Unraveling the oral microbiome's role in Alzheimer's disease: From pathophysiology to therapeutic potential.

Oral dysbiosis contributes to Alzheimer's disease (AD) by promoting neuroinflammation. Pathobionts such as Porphyromonas gingivalis, Treponema denticola, and Fusobacterium nucleatum release virulence factors that induce amyloid beta aggregation and tau hyperphosphorylation, while the loss of commensals like Streptococcus salivarius and Neisseria spp. impairs anti-inflammatory protection, worsening neuronal damage. P. gingivalis is strongly linked to an increased risk of AD, especially in individuals with systemic conditions like diabetes, hypertension, and chronic kidney disease. Its presence in brain tissue correlates with a higher likelihood of AD, while salivary Veillonella and periodontal pathogens in gingival crevicular fluid show potential as non-invasive biomarkers for early AD detection. Therapeutic strategies targeting the oral microbiota, such as gingipain inhibitors, antimicrobials, probiotics, and prebiotics, show promise for mitigating AD risk. However, causal mechanisms and clinical efficacy remain to be fully established. Maintaining microbial balance through preventive and targeted modulation represents an innovative approach to reducing AD susceptibility. HIGHLIGHTS: We identified Porphyromonas gingivalis, Treponema denticola, and Fusobacterium nucleatum as key oral pathogens driving Alzheimer's disease (AD) via gingipain-induced amyloid beta aggregation, systemic inflammation, and blood-brain barrier disruption. Our study revealed diabetes, hypertension, and chronic kidney disease (CKD) amplify AD risk through shared oral dysbiosis, with uremic toxins (CKD) and hyperglycemia (diabetes) exacerbating neuroinflammation. We propose Veillonella in saliva and Porphyromonas gingivalis in gingival crevicular fluid as non-invasive AD biomarkers, correlating with 6 to 10× higher AD risk when detected in brain tissue. Gingipain inhibitors (e.g., COR388), nitrate-reducing probiotics, and integrated dental-neurology care are promising interventions to disrupt the oral-brain axis. We advocate for oral microbiome screening in high-risk populations (apolipoprotein E ε4 carriers, diabetics) and interdisciplinary approaches to AD prevention.