Alzheimer’s disease (AD) is often co-morbid with chronic pain. Given the anticipated increase in magnitude and median age of the global population, the interaction of these 2 clinically unmet needs will become an increasingly pressing challenge. The reported prevalence of chronic pain in AD patients is 45.8% in the 50 million people worldwide. Pain may be underestimated in AD patients as they may be unable to communicate their pain, particularly in more severe stages of dementia. Chronic pain may result from injuries resulting from falls (e.g., fractures, which are high in AD populations compared to non-AD population), surgeries, diseases, etc. Additionally, AD-specific neurodegenerative changes may affect a multitude of regions implicated in the pain control. Despite this, the effects of AD-associated neurodegeneration on the experience of pain remain equivocal, and whether this may result in differential responses to analgesic treatment remains largely unexplored. Therefore, the main goal of this supplement is to establish the first comprehensive and rigorous studies to address the following questions: Is the neuropathic pain response altered (enhanced or decreased) in AD compared to non-AD mice? Are there differences between AD models of tauopathy and beta- amyloidogenesis? Is effectiveness of analgesic pharmacotherapy altered in AD models? Conversely, does the pain state affect AD-associated cognitive functioning and AD pathology? Is there evidence for age- and sex- dependent effects? Practically, it is impossible to advance the field of pain research and management in the context of AD without addressing these questions. Aim 1. We will test the hypothesis that pain sensitivity in AD mouse models with chronic neuropathic pain is enhanced compared to wild-type. We will use various behavioral assessments of sensory and ongoing qualities of pain, two different AD mouse models (that address tauopathy and amyloidogenesis), a well-established chronic neuropathic pain model. We will test the analgesic efficacy of clinically relevant analgesic (e.g., gabapentin). For enhanced rigor as well as to have a holistic picture of neuropathic pain and AD interaction, we will determine the effects of neuropathic pain on cognitive decline and key mechanisms driving the pathogenesis of AD (e.g., levels of amyloid β, tau) in the brain areas involved in AD. The proposed studies will significantly advance the field of pain and AD by providing fundamental knowledge about the interaction between neuropathic pain, analgesic effectiveness and AD while considering age and sex differences. A potential outcome would be that AD exacerbates pain and alters the efficacy of analgesics. This concept would create a paradigm shift for therapeutic regimen in neuropathic pain management in the context of AD with significant clinical implications. This project would provide the rationale for an in depth analysis of mechanisms underlying the pain-AD interaction in subsequent studies...