Alzheimer’s disease (AD) affects 1 in 8 Americans, and is the sixth leading cause of death in the United States. Nearly a quarter of a million of those living with AD are Veterans, and recent studies have shown that Veterans have a 60% increased risk of developing AD. Behavioral changes, such as agitation and aggression, confusion, and dramatic personality changes, termed neuropsychiatric symptoms (NPS) are highly prevalent in AD patients, and are extremely challenging for caregivers, placing significant emotional and financial burdens on those caring for patients with AD, yet current pharmacological treatments for NPS, such as antipsychotics, sedative/hypnotics, anxiolytics, and antidepressants, often have significant adverse effects that outweigh the benefits of these treatments. Thus, it is critical to develop better therapeutic approaches to NPS in AD patients. In the general psychiatric literature, there is an emerging idea that inflammation may be a critical contributor to the etiology of psychiatric conditions including mood disorder, major depression, post-traumatic stress disorder (PTSD), and even schizophrenia. How inflammatory processes contribute to neuropsychiatric symptoms in AD has not yet been studied. Neuropsychiatric manifestations in AD patients occur in the context of a progressive neurodegenerative disease – the characteristic of AD - which produces substantial inflammation, itself, so we believe it is critical to understand the role of inflammation in NPS specifically in the context of AD, the ultimate goal of this application. This application is based on the emerging idea that brain inflammation may contribute to psychiatric conditions including depression, post-traumatic stress disorder (PTSD), and even schizophrenia. We propose the hypothesis that treating neuroinflammation in AD patients will prevent or decrease neuropsychiatric symptoms such as agitation, aggression, and apathy, with the potential of finding alternative and better treatments for Veterans with these difficult-to-treat and often devastating behavioral symptoms of AD. The premise for this grant is based on the literature, our published data, and new preliminary data, which show that anti-inflammatory treatment treatments directed at interleukin-6 (IL-6) signaling, specifically, will be effective in attenuating NPS in relevant models. Aim 1 will ask whether evidence of inflammation predicts increased risk of NPS in a new mouse model of AD (the hAPP knockin mice recently developed at the Riken Institute) - mice known to exhibit progressive brain inflammation - and will characterize how aged AD mice perform on behavioral tasks relevant to human NPS. Markers of inflammation to be correlated with behavior will include serum C- reactive protein and IL-6, which have been strongly associated with many psychiatric disease states. In addition, neuroinflammation will be assessed by quantifying the number of activated astrocytes (GFAP) and microglia (Iba1) using con...