ABSTRACT Higher prevalence of sepsis in older individuals is also linked to increased rate of diagnoses for multiple types of dementia including Alzheimer’s disease and related dementias (ADRD). Chronic impairments include changes in memory and attention, emotional function and neuromuscular strength which each have a major impact on patients and families. Exact mechanisms underlying this persistent damage are unknown but data support a role for chronically activated microglia following infection. Understanding of neurological changes during this critical time period is hampered by a lack of appropriate animal models and short experimental endpoints. Behavioral assessments can be severely confounded by hypoactive delirious states and sickness behaviors, and many studies have been conducted in young rather than aged animals, without additional AD-relevant neuropathology further limiting interpretive and predictive power. We will address each of these challenges and test the overarching hypothesis that overarching hypothesis that age and AD neuropathology predispose the brain to greater neuronal damage, prolonged microglial activation and poorer cognitive outcomes following sepsis. Further, we hypothesize that microglia of older adults have a more robust inflammatory response and a reduced ability to downregulate inflammation leading to persistent cognitive impairment, particularly in the presence of additional AD-relevant neuropathology. Our three aims will be conducted in young adult (3 months) and aged mice (up to 18 months), and in vivo data will be supported by ex vivo electrophysiology, immunohistochemistry and molecular biology approaches. We will assess our key outcomes up to 90 days following recovery from illness. In Aim 1 we will demonstrate the extent of increased risk for persistent cognitive impairment and prolonged neuroinflammation following sepsis in aged compared to young animals. We will use a cecal slurry injection to induce sepsis in mice up to 18 months using a rodent model that recapitulates the major defining features of acute brain dysfunction including: acute neuroinflammatory response, disrupted EEG patterns, behavioral deficits across a range of cognitive and neuromuscular domains, and impaired hippocampal long-term potentiation. In Aim 2 we will directly examine the role of microglia in persistent cognitive impairment following sepsis using clinically relevant biomarkers, immunohistochemistry morphological quantification of microglia and whole tissue and single cell RNA approaches. In Aim 3 we will determine the extent to which AD neuropathology contributes to sepsis- induced cognitive impairment and brain dysfunction. We will compare behavioral outcomes and microglial response in two different mouse models of AD to test the potential for increased sensitivity to CS in the presence of common AD neuropathology and gene variants.