Chronic inflammatory conditions like periodontitis and inflammatory bowel disease (IBD) are reported to contribute to the pathogenesis of late-onset Alzheimer's disease (AD). Gram-negative bacteria are the main bacterial species causing oral and gut mucosal infections. Lipopolysaccharide (LPS) is a major inflammation-inducing molecule in Gram-negative bacteria. LPS derived from the oral bacterium Porphyromonas gingivalis exhibits heterogeneous tetra-acylated and penta-acylated lipid A, while LPS from Escherichia coli exhibits the classical hexa-acylated lipid A. Whether P. gingivalis-LPS and E. coli-LPS play a similar role in the progression of late-onset AD is unknown. Using adult, wild-type C57BL/6J mice to mimic the adult population without genetically determined predisposition to AD, we showed that chronic inflammation induced by a 28-day, subcutaneous infusion of P. gingivalis-LPS or E. coli-LPS can lead to neuroinflammation and AD-like cognitive decline and pathology in male mice. At this relatively early stage (4 weeks) of chronic inflammation when the blood-brain barrier is intact, both P. gingivalis-LPS and E. coli-LPS cause neuroinflammation through Toll-like receptor 4 (TLR4) and Toll-like receptor 2 (TLR2) expressed at microglia in the brain. Notably, only E. coli-LPS induces significant inflammatory responses systemically. In short, our results suggest that chronic P. gingivalis-LPS release (occurring in chronic periodontitis) or E. coli-LPS release (occurring in IBD) could harm the brain before the blood-brain barrier is disrupted; continuous local P. gingivalis-LPS release might do harm to the brain before exhibiting adverse effects systemically.