Confounding in observational studies evaluating the association between Alzheimer's disease and periodontal disease: A systematic review

Background: Studies investigating the association between periodontitis and Alzheimer's disease (AD) suggested indirect (periodontitis would increase the circulation of inflammation-inducible molecules) and direct (periodontopathogens might colonize brains affected by Alzheimer's disease) pathways. While there seems to be a positive relationship between periodontitis and AD, concerns have been raised about the role of confounding. Aim: To systematically review the literature to assess confounding and their level of heterogeneity in the association between periodontitis and AD. Also, to examine data reporting and interpretation regarding confounding bias. Methods: This review followed the PRISMA guidelines and was registered within PROSPERO. Electronic searches were performed in seven main databases and three others to capture the "grey literature". The PECO strategy was used to identify observational studies (cross-sectional, case-control, or cohort studies) assessing the association between periodontal disease and AD without restricting publication language and year. Critical appraisal was performed according to the Joanna Briggs Institute guidelines. Confounders were evaluated following a two-step approach. Results: A total of 3255 studies were found, of which 18 (13 case-control, four cross-sectional, and one cohort) met the eligibility criteria. Participants with AD were 1399 (mean age 64 ± 9 to 84.8 ± 5.6 years), whereas those without AD were 1730 (mean age 62.6 ± 7.1 to 81.4 ± 4.6). Female patients composed most of the sample for both groups. The confounding variables "age" and "sex" were present in all studies. Four studies used the 2017 AAP/EFP periodontal classification. Most studies had a low risk of bias. Fifty percent of the articles did not consider confounding; variation in the adjustment approaches was observed. Additionally, 62% of the studies did not mention bias, and 40% did not discuss any limitations about confounders. Conclusions: Given the study's limitations, caution must be taken to properly interpret the association between periodontitis and AD.Registration: CRD42022293884.