The NIA Oral Health and Alzheimer’s and Related Dementias Workshop

10:00 a.m. Introductions and Welcome: Richard Hodes, MD, Director, NIA and Eliezer Masliah, MD, Director, Division of Neuroscience, NIA

10:20 a.m. Meeting overview and logistics: Maryam Ghaleh, NIA

Keynote Speakers

Session Chair: Steffany Chamut, DDS, MPH, Department of Oral Health Policy and Epidemiology, Harvard School of Dental Medicine

10:30 a.m. Overview of Oral Health among older populations, Rena D’Souza, DDS, MS, PhD, Director, NIDCR

11:00 a.m. Poor Oral Health as a Chronic, Potentially Modifiable Dementia Risk Factor, James Noble, MD, MS Columbia University

11:30 a.m. Q+A, Panel of speakers 
 
12:00 p.m. BREAK

Session I | Epidemiology of Oral Health and Alzheimer’s Disease 

Session Chair: Dallas Anderson, PhD, MPH, NIA 
Session Co-Chair: Maryam Ghaleh, PhD, MA, NIA 

12:10 p.m. Oral Health, AD/ADRD, and Aging: Advancing Health Through an Integrated Practice, Steffany Chamut, DDS, MPH, Department of Oral Health Policy and Epidemiology, Harvard School of Dental Medicine, Harvard University

12:25 p.m. Using Observational Data and Assembling a Team to better understand the Epidemiology of Oral Health and AD, Richard Manski, DDS, MBA, PhD, University of Maryland, Baltimore

12:40 p.m. Improving Oral Health for Diverse Aging Populations, Bei Wu, PhD, MS, New York University

12:55 p.m. Q+A, Panel of speakers

1:25 p.m. LUNCH

Session II | Biology, Mechanisms, Oral Microbiome and Alzheimer’s Disease 

Session Chair: Maja Maric, PhD, NIA
Session Co-Chair: Ozlem Yilmaz, DDS, PhD, Medical University of South Carolina 

2:25 p.m. Periodontal microbiome and inflammation and their systemic impact, George Hajishengallis, DDS, PhD, University of Pennsylvania

2:40 p.m. A New Frontier in Oral and Chronic Systemic Diseases: Live Microcolonies of P. gingivalis in the Brain Vasculature, Ozlem Yilmaz, DDS, PhD, Medical University of So. Carolina

2:55 p.m. Mechanisms behind the connection between periodontitis and Alzheimer’s Disease, Alexandru Movila, PhD, Indiana University of Dentistry

3:10 p.m. Targeting P. gingivalis gingipain virulence factors in Alzheimer's disease, Stephen S. Dominy, M.D., Stanford University/Lighthouse Pharmaceuticals; Gingipains in Down syndrome and animal models, Yorka Munoz, PhD, McGill University, Canada

3:30 p.m. Q & A, Panel of speakers

4:00 p.m. Wrap Up

10:00 a.m. Goals for the day’s activities, Maryam Ghaleh, NIA

Keynote Speaker

Session Chair: Steffany Chamut, DDS, MPH, Department of Oral Health Policy and Epidemiology, Harvard School of Dental Medicine

10:10 a.m. Turning Vision into Reality, Leonard Brennan, DMD, Department of Oral Health Policy and Epidemiology, Harvard School of Dental Medicine, Harvard University

10:40 a.m. Q+A, Panel of speakers

Session III | Global Perspectives

Session Chair: Camille Pottinger, MPH, NIA
Session Co-Chair: Damali Martin, PhD, MPH, NIA

11:10 a.m. Global trends and transitions: A historic moment for oral health and our aging population, Brittany Seymour, DDS, MPH, Department of Oral Health Policy and Epidemiology, Harvard School of Dental Medicine, Harvard University

11:25 a.m. The mouth-brain-heart axis: Poor oral health is associated with higher inflammation, greater aortic valve calcification, and smaller brain volumes among Tsimane forager-farmers, Ben Trumble, PhD, MA, Arizona State University

11:40 a.m. A role of oral Streptococcus mutans in hemorrhagic stroke and dementia—a potential target of preventive interventions, Masafumi Ihara, MD, PhD, National Cerebral and Cardiovascular Center, Suita, Japan

11:55 a.m. Q & A, Panel of Speakers

12:25 p.m. LUNCH 

1:25 p.m. BREAKOUT SESSION 
    Participants will contribute ideas that address current gaps in the field and set future research directions. Each group will have a facilitator and note-taker.
 
