Oral Microbial Extracellular Vesicles as Novel Mediators of Alzheimer’s Pathogenesis: A Critical Review of the Periodontal–Brain Axis

Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose origins extend beyond the brain. Chronic periodontitis has emerged as a modifiable risk factor, and extracellular vesicles (EVs) have recently been proposed as important mediators of the periodontal-brain axis. Periodontal pathogens such as Porphyromonas gingivalis (P. gingivalis) release bacterial EVs enriched with virulence factors including gingipains, lipopolysaccharide, and regulatory RNAs. These vesicles can enter systemic circulation, interact with the blood-brain barrier, activate microglia, and trigger inflammatory signaling pathways such as NF-κB and NLRP3. These processes contribute to neuroinflammation, amyloid-β accumulation, and tau hyperphosphorylation, hallmarks of AD pathology. Host-derived EVs further contribute to this complex signaling network by facilitating intercellular communication and potentially propagating pathogenic proteins while also carrying protective molecules. Preclinical studies suggest that periodontal-derived vesicles can reach the hippocampus and impair cognition, while clinical studies have detected P. gingivalis DNA and gingipains in AD brain tissues. EV-associated biomarkers in blood or cerebrospinal fluid and engineered therapeutic vesicles represent promising tools for early diagnosis and intervention. Targeting oral microbial EVs may therefore offer novel avenues for AD prevention and therapy.