As the U.S. population ages, the number of individuals living with dementia is rapidly increasing, making the identification of modifiable risk factors more urgent than ever. Recent research, including our own studies, suggests a significant association between poor oral health, such as periodontitis and tooth loss, and an increased risk of developing dementia. However, the specifics of how poor oral health influences dementia, particularly its association with two different subtypes of dementia, like Alzheimer’s disease (AD) and vascular dementia (VaD), remain largely unexplored. The systemic inflammatory responses caused by periodontal diseases will lead to the formation of amyloid-beta peptides (A!) and intraneuronal neurofibrillary tangles, contributing to the progression of AD. Our prior study also found subgingival periodontal bacteria at both genera and species levels is associated with reduced cerebrospinal fluid A!-42. However, the biological mechanisms underpinning the relationship between oral health and different subtypes of dementia are understudied. It is also unknow how social determinants of health (SDoH) impact the link between oral health and dementia. Our study aims to address these knowledge gaps by analyzing UK Biobank and Genome-Wide Association Study datasets (i.e., UKB, FinnGen Biobank, and MRC Integrative Epidemiology Unit). Our specific aims include Aim 1: Establish the relationship between poor oral health and clinical biomarkers of dementia (A!, tau proteins, and brain atrophy) and AD or VaD. We hypothesize that poor oral health will be associated with the presence of clinical biomarkers of dementia and incident AD or VaD. Aim 2: Test the three hypothetical biological pathways (i.e., systemic inflammation, accelerated biological aging, and dysbiotic oral microbiome) linking oral health with AD and VaD. We hypothesize that systemic inflammation and accelerated biological aging will mediate the association between poor oral health and incident AD or VaD. We will conduct exploratory analyses of the links among poor oral health, dysbiotic oral microbiome, and AD/VaD. Aim 3: Determine potential moderators that can influence the relationships of poor oral health with AD and VaD. The findings will illuminate the causal relationship between poor oral health and dementia, guide targeted interventions to reduce dementia risks, and contribute to dementia prevention and control strategies including early diagnosis, management, treatment, and genetic counseling.