3:25 p.m. Report back

3:40 p.m. Open discussion of future directions 

4:00 p.m. Closing remarks 

The National Institute of Aging (NIA) hosted a virtual workshop “Oral Health and Alzheimer's and Related Dementias” on June 13th – 14th, 2023. The workshop was organized by the Division of Neuroscience in collaboration with the National Institute of Dental and Craniofacial Research (NIDCR) to highlight current research, address gaps and challenges, and determine future research priorities.

NIA director, Richard J. Hodes, M.D., and director of the Division of Neuroscience, Eliezer Masliah, M.D., delivered the opening remarks. They welcomed all participants and thanked the meeting organizers. They stated how the meeting was a convergence of two important public health issues as it explored the emerging interest in the possible role of oral health as a potentially modifiable risk factor for Alzheimer’s
related dementias. They reminded participants that oral health is an important aspect of the aging process that impacts cognitive performance and brain neurophysiology. Oral health is also relevant to understanding the impact of environmental interactions with genetics and aging in Alzheimer’s disease and related dementias. They expressed their enthusiasm for the scientific sessions and discussions that were scheduled during the meeting.

Maryam Galeh, Ph.D., the program director for the Population Studies and Genetics Branch of the Division of Neuroscience at NIA provided a meeting overview and briefed the participants on meeting logistics. She stated the following goals for the workshop:

• Understand the association between oral health and Alzheimer’s disease (AD)/Alzheimer’s
• disease-related dementias (ADRD)
• Identify research gaps and opportunities
• Inform scientific priorities
• Determine possible future directions for research in this area

Both days of the workshop started with keynote presentations followed by scientific sessions. Each of the three scientific sessions included three to five talks that were followed by an audience question-and answer session. This report is broken down by workshop sessions and provides a brief overview of workshop presentations and discussions.

Session Chair: Steffany Chamut, D.D.S., M.P.H., FICD, Department of Oral Health Policy and Epidemiology, Harvard School of Dental Medicine

James M. Noble, M.D., delivered the first keynote session of the workshop. His talk focused on poor oral health as a chronic, potentially modifiable dementia risk factor. He briefly reviewed AD, periodontal disease, and their epidemiology and pathobiology. He also discussed associations between periodontal disease and cognitive decline. He reminded participants of the nine core principles of the Bradford Hill criteria to understand if causal associations in epidemiology were worth pursuing or how to better understand them. He stated that AD is a commonly occurring but complex disease with an estimated 10- 50 biological indicators with five general categories of sequential problems and complex genetical features. He described the etiologic fraction which considers multiple risk factors throughout life course and questioned if periodontal disease should be added to the list.

Noble also provided a brief review of periodontal disease. It is a common cause of tooth loss and is highly prevalent in U.S. adults more often affecting men and disadvantaged populations. Earlier studies suggested that periodontal disease increased the risk of coronary disease, stroke, and premature delivery. He stated the importance of developing new methods of measuring periodontal disease as the current methods may be inaccurate or time intensive and there are three different definitions of periodontal disease. Evolving concepts in the microbial etiology of periodontitis suggest a very complex pathobiology.

In the latter part of his presentation, Noble discussed his experience with the Washington Heights- Inwood Columbia Aging Project (WHICAP), beginning with a pilot case-cohort study and leading to the current longitudinal cohort study, the WHICAP Ancillary Study of Oral Health. The study uncovered associations between high levels of two bacterial antibodies and incident AD. About 75% of the study participants across four different age groups had moderate to severe periodontal disease. The study also found associations between the genetics of periodontal disease and known neurological conditions. Noble concluded that various measures of periodontitis were associated with cross-sectional AD related changes observed in neuroimaging, incident cognitive decline, and poor longitudinal cognitive performance. He also described the future directions of the WHICAP study.

