This chapter explores the interconnections between periodontal disease, atherosclerosis, and Alzheimer’s disease (AD), particularly emphasizing the role of apolipoprotein E (apoE). It provides a comprehensive summary of preclinical and clinical evidence linking periodontitis to atherosclerosis and AD. Periodontal disease driven by periodontophatogenic bacterial infections is believed to accelerate the progression of atherosclerotic plaque formation in blood vessels and β-amyloid (Aβ) deposition in the brain, a process exacerbated in experimental models using APOE knockout(−/−) mice. We discuss the pathogenic role of Porphyromonas gingivalis and its virulence factors, particularly lipopolysaccharide (LPS) and gingipain, which trigger inflammatory cascades that promote Aβ accumulation. Furthermore, we discuss how persistent translocation of Porphyromonas gingivalis from the oral cavity to the bloodstream may lead to chronic systemic inflammation, contributing to microglial activation and neuroinflammation in the brain. Special attention is given to the role of gingipains in selectively cleaving apoE proteins, with a preference for apoE4 over apoE3. The chapter explores the implications of this process in neurodegenerative processes, highlighting its potential impact on Alzheimer’s disease progression.