Beyond the Microbial Hypothesis: Shared Genetic, Osteoimmune and Vascular Mechanisms in the Oral–Brain Axis Linking Periodontitis and Alzheimer's Disease

Periodontitis, a chronic inflammatory disease of the tooth-supporting tissues, is increasingly linked to Alzheimer's disease (AD), yet mechanistic accounts of this 'oral-brain axis' have been dominated by microbial translocation and the gingipain hypothesis. This review argues that the convergence between periodontitis and AD extends well beyond microbes, integrating shared genetic, osteoimmune and vascular-inflammatory mechanisms that are rarely considered together. Genetic susceptibility reaches beyond APOE ε4 to the osteoprotegerin (OPG) axis, with APOE ε4 linking the two conditions through impaired amyloid-β clearance, blood-brain barrier dysfunction and altered lipid handling. The OPG/RANK/RANKL system emerges as a bone-brain (osteoimmune) interface, in which OPG shows a dual-role paradox, reduced locally in periodontal bone loss yet elevated systematically in AD, while soluble RANKL displays neuroprotective properties. Because OPG acts as a decoy receptor for RANKL, we hypothesise that elevated OPG in AD limits RANKL-dependent microglial amyloid-β clearance. Endothelial dysfunction, reflected in circulating endocan, provides a shared vascular readout that is raised in both diseases and responsive to periodontal therapy. We propose that these genetic, microbial and vascular inputs converge on microglial priming and trained immunity, a unifying immunological node through which chronic peripheral inflammation may act during the decades-long preclinical phase of AD. Current evidence nonetheless remains predominantly associative, causality is unproven and mechanistic data rely heavily on animal models. The oral-brain axis is therefore best regarded as a promising yet still unproven framework in which osteoimmune and vascular pathways, and candidate biomarkers such as endocan, represent underexplored targets for future longitudinal and interventional research.