Rena D’Souza, D.D.S., Ph.D., the director of NIDCR delivered the second keynote session on the first day of the workshop. She provided an overview of oral health among older populations. She stated that the fundamental mission of the NIDCR was to transform human lives through scientific discoveries and innovations that advance dental, oral, and craniofacial health and overall well-being for all. She mentioned that the dental, oral, and craniofacial complex contained a variety of biological systems that are used as paradigms to study different biological functions. The oral cavity is a portal of entry for common risk factors and can also be used to monitor healing and the effects of therapy on systems. D’Souza also reviewed the Oral Health in America (OHIA) 2021 report. The report stated that oral health problems were global, and that scientific evidence would drive the policy reforms required in the U.S. The report identified challenges in insurance and access for older adults and found that disparities persisted for race and ethnic groups.

D’Souza discussed the strategic plan and extramural research portfolio of the NIDCR. She also presented some key findings of NIDCR-funded research. One study discovered a connection between periodontitis induced systemic inflammation and exacerbated conditions elsewhere in the body while another found that treatment with rapamycin decreased the amount of periodontal bone loss. Research in mice identified the molecular pathways through with the periodontal pathogen F. nucleatum modulated the enhancement of AD signs and symptoms.

Research funded by the NIA found that tooth loss in older adults was linked to higher risk of dementia. Individuals with dentures showed a slower rate of cognitive decline. NIA investigators also discovered that in adults 65 years or older, both AD diagnoses and deaths were associated with antibodies against the oral bacterium P. gingivalis. The transition from private insurance to Medicare was associated with a decline in dental services and worsening dental health including complete edentulism. D’Souza emphasized the unique complexity of biological systems in aging and oral health and recommended a holistic approach for care. She concluded with a reminder of the upstream determinants of health as applicable to older individuals and suggested that those parameters be factored into research.

Leonard Brennan, D.M.D., delivered the keynote session on the second day of the workshop. He shared his thoughts on turning vision into reality. He remarked that dentistry was siloed from other medical practitioners. He started the presentation by posing the question of what should be done to help people understand the importance of oral health. He presented a few dental myths and assumptions that affected research, patient care, and health policy. Obstacles to care such as finances, education, geography, diet, chronic diseases, and provider shortages increased the disease burden in older adults which impacted chronic diseases including dementia. Brennan stated that an obstacle for collaborative medical and dental research was the lack of education and communication.

Brennan discussed his experience with an educational program titled “MOTIVATE” to improve oral health amongst older adults in long-term care facilities and at home. This was an integrative approach to health care for all disciplines to advance their knowledge and connections between oral health and cardiac health at all levels. The tagline of MOTIVATE is “Health education is a powerful medicine.” Education plays a role in meeting challenges of modern health care and enhancing quality, safety, and efficiency of care. Implementation strategy for this program begins with an assessment of knowledge gaps of providers in order to develop tailored education and training. The program also provides organizational changes, and expert consultation and facilitation. All members of the nursing home facility are required to study the MOTIVATE modules. Upon completion of a live workshop, 98.6% of individuals indicated that the workshop helped them to identify the warning signs of an oral health problem. Brennan concluded his presentation by discussing an upcoming applied learning center for health care.

Open Discussion

Attendees asked if WHICAP study participants were offered access to dental care. Noble responded that the study offered emergent and urgent care to older participants. He also remarked that there was a need to think about broader dental coverage in aging populations.

Participants mentioned that despite employment opportunities, there was a lack of qualified dentists and hygienists in rural areas1. Speakers discussed the need to increase training initiatives towards hygienists by developing targeted training programs for dental students. Speakers also emphasized the need to support dental health care by creating geriatric dentistry programs, programs that integrate different fields, and increasing trainee stipends.

Brennan emphasized the need for caregivers to work together as a team to reduce the burden of disease. He mentioned that it was difficult for caregivers to get into geriatric dentistry and there was a need to think about a system that educated and trained professionals. He stated that care professionals were dedicated but they needed supplemental education. He also suggested that dentistry in older adults should be weaved into the medical curriculum.

