EFFECT OF SURGICAL AND NON-SURGICAL PERIODONTAL TREATMENT ON ALZHEIMER DISEASE-ASSOCIATED OUTCOMES: A Randomized Clinical Trial

Impact of Periodontal Treatment on Alzheimer's Disease Progression (PETAL Study)

**Study Overview** This randomized controlled clinical trial aims to investigate the impact of comprehensive periodontal treatment on cognitive, functional, biomarker, and neuroinflammatory outcomes in patients with mild to moderate Alzheimer's disease (AD) presenting advanced periodontitis. The study evaluates whether the reduction of oral and systemic inflammation through periodontal therapy can influence the progression of Alzheimer's disease. The trial will be conducted at the University Hospital of Liège, Belgium, under the collaboration between the Departments of Neurology and Periodontology. The project is titled PETAL (Periodontal Treatment in Alzheimer's Disease) and will recruit seventy participants over a 24-month follow-up period.

**Background and Rationale** Alzheimer's disease is a chronic neurodegenerative condition characterized by progressive decline in cognitive and memory functions, ultimately leading to functional impairment and loss of independence. The disease is associated with the accumulation of amyloid-beta plaques and neurofibrillary tangles, synaptic dysfunction, and neuroinflammation. Periodontitis, a chronic inflammatory disease affecting the supporting structures of the teeth, is a highly prevalent condition that induces local and systemic inflammation through the dissemination of periodontal pathogens and their by-products into the bloodstream. Increasing evidence supports a bidirectional relationship between chronic periodontitis and systemic conditions, including diabetes, cardiovascular disease, and neurodegenerative disorders such as Alzheimer's disease. Inflammatory mediators derived from periodontal infection may contribute to neuroinflammatory processes that exacerbate neuronal injury and cognitive decline.

The proposed biological mechanism linking periodontitis and Alzheimer's disease involves the entry of periodontal bacteria and their toxins into systemic circulation, triggering immune responses that elevate levels of inflammatory cytokines such as IL-1β, IL-6, TNF-α, and CRP. These mediators can cross the blood-brain barrier, contributing to microglial activation and neuroinflammation. Pathogens like *Porphyromonas gingivalis* and their virulence factors (gingipains) have been detected in brain tissue, supporting a mechanistic link. Preclinical studies have shown that periodontal infection may increase amyloid-beta production, activate the complement cascade, and promote neurodegeneration. Therefore, periodontal therapy aimed at reducing bacterial load and systemic inflammation could potentially attenuate Alzheimer's-related pathology.

**Objectives** The primary objective is to determine whether initial non-surgical periodontal therapy combined with intensive supportive periodontal care improves cognitive performance and neuroinflammatory biomarkers in patients with Alzheimer's disease and advanced periodontitis. The secondary objective is to evaluate whether additional periodontal surgical therapy followed by intensive supportive periodontal care enhances cognitive and biological outcomes over 24 months.