Association between spirochaetal infection and neurodegenerative diseases: a systematic review and quantitative...

Introduction. Neurodegenerative diseases, including Alzheimer's and Parkinson's, are a growing global health concern. While age remains the primary risk factor, infectious agents have been proposed as potential contributors to disease onset or progression.Gap statement. Spirochaetal bacteria, such as Treponema pallidum, Borrelia burgdorferi and Leptospira spp., can invade the central nervous system, yet the extent to which these infections influence neurodegenerative outcomes remains unclear.Aim. This systematic review aimed to evaluate observational evidence on the association between spirochaetal infections and neurodegenerative diseases and to identify gaps in the literature to inform future research.Methodology. A systematic search of SCOPUS, EMBASE, PubMed/MEDLINE, Web of Science and CINAHL was conducted for studies published between January 2000 and May 2025. Eligible studies were observational, involved adult human populations and reported both spirochaetal infection and cognitive or neurodegenerative outcomes using standardized methods. Data were extracted using a standardized form. Owing to heterogeneity in study design, diagnostic approaches, outcome measures and reporting formats, an overall pooled meta-analysis was not feasible; however, a quantitative synthesis using meta-analytic methods was conducted for studies reporting mini-mental state examination data. Risk of bias was assessed using the Newcastle-Ottawa Scale.Results. Twenty-seven studies met the inclusion criteria: 13 on T. pallidum, 13 on B. burgdorferi and one on Leptospira spp. No eligible studies were found for Brachyspira spp., and studies involving Treponema denticola were excluded due to confounding by periodontitis. Studies investigating syphilis and leptospirosis consistently reported cognitive impairment and increased dementia risk. In contrast, findings for Lyme disease were heterogeneous, with some studies reporting persistent symptoms or increased Alzheimer's risk, while others found no long-term cognitive effects.Conclusion. This review highlights a potential link between spirochaetal infections and neurodegenerative outcomes, particularly for syphilis and leptospirosis. Evidence for Lyme disease remains inconclusive. Future research should prioritize longitudinal studies with standardized diagnostic criteria, integration of neuroimaging and biomarker data and improved diagnostic accuracy for spirochaetal infections.