Periodontitis and Alzheimer's disease: Porphyromonas gingivalis, gingipains and neuroinflammation

Periodontitis is a chronic inflammatory disease of the tooth-supporting tissues whose principal microbial driver, Porphyromonas gingivalis, has been detected repeatedly in the brains of people with Alzheimer's disease. This narrative review synthesizes the evidence linking periodontitis to Alzheimer's disease through P. gingivalis, its gingipain proteases and neuroinflammation, drawing on epidemiological cohorts and meta-analyses, postmortem human studies and experimental models published between 2018 and 2025. Umbrella and conventional meta-analyses estimate that periodontitis and tooth loss raise the risk of cognitive disorders by 51% to 65%, although residual confounding limits causal inference. Postmortem studies localize gingipains to neurons and to tau and ubiquitin pathology, and experimental oral infection of wild-type mice and rats reproduces amyloid-beta and tau lesions that depend on gingipain activity. Mechanistically, the bacterium reaches the central nervous system through bacteremia, the trigeminal nerve and outer membrane vesicles, and gingipains open the blood-brain barrier and activate microglia through protease-activated receptor 2, sustaining neuroinflammation. Gingipain inhibitors reduce pathology in animal models and have reached clinical trials, although the phase 2/3 GAIN trial missed its primary endpoint in the overall population. Periodontal treatment is biologically plausible but remains unproven for cognitive protection. Neuroinflammation is supported as a mechanistic bridge, while causation in humans remains to be demonstrated.