Session Chair: Dallas Anderson, Ph.D., M.P.H., National Institute of Aging
Session Co-Chair: Maryam Ghaleh, Ph.D., M.A., National Institute of Aging

Steffany Chamut, D.D.S, M.P.H., FICD, presented on oral health, AD/ADRD, aging, and advancing health through an integrated practice. Dr. Chamut shared a historical exploration of oral health, tracing back to George Washington's era who was not immune to suffering dental problems throughout his life. Dr. Chamut also discussed the relationship between oral health, global population trends, and its historical foundations within the context of social determinants of health (SDOH). This sheds light on the gradual evolution of oral health and emphasizes the need for more rapid progress and innovative integration of oral health into comprehensive care as an essential element of overall well-being. Her insights also underscore the ongoing significance of addressing systemic factors to ensure equitable oral health for all. Dr. Chamut highlighted that the growing aging population, with their extended lifespans and retention of more natural teeth, is poised to exacerbate oral health disparities. She also pointed out that the field of dentistry has not fully recognized the critical importance of geriatric dentistry as a specialized discipline to effectively address these forthcoming challenges and workforce shortages. Tooth decay is the most prevalent non-communicable disease (NCD), and severe periodontitis ranks as the sixth most widespread condition globally, emphasizing the urgent need for comprehensive oral health strategies as numerous health systemic brain complications have been associated with oral bacteria. She highlighted the emergence of health issues stemming from the neglect of preventive oral health practices and the prevalence of oral diseases, largely attributed to insufficient access to dental care, limited insurance coverage, and a deficiency in oral health literacy among healthcare providers, patients, and caregivers. Older adults have unique needs and circumstances that require different approaches, and their needs have to be identified at individual levels. Significant associations have been discovered between the number of lost teeth and the risk of developing AD/ADRD or cognitive impairment. Poor oral health and its impact on quality of life can be significantly mitigated through the provision of appropriate support, as almost all dental diseases are preventable. She suggested future directions which included encouraging interdisciplinary collaborations, conducting further research that encompassed longitudinal and experimental studies, and expanding access to quality and affordable care.

Richard Manski, D.D.S., M.B.A., Ph.D., presented on using observational data and assembling a team to better understand the epidemiology of oral health and AD. Studies have provided a biological and epidemiological rationale showing a possible relationship between oral health and ADRD. Studies also suggest that regular preventative oral health care might serve as a protective factor and reduce the risk for ADRD among older adults. Medicare doesn’t usually provide dental coverage. Manski questioned whether providing dental coverage would improve oral health and consequently reduce the risk of chronic illness including ADRD. He stated that current evidence wasn’t enough to establish a causal relationship between poor oral health and ADRD. He suggested using existing observational data to study this causal relationship. He also discussed the problems around obtaining and using existing datasets. He emphasized the need for assembling an interdisciplinary scientific team including a data team when undertaking complex research projects.

Bei Wu, Ph.D., discussed improving oral health for diverse populations. She stated that oral health disparities reflected some of the most challenging issues in the U.S. including lack of access to healthcare, lack of dental insurance, poverty, and disparities in socioeconomic status. She mentioned that an age-period-cohort analysis of oral health and diabetes discovered that adults with diabetes experienced twice as much tooth loss as those without diabetes. Despite differences in diabetes status, the persistence of tooth loss disparities remains evident among minority older adults. A systematic review and meta-analysis in 2021 showed that older adults with more tooth loss had 1.48 times higher risk of cognitive impairment and 1.28 times higher risk of being diagnosed with dementia. Her study on the moderating effects of age at immigration found that immigrants who had significant tooth loss and had immigrated to the U.S. at ages 35-49 were at an increased risk of mild cognitive impairment compared to those who immigrated at age 18 or younger. Her research also discovered that racial or ethnic disparities existed in the use of dental services in the U.S., and the disparities increased as people aged. She suggested potential solutions to improve oral health including Medicare coverage of oral health services and increasing awareness about oral health in older adults through health promotions.

