ABSTRACT It is suggested that infections increase the risk for Alzheimer's disease (AD). However, the evidence behind this is not well described. Infections, infectious agents, and their toxic products are associated with short- and long -term cognitive decline and neurodegeneration. Potential links between infections and AD include the activation of the peripheral immune system, the increase in the permeability of the blood-brain barrier, the production of inflammatory mediators, and the presence of peripheral immune cells in the brain triggering a severe glial cell activation, among others. Imbalance of the immune system also increase the synthesis and accumulation of the amyloid-beta (Aβ) peptide, the hyperphosphorylation of tau, and the induction of chronic inflammation in the brain. The main goal of this project is to investigate the role of peripheral and brain infections in the development of AD. Our aims are to study the role of sepsis and meningitis in brain amyloid and tau pathology, associated cognitive decline, and brain inflammation. We expect that outcomes from this project will help us to identify and understand the molecular and cellular mechanisms underlying the role of infection in the pathogenesis of AD. For this purpose, we will use a series of established and novel biochemical assays in animal models of AD and human-derived samples. Mouse models of brain Aβ and tau accumulation will be subjected to peripheral infection through cecal ligation and perforation (CLP) surgery, or to bacteria administration into the cisterna magna to induce meningitis. Then, we will assess whether these infection modalities trigger, accelerate, or worsen AD pathology. The participation of the peripheral immune system in these events will be explored by bone marrow transplants from non-AD mice subjected to infection to naïve AD mouse models. Clinically, we will test for the presence of disease-associated Aβ and tau in the blood of septic and post-septic patients and the cerebrospinal fluid (CSF) of individuals afflicted by meningitis. This project will provide us with valuable insights into events associated with AD risk and will produce critical data for understanding the role of the immune system in dementia. Clinically, this research may help identify individuals with an increased risk for developing AD.