The Interface of Oral and Brain Health: Current Insights Into the Bidirectional Relationship Between Alzheimer's...

The bidirectional relationship between Alzheimer's disease (AD) and periodontitis highlights a critical interface between oral and brain health, increasingly recognized as a key axis in aging-related degenerative diseases. This review synthesizes epidemiological, pathological, and mechanistic evidence underpinning their interconnected pathogenesis.

Epidemiologically, periodontitis is associated with an increased risk of AD, while AD patients exhibit a higher prevalence of periodontitis, driven by cognitive decline-impaired oral hygiene and synergistic inflammatory mechanisms. Pathologically, periodontal pathogens (e.g., Porphyromonas gingivalis) translocate to the brain via hematogenous, trigeminal, or oral-intestinal pathways, inducing neuroinflammation, β-amyloid (Aβ) aggregation, and tau hyperphosphorylation through virulence factors like gingipains and LPS. Conversely, AD-related neurodegeneration disrupts bone homeostasis to aggravate periodontitis via multiple mechanisms: (1) Aβ-mediated osteoclast activation through RAGE/NF-κB signaling and suppression of osteoblastogenesis; (2) autonomic nervous system dysregulation, where sympathetic hyperactivity promotes RANKL-dependent bone resorption; and (3) endocrine dysfunction, including HPA axis hyperactivation (chronic hypercortisolism), sex hormone deficiency, insulin resistance, and growth hormone/IGF-1 insufficiency, all of which perturb the balance between bone formation and resorption. Aging exacerbates this bidirectional interplay through immunosenescence (e.g., impaired neutrophil phagocytosis, senescent microglia) and inflammaging, creating a pro-degenerative milieu that amplifies both diseases. Clinical interventions, such as periodontal therapy and microbiota modulation, show promise in reducing systemic inflammation and slowing AD progression, though causal links require validation. Future research must prioritize longitudinal cohort studies, pathogen-specific mechanistic investigations, and translational strategies targeting the oral-brain axis to develop preventive interventions for aging populations.