Open Discussion

Attendees asked if it made sense to have a geriatric dental care specialty rather than enhanced training in broader dental education. Chamut mentioned that the geriatric component in dental curriculum is limited and that geriatric patients often faced more limitations and challenges. Without appropriate guidance, dental care professionals found it difficult to handle such patients and preferred to care for younger populations.

Participants asked whether there was a lack of appropriate oral health literacy. Panelists emphasized the need for promotion of oral health and literacy, especially in immigrants to overcome cultural beliefs. They also mentioned the lack of access and insurance among older adults. Panelists also discussed how oral health care in older adults may be complicated as older adults may rely on others for their oral health or face side effects arising from medications.

Session Chair: Maja Maric, Ph.D., NIA
Session Co-Chair: Ozlem Yilmaz, D.D.S., Ph.D., Medical University of South Carolina

George Hajishengallis, D.D.S., Ph.D., discussed periodontal microbiome and inflammation and their systemic impact. Periodontitis increases the risk of systemic inflammatory diseases. Hajishengallis discussed the development of a complement-targeted host-modulation therapy in periodontitis. In a phase 2 clinical trial of this therapy, patients treated with a complement C3 inhibitor had significantly reduced clinical inflammation. He also presented possible mechanisms underlying the association of periodontitis with comorbidities. His research showed that maladaptive epigenetic rewiring of bone marrow progenitors as a result of periodontitis enhanced susceptibility to arthritis. An analysis of participants in the Dental ARIC study revealed that individuals with clonal hematopoiesis of indeterminate potential (CHIP) due to mutations in epigenetic modifier genes had significantly increased prevalence of periodontitis and increased extent of gingival inflammation. Whether this association is causal is being addressed in a mouse model. Initial evidence suggests that CHIP may be a possible mechanistic basis for periodontitis and inflammatory comorbidities.

Ozlem Yilmaz, D.D.S., Ph.D., presented a new frontier in oral and systemic diseases such as live microcolonies of P. gingivalis in the brain vasculature. The mouth contains a vast number of microbial inhabitants and over 700 different species of microorganisms have been identified in the human oral cavity. Among these, P. gingivalis can exclusively invade, multiply, and survive in human primary gingival epithelial cells (GEC) by inducing a noncanonical autophagy and modulating host cell homeostatic pathways. The microbe can also spread from cell-to-cell in a time-dependent manner via actin cytoskeleton thus evading the immune system. Yilmaz’s study detected intact P. gingivalis colonies in the brain perivasculature and in some neurons of ADRD patients. P. gingivalis DNA was also detected in the cerebrospinal fluid of early and late ADRD patients. Mice fed with P. gingivalis significantly increased risk-taking behavior compared to controls and also developed periodontal disease. Future directions for this research include identifying molecular targets for the treatment of ADRD in the context of chronic oral microbial infections and the virulence factors.

Alexandru Movila, Ph.D., discussed mechanisms behind the connection between periodontitis and AD. He discussed the crosstalk between periodontitis and AD. Periodontitis had elevated prevalence in males while two-thirds of AD cases were detected in females. Patients with AD had elevated periodontal bone loss but there were no established therapeutic regimens for periodontitis in AD patients. Studies showed that AD mice had a higher baseline of periodontal inflammation. However, there was limited knowledge on the impact of sex on periodontal bone loss and AD. Research in AD mouse models revealed that female mice had higher amyloid beta and p-tau accumulation in the periodontal lesions
and brain cortex. These female mice also showed an increased risk for periodontal bone loss compared to males. Movilla’s research showed that IL-34 signaling promoted sex-associated periodontal bone loss and neuroinflammation in experimental models of AD suggesting that sex and IL-34 were key factors underlying the connections between periodontal dysbiosis and AD.

