Periodontal Pathogens and Their Association with Incident All-Cause and Alzheimer's Disease Dementia in a Large National Survey

Abstract

Background: Infectious agents including periodontal pathogens and their neuroinflammatory sequelae have been at the forefront of Alzheimer's Disease (AD) pathology. We investigated whether periodontal disease (Pd) markers and periodontal pathogens in mid-life are associated with clinical outcomes of cognitive impairment after decades of follow-up. Methods: We conducted a retrospective cohort analysis using data from the third National Health and Nutrition Examination Surveys (NHANES III) linked with restricted mortality and incident outcomes derived from the National Death Index and Medicare data [≥45y, 43% men, Nmax=6,650, 1988-1994 through January 1st, 2014, mean follow-up times (45+, all outcomes): 15-17y]. Outcomes of interest included AD mortality (nmax=102), incidence of AD (nmax=888) and all-cause dementia (nmax=1,737). Exposures included Pd markers [mean clinical attachment loss (CAL) and Probing Depth (PD)] and 19 periodontal pathogens (1988-1994: k=19; 1991-1994 (phase 2): k=2). Multiple Cox proportional hazards models were conducted, stratified by age and sex. Findings: In those ≥65 years old, AD incidence was associated with a composite factor comprised of C. Rectus and P. Gingivalis (Pg) titers (per SD, aHR=1.22; 95% CI, 1.04-1.43, P=0.012), whereas AD mortality risk increased with higher baseline levels in a factor comprised of Pg, P. intermedia, P. nigrescens, F. nucleatum, Cr, S. intermedius, C. ochracea and P. melaninogenica (per SD, aHR=1.46; 95% CI, 1.09-1.96, P=0.017). In both the 55+ and 65+ age groups, the Orange-Red cluster (Pm, Pi, Pn, Pg) was associated with increased AD mortality risk. PD and phase 2 (1991-1994) measured Pg were consistently and directly associated with incident AD among older individuals. Interpretation: Evidence for an association between periodontal pathogens and AD and dementia-related outcomes was stronger for older adults. This study presents information that may inform periodontists who treat older adults and calls for a line of inquiry between practitioners focused on Pd and neurodegenerative processes. Funding Statement: This study was entirely supported by the National Institute on Aging, Intramural Research Program (NIA/NIH/IRP). Declaration of Interests: All authors declare no conflict of interest. Ethics Approval Statement: The present study was approved for ethical treatment of participants by the Institutional Review Board of the National Institute on Aging, Intramural Research Program.