Bacterial Markers of Periodontitis and Their Association with Incident All-Cause and Alzheimer’s Disease Dementia in a Large National Survey. J Alzheimers Dis. 2020;75(1):157-172.
[8]. Schwahn C, et al. Effect of periodontal treatment on preclinical Alzheimer’s disease-Results of a trial emulation approach. Alzheimers Dement. 2021 May 29.
[9]. Matsushita K, et al. Periodontal Disease and Periodontal Disease-Related Bacteria Involved in the Pathogenesis of Alzheimer’s Disease. J Inflamm Res. 2020 Jun 30;13:275-283.
[10]. Wu B, et al. Association Between Oral Health and Cognitive Status: A Systematic Review. J Am Geriatr Soc. 2016 Apr;64(4):739-51.
[11]. Genco RJ, Borgnakke WS. Risk factors for periodontal disease. Periodontol 2000. 2013 Jun;62(1):59-94.
[12]. Hu X, Wang T, Jin F. Alzheimer’s disease and gut microbiota. Sci China Life Sci. 2016 Aug 26.
[13]. Rowińska I, et al. The Influence of Diet on Oxidative Stress and Inflammation Induced by Bacterial Biofilms in the Human Oral Cavity. Materials (Basel). 2021;14(6):1444. Published 2021 Mar 16.
[14]. Dodington DW et al. Higher Intakes of Fruits and Vegetables, beta-Carotene, Vitamin C, alpha-Tocopherol, EPA, and DHA Are Positively Associated with Periodontal Healing after Nonsurgical Periodontal Therapy in Nonsmokers but Not in Smokers. J. Nutr. 2015, 145, 2512–2519.
[15]. Woelber JP, et al. An oral health optimized diet can reduce gingival and periodontal inflammation in humans – a randomized controlled pilot study. BMC Oral Health. 2016 Jul 26;17(1):28.
[16]. Manthena S, et al. Effectiveness of CoQ10 Oral Supplements as an Adjunct to Scaling and Root Planing in Improving Periodontal Health. J Clin Diagn Res. 2015; 9: ZC26–ZC28.
[17]. Yelins’ka AM, Liashenko LI, Kostenko VO. Quercetin potentiates antiradical properties of epigallocatechin-3-gallate in periodontium of rats under systemic and local administration of lipopolisaccharide of salmonella typhi. Wiad Lek. 2019 Aug 31;72(8):1499-1503.
[18]. Pitzurra L, Loos BG. Stress en parodontitis [Stress and periodontitis]. Ned Tijdschr Tandheelkd. 2020 Jun;127(6):358-364.
[19]. Yu Q, Hu F, Zhu T. [Correlation between salivary stress markers and clinical parameters of periodontitis]. Shanghai Kou Qiang Yi Xue. 2020 Feb;29(1):93-96. Chinese.
[20]. Sczepanik FSC, et al. Periodontitis is an inflammatory disease of oxidative stress: We should treat it that way. Periodontol 2000. 2020 Oct;84(1):45-68.
[21]. Singh GK, Lee H. Psychological Distress and Alzheimer’s Disease Mortality in the United States: Results from the 1997-2014 National Health Interview Survey-National Death Index Record Linkage Study. J Aging Health. 2021 Mar;33(3-4):260-272.
[22]. Norton MC, et al. Greater risk of dementia when spouse has dementia? The Cache County study. J Am Geriatr Soc. 2010 May;58(5):895-900.
[23]. Hardman RJ, et al. Findings of a Pilot Study Investigating the Effects of Mediterranean Diet and Aerobic Exercise on Cognition in Cognitively Healthy Older People Living Independently within Aged-Care Facilities: The Lifestyle Intervention in Independent Living Aged Care (LIILAC) Study. Curr Dev Nutr. 2020 Apr 18;4(5):nzaa077.
[24]. El-Shinnawi U, Soory M. Actions of Adjunctive Nutritional Antioxidants in Periodontitis and Prevalent Systemic Inflammatory Diseases. Endocr Metab Immune Disord Drug Targets. 2015;15(4):261-76.
[25]. Martinon P, et al. Nutrition as a Key Modifiable Factor for Periodontitis and Main Chronic Diseases. J Clin Med. 2021 Jan 7;10(2):197.
[26]. Iwasaki M, et al. Association between periodontitis and the Mediterranean diet in young Moroccan individuals. J Periodontal Res. 2021 Apr;56(2):408-414.
[27]. Laiola M, et al. A Mediterranean Diet Intervention Reduces the Levels of Salivary Periodontopathogenic Bacteria in Overweight and Obese Subjects. Appl Environ Microbiol. 2020 Jun 2;86(12):e00777-20.