Stephen S. Dominy, M.D., talked about targeting P. gingivalis gingipain virulence factor in AD. A study published in 2018 found that oral P. gingivalis infection in wild-type mice induced AD brain pathology after 22 weeks. Gingipain was detected in the hippocampus and neural cells of the mouse brains. Dominy’s research discovered gingipains in human AD brains and was published in 2019. The study showed that the gingipain load in human brain correlated with AD diagnosis and tau pathology. The study also found that tau was fragmented by gingipains, and that oral infection of wild-type mice with P. gingivalis induced amyloid beta in the brain which was blocked by small molecule gingipain inhibitors. A separate study demonstrated that gingipains were localized in the mitochondria of human AD brains. The GAIN clinical trial showed a 40-50% slowing of cognitive decline in mild-moderate AD patients with Pg+ saliva when treated with an oral gingipain inhibitor. Dominy mentioned that future studies include a new trial in mild-moderate AD and Pg+ saliva with a next generation gingipain inhibitor.

Yorka Muñoz, Ph.D., presented on Porphyromonas gingivalis infection in Down syndrome (DS) and in non-human primate model and its possible role in neurodegeneration. She stated that DS was characterized by the triplication of chromosome 21 and there was a genetic basis for a strong association between DS and AD. P. gingivalis and its gingipains were observed in the brains of DS individuals. High levels of neurodegeneration and extracellular DNA containing Pg+ aggregates, were detected in DS individuals over 40 years of age. P. gingivalis infected neurons showed DNA condensation and intracellular gingipain accumulation in young adult DS individuals. Muñoz’s study using the animal model marmosets showed that P. gingivalis and its gingipains could get access to the brain of marmosets. Preliminary results suggested that P. gingivalis infection in aged animals with an inflammatory disease produced an exacerbated glial activation which could trigger neurodegeneration.

Open Discussion

Participants asked the extent to which P. gingivalis reactive antibodies in AD patients cross-reacted with human self-antigens. Panelists responded that the antibodies were highly specific to P. gingivalis.

Participants also asked how P. gingivalis positive status was measured in saliva. Dominy responded that they used an oral rinse and worked with a company that performed qPCR to identify P. gingivalis DNA. In response to a question about other species of Porphyromonas, Yilmaz responded that there were differences between subspecies of P. gingivalis and that some species were more competitive in biofilm environment while these strains lacked the ability to survive intracellularly.

Session Chair: Camille Pottinger, M.P.H., NIA
Session Co-Chair: Damali Martin, Ph.D., M.P.H., NIA

Brittany Seymour, DDS, MPH, presented on global trends and transitions as a historic moment for oral health and aging populations. She stated that there has been a shift in the global disease burden and oral health and AD are on the rise. Noncommunicable diseases contribute to 74% of the global disease burden. The burden of AD and oral health is increasing worldwide. There are more people, they are living longer, they are keeping their teeth longer, and they are living with multiple complex chronic conditions. Seymour mentioned that the reports and summits over the last 30 years to create awareness about oral health have led to a watershed moment. The World Health Organization has formally adopted an oral health strategy and action plans in 2023. She emphasized that it wasn’t possible to treat each disease alone and there was a need for a robust research agenda and political prioritization in every nation. She mentioned that the focus should be on prevention and health promotion, and oral health integration across the spectrum and universal health coverage.

Benjamin Trumble, Ph.D., shared his experience researching the mouth-brain axis in the Tsimane forager- farmer population. Poor oral health is associated with higher inflammation, greater aortic valve calcification, and smaller brain volumes among Tsimane forager-farmers. He noted that nearly all research about oral health and dementia is from sedentary populations. Lack of research outside urban populations has led to missing global variation in oral health. He mentioned how historically human populations used teeth as tools for cutting, making tools, and processing foods. Trumble mentioned that his study of the Tsimane population showed that they have low rates of cardiovascular disease, slower brain aging, and lower rates of ADRD. However, they had poor oral health. There was increasing tooth loss with age, especially in women, and a high degree of broken teeth. The study found evidence of higher inflammatory biomarkers in individuals who had more teeth with exposed pulp. Exposed pulp was also associated with lower brain volume. Trumble concluded that the future steps would include identifying a mechanism using microbiome and transcriptomic approaches.

