ABSTRACT Inflammation is believed to aggravate most of the chronic pathologies associated with aging, including neurodegeneration and Alzheimer’s disease (AD). In contrast to that, there is accumulating evidence that certain infections may delay AD onset. Beneficial and detrimental impacts of infection and inflammation upon AD have not been systematically studied. This supplement proposal will directly address this issue, leveraging and consistent with, the goals of the parent award. Our hypothesis for the supplement is that at least some types of infection-induced inflammation may stimulate brain immune mechanisms to delay/beneficially modulate the onset and severity of AD. To test it, we will cohouse AD mice with polymicrobial flora (the major focus of the parent award), or with persistent or acute viruses (another major focus of the parent award), or innate immune sensor ligands (TLR) as signals that induce localized (brain) infection, systemic persistent infection or systemic acute sterile inflammation. We will assess whether and how these infection-based manipulations modulate AD onset and severity (using flow cytometric – for immune cell activation - immunohistochemical and, where possible, inflammatory markers) in two models of familial AD in mice. The results should pave the way for a fully developed R01 proposal to mechanistically dissect the influence of infection and inflammation on AD and AD- associated cognitive and behavioral changes.