The exact cause of Alzheimer’s disease (AD) and its related dementias is still unclear. However, accumulating evidence supports that chronic bacterial infection is one cause of AD and its related dementias. Bacteria can directly infect in the brain or only the secreted protein virulence factor(s) from bacteria chronically infected in another organ can traffic to the brain, attributing to neuronal damage and loss. One of the most well-characterized bacterial infections associated with AD is chronic infection of an oral pathogen Porphyromonas gingivalis and its secreted virulence factors gingipains. Some bacterial virulence factors secreted by bacterial pathogens during chronic infection are also known to have tropism to the brain. Here, we propose a series of experiments using bacteria and bacterial secreted virulence factors known to traffic to the brain to begin (1) to obtain a mechanistic understanding of the host-bacterial pathogen interactions with an emphasis on bacterial infection-induced processes associated with inflammation and neuronal damage and loss, and (2) to obtain information enabling for tackling chronic bacterial infection in the brain. The proposed work is within the scope of the parent R01 award aimed at understanding the molecular mechanism of the host-pathogen interactions promoting persistent/chronic infection in host cells, and there is an anticipated synergism between the two. Bacterial AD and its related dementias are significantly understudied and therefore the outcomes from the proposed work are anticipated to stimulate additional activities in the field concerning infection-mediated inflammation and neurodegeneration, as well as the fight against bacterial infection in the brain.