Masafumi Ihara, M.D., Ph.D., presented on a role of oral Streptococcus mutans (S.mutans) in hemorrhagic stroke and dementia as a potential target of preventive interventions. Research had shown that intracerebral hemorrhage can be induced by S.mutans injected in tails of animal models. Another study found that S.mutans used cellular machinery of endocytosis and localized in the endothelial cells to escape immune detection. Ihara was involved in conducting a clinical study that showed an association of cnm+ S.mutans infection with small vessel disease. The presence of cnm+ S.mutans in the oral cavity also resulted in multiple cerebral microbleeds. Clinical study in a population cohort showed
subjects with cnm+ S.mutans in their oral cavities had a larger number of cerebral microbleeds and developed cognitive impairments. Ihara suggested several pathways for oral bacteria to enter the brain including periodontal disease and gut dysbiosis. He concluded by discussing an interventional study that includes using toothpaste or tables containing antibodies against S.mutans as preliminary research showed a reduction in S.mutans in the oral cavity.

Open Discussion

Participants asked why some countries seemed to have better oral health than others. Panelists mentioned that it was important to do a deep dive into the data instead of drawing conclusions based on averages. It was also important to look at preventative or precautionary measures such as access to fluoride containing toothpaste.

When asked about the biological mechanism of the dramatic cognitive decline associated with hemorrhagic stroke, Ihara responded that they thought the mechanism was through the direct invasion of S.mutans in brain or brain parenchyma and caused multiple microbleeds. If they accumulated in the brain, they would introduce cognitive changes.

A breakout session was conducted on the second day of the workshop. The purpose of the breakout sessions was to :

• Identify research priorities
• Identify existing resources (i.e., cohorts)
• Identify interdisciplinary opportunities
• Address existing gaps
• Look toward future directions
• Understand newer and broader perspectives

Meeting organizers encouraged participants to contribute ideas that addressed current gaps in the field and set future research directions. Participants were divided into four groups and each group was asked the following questions:

What is the current data/existing research in the field of Oral Health and Alzheimer’s Disease? How strong is the evidence? What are the major challenges?

Participants mentioned that the current evidence was associative, and more research was required to identify mechanisms that link oral health to AD. They also remarked on the unorthodox paradigm of microbial infections. Despite compelling evidence linking infections to AD, oral bacteria presented an open question.

Participants mentioned that the current evidence was associative, and more research was required to identify mechanisms that link oral health to AD. They also remarked on the unorthodox paradigm of microbial infections. Despite compelling evidence linking infections to AD, oral bacteria presented an open question.

Participants noted that not all data and research was available. They suggested that NIH could have a page to highlight currently funded projects and research. They also discussed difficulties in data integration as different groups use different methods for collecting information. For example, though the NHANES provided pretty good data on oral health assessment including periodontal disease, it had limited cognitive assessment. Participants noted the lack of a gold standard for evaluation.

Participants stated that a major challenge was lack of longitudinal data looking at oral health and cognitive impairments due to lack of clinical evaluation data. They also noted the challenge of using existing data to meet criteria with quality measurements for key outcomes. They emphasized the need for funding to support robust longitudinal studies to understand the link between oral health and AD.

How can we optimize existing infrastructures (e.g., epidemiology cohorts, research consortia, animal models) and/or leverage Big Data (including linkages to other databases) to investigate oral health and AD and the mechanisms through which they operate?

Participants suggested leveraging the National Alzheimer’s Coordinating Center’s resources for engagement with an existing nationwide study of cognitive aging, and its National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD) in order to help establish
harmonized protocols for saliva or blood collection and processing, overall aiming for a harmonized model for oral health assessment and central repository for microbial analyses. They mentioned that any longitudinal AD study should collect saliva samples and an oral proponent be added to existing long term AD studies. Participants also suggested collaborating with community dentists, healthcare providers, and public health hygienists to collect saliva and plaque samples for research.

Participants mentioned additional support is required in order to take advantage of existing data. They suggested a secondary analysis of existing data. They also suggested specialized review panels at NIA with people who have dental experience to review and fund bigger projects.

Participants emphasized the need to identify pathways in order to develop targeted treatments or interventions. They also discussed developing ways or using current methods to identify people who are more susceptible or may respond better to treatments. They stated that preventing the disease may be easier and cheaper than treating it. They also suggested fostering multi-omic studies in diverse populations of the gene/exposome interactions to determine a mechanistic link between oral health and ADRD.

