Project Summary/Abstract: Alzheimer’s Disease (AD) and osteoarthritis (OA) are two of the most common health conditions affecting the elderly population, and the economic and health impacts of AD and OA will markedly increase over the next several decades as the elderly population grows. Deposition of beta-amyloid protein (Aβ) outside neurons and abnormally phosphorylated Tau protein (pTau) inside neurons are two hallmark changes in the brain associated with AD. Interestingly, our preliminary studies also found Aβ deposition and higher levels of pTau in the joints of aged mice (96-weeks-old) and during OA progression in mouse knee joints following non-invasive ACL injury. Additionally, we found that 17-month-old APP/PS1 mice, an established model of AD, had Aβ plaques in the synovium of their knee joints. Taken together, these observations suggest a common underlying mechanism between OA and AD, and raise the possibility that systemic inflammation associated with OA may accelerate the progression of AD. The overall goal of our funded R01 grant is to determine how biomechanical interventions can be utilized following joint injury to mitigate joint inflammation and affect the progression of post-traumatic osteoarthritis (PTOA). The research proposed in this supplement will extend this line of investigation to determine if systemic inflammation during OA progression accelerates AD progression in a genetic mouse model of AD (APP/PS1 mice), and whether this effect can be mitigated by joint unloading during the early phase post-injury. We hypothesize that OA and AD share a similar pathogenetic mechanism, and that inflammation associated with OA progression can accelerate AD progression and cognitive decline. Our specific aim is to determine whether OA-associated systemic inflammation accelerates the onset of AD progression and deterioration of cognitive function in APP/PS1 mice, and whether this acceleration can be mitigated by early phase unloading. This supplement extends the focus of our research to investigate the connection between OA and AD pathologies in the joint and brain. This supplement study will lead to future R01 applications that will expand these results into more comprehensive translational research on whether systemic inflammation from the peripheral organs such as synovial joints may be associated with early-onset and faster progression of AD. It is also our long-term goal to develop early diagnostic strategies and novel pharmaceutical interventions to prevent the accumulation of Aβ and pTau in the joint and brain, which could potentially slow or prevent the progression of both OA and AD.