Porphyromonas gingivalis links Alzheimer’s disease and periodontal disease: Neuroinflammatory mechanisms and therapeutic implications

The global increase in the aging population has significantly increased the prevalence of Alzheimer’s disease (AD), placing substantial burdens on healthcare systems. Emerging evidence highlights a potential link between AD and periodontal disease (PD), implicating Porphyromonas gingivalis (Pg) as a key microbial driver. In this review, we explore the bidirectional relationship between AD and PD through epidemiological evidence, Pg dissemination along the oral–brain axis, virulence factor-driven neuroinflammation and blood–brain barrier dysfunction, as well as aging-mediated susceptibility and therapeutic implications. Available data suggest that Pg and its virulence factors reach the central nervous system through hematogenous dissemination and neural pathways. Once in the brain, these agents trigger microglial and astrocytic activation, fostering chronic neuroinflammation and accelerating amyloid-β deposition and tau hyperphosphorylation, two hallmark pathologies of AD. Aging may further amplify host susceptibility and inflammatory responses. Although gingipain inhibitors have demonstrated neuroprotective potential in preclinical models, their clinical applications remain limited. Importantly, most existing evidence is based on preclinical and epidemiological studies and remains to be validated in well-designed human studies. Future studies integrating multi-omics approaches and precision medicine strategies are warranted to identify individuals at high risk and develop targeted interventions aimed at mitigating Pg-associated neurodegenerative processes and reducing the AD burden.