Association of Periodontal Pathogens and Their Inflammatory Mediators With Alzheimer’s Disease Neurodegeneration: A Systematic Review

Periodontitis is implicated in a range of systemic conditions, including cardiovascular disease, diabetes, and respiratory disorders. Emerging evidence suggests a link between periodontal infection, inflammation, and the neurodegenerative process of Alzheimer's disease (AD). This paper aimed to systematically review observational studies examining the association of periodontal pathogens and their inflammatory products with AD neurodegeneration. The review was registered in the International Prospective Register of Systematic Reviews (PROSPERO - No. CRD42020150043). Methods followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. An electronic search (PubMed/Medical Literature Analysis and Retrieval System Online (MEDLINE), Web of Science, Scopus, Cochrane Library, grey literature) was conducted until September 2025 with no language or date restrictions. Two independent reviewers screened and extracted data. The risk of bias was assessed via the Risk Of Bias In Non-randomized Studies - of Exposures (ROBINS‑E) tool. Of 1,421 identified citations, eight studies met the inclusion criteria. Participant numbers ranged from 349 to 2,191, and ages ranged from 40 to 90 years old. Meta‑analysis was not feasible due to methodological heterogeneity. Risk of bias was moderate in five studies and serious in three. Findings indicated that higher serum IgG antibodies to periodontal pathogens and elevated inflammatory mediators, notably tumor necrosis factor-alpha (TNF‑α), correlated with greater cognitive decline and markers of AD neurodegeneration, including MRI outcomes and APOE ε4 status. In conclusion, the current body of evidence suggests a potential association between periodontitis‑related inflammatory mediators, particularly TNF‑α, and elevated antibody responses to periodontal pathogens with AD progression. However, causality remains unestablished. Future prospective cohort and interventional studies are warranted to clarify the role of periodontal infection and inflammation in AD and to guide clinical strategies that may improve outcomes in AD populations.