## 4 _P. gingivalis_ and Systemic Diseases
### Alzheimer's Disease  
Alzheimer's disease (AD) is a neurodegenerative disease that affects millions of individuals worldwide, with its prevalence rapidly increasing with increasing life expectancy and the aging of the global population [55; 56]. [PERSON] et al. [57] demonstrated that exposure to periodontal disease is associated with a 1.7-fold increased risk of developing AD. This disease is characterized by progressive neuronal loss, resulting in gradual decline in memory, language, and cognitive functions, ultimately leading to death in the advanced stages (Alzheimer's Association, 2016) [58].  
Scientific evidence emphasizes that individuals with Alzheimer's disease or dementia often experience compromised oral health, making them more susceptible to chronic oral diseases. Periodontal pathogens not only invade the oral cavity but can also infiltrate the periodontal pocket epithelium, from where they enter the bloodstream. Once in circulation, these pathogens release various endotoxins and exotoxins that propagate the infection in different body compartments, including the brain. Significant amounts of lipopolysaccharide-charide (LPS) have been found in the brains of AD patients. The interaction between periodontal disease (PD) and Alzheimer's disease (AD) can induce neuronal degeneration through a multifaceted process that begins with oral dysbiosis, leading to microbiome formation and proliferation [59]. Invasion of periodontal tissues by oral pathogens results in their release into the bloodstream. These pathogens and their toxic molecules, such as LPSs, subsequently bind to microglia through Toll-like receptors 2/4 (TLR2/4), triggering the release of cytokines and inflammatory mediators [60]. This inflammatory response induces the production of amyloid precursor protein (APP) by neuronal cells. Activation of \(\beta\)- and \(\gamma\)-secretase enzymes leads to increased secretion of amyloid-beta (A\(\beta\)) peptides, particularly A\(\beta\)42 monomers and sAPP\(\beta\), both of which accumulate extracellularly and generate intracellular AICD. These A\(\beta\) peptides aggregate into oligomers, protofibrils, or fibrils, ultimately forming amyloid plaques [61].  
These plaques are recognized by Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) receptors on the membranes of microglia, triggering an additional inflammatory response that further stimulates A\(\beta\) production. Furthermore, dysfunctional neurons show increased phosphorylation of tau (p-tau), resulting in the formation of neurofibrillary tangles (p-tau tangles) [62]. Chronic periodontitis (CP) and _P. gingivalis_ infection have been identified as significant risk factors for the development of A\(\beta\) plaques, dementia, and AD [63].  
[PERSON]'s studies hypothesized that _P. gingivalis_ infection contributes to the pathogenesis of AD through the secretion of gingipains to promote neuronal damage and found that gingipain immunoreactivity (IR) was significantly present in AD brains. In addition, they identified _P. gingivalis_ DNA in AD brains and cerebrospinal fluid (CSF) of living subjects diagnosed with probable AD, suggesting that _P. gingivalis_ DNA in CSF could serve as a differential diagnostic marker [64]. In addition, [PERSON]'s article suggests that excessive neuroinflammation may contribute to synaptic protein and memory loss, offering mechanistic insights into _P. gingivalis_-LPS-mediated inflammatory pathways in periodontitis [65]. Recent studies have further elucidated the role of periodontal pathogens in exacerbating neuroinflammation by modulating microglial activation, which may accelerate neurodegenerative processes in AD [66]. Moreover, longitudinal cohort studies have confirmed that effective periodontal treatment correlates with slower cognitive decline in patients at risk for Alzheimer's disease, suggesting potential benefits of oral health interventions in AD management [67].