Participants mentioned developing an intentional follow-up to the Human Microbiome Project (HMP). The infrastructure could be reconsidered in the framework of a cognitive outcome research program or to invite participants who previously gave various samples back for further study.

What analytic approaches or other research methods, additional data elements, and tools will be needed to advance research for oral health and AD?

Participants recognized the need for a larger body of evidence and pointed out that although most studies were missing an oral health component, it was never too late to add one. They suggested that NIH funding be available to add oral health component as a supplement to existing projects. They also mentioned the lack of dentists on grant review panels even for proposals regarding oral health.

Participants also discussed the need for federal funding to support clinical trials to advance research into oral health and AD.

Participants noted that there were relatively few ongoing studies which enable opportunities to explore the complex multi-modal relationships between oral health and incident cognitive impairment. They identified a need for well-developed integrated methods for multi-omics data. They also identified a need to integrate health disparity data into existing models.

What concrete opportunities should we consider accelerating a trans- and multidisciplinary approach to studying oral health and AD? What unique collaborative opportunities should we consider to enhance cross-cutting research in the field?

Participants mentioned a need for a collaborative team of specialists which includes experts from the fields of dentistry, genetics, AD, data science etc. They noted the lack of dentists in AD meetings and suggested a new professional society to link these professions (dentist, microbiologists, neurobiologists, immunologists, etc.).

Participants stated that AD centers are funded as P30 grants with multiple cores and pointed out that NIA or NIH had an opportunity to fund optional cores such as neuro-infection cores to ADRC infrastructure. They suggested dedicated P-level funding and center grants (P30) that would allow for not just R01 funding, but also pilot projects. This would generate more interest from early-stage investigators and add to their training. They also emphasized the need to create centers of excellence that would provide a large-scale standardization of data and act as a repository.

Participants also mentioned that academic institutions that have both an ADRC and a dental research center, similar to the Comprehensive Oral Health Research Centers of Discovery, can be leveraged to develop new research centers of dual expertise in AD and dental research.

Conclusion

A report back followed the breakout sessions. Volunteers from each breakout room discussed the key highlights discussed in the rooms. These included:

• Multidisciplinary approach and integration are critical to continue to have conversations and collaborations between people in oral health, microbial experts, and neuroscientists which can lead to innovations and progress.
• This workshop was an excellent example of cross disciplinary representation needed for the field of oral health and AD. Participants wanted to see more cross disciplinary presentations at the Alzheimer’s meetings and AD presentations at the oral health meetings with more encouragement from NIH or NIA.
• Evidence around the link between oral health and AD is building, but there’s still a lot more to do. Group members thought it was important to continue to build that evidence through rigorous human studies with prospective design and using animal models. They also thought that more research about treatment studies, current standard of care, novel experimental treatments were required to help patients.
• Breakout session participants suggested creating research networks with academic partnerships, CTSA, and Alzheimer’s research network to collect plaque samples in community dentistry settings. Participants discussed leveraging existing resources to create a central repository where samples would be shipped to for storage and analysis.
• Participants suggested involving more private sector and international collaborations as AD is a global problem.
• Participants emphasized the need for more funding at different levels. They suggested a large funding mechanism such as P30 where experts from different areas would be included and would work together to address different needs in the field.
• Participants remarked on the tremendous public health implications of the current research evidence, and it was important to use this research to shape public policy in a data driven manner which may end up integrating oral health care into Medicare.
• Participants felt strongly that there was a lead in the pre-clinical etiology in a virulent form of P. gingivalis infection. They suggested collaborating with companies in the private sector for further clinical development. They also pointed out that the NIA should use the opportunity to develop strong clinical infrastructure and centers of excellence.

The chief of the Population Studies and Genetics Branch in the Division of Neurosciences at the NIA, Damali Martin, Ph.D., delivered the closing remarks. She thanked the workshop organizers for planning the workshop. She also thanked all the participants for their presentations and discussions that helped guide the organizers. Martin stated that there was a lot of work to be done by the NIA to integrate oral health into its work and research. She also encouraged the participants to share their research results with the NIA.