This is an administrative supplement application to R01AR070181. The focus of the initial award is corrosion and fretting wear of total hip replacements and subsequent adverse local tissue reactions. This new supple- mentary project will now further investigate the dissemination of corrosion and wear debris from total joint ar- throplasties (TJA) to the brain and its implications on Alzheimer's disease (AD) and cognitive decline. This re- search addresses an important problem because AD and TJA—the end-stage treatment of osteoarthritis (OA)—affect large and overlapping patient groups. Our preliminary data shows 69% of TJA patients have inter- mediate to high likelihood of AD based on NIA-Reagan criteria. Hallmarks of AD are neuropathologic findings of amyloid plaque and neurofibrillary tangles in the brain. Plaques aggregation is mediated by interactions with specific metals such as Cu, Zn, Cd, Al and Fe. There is little knowledge on the role of prominent implant metals such as Co and Ti, which naturally would not occur in high quantities in the brain. Yet, our current award demonstrated metal particle and ion release under corrosion/wear linked to local and systemic reactions. To date, no studies have investigated links between TJA and AD, likely due to insufficient patient numbers and brain tissue availability. Our preliminary data shows numerous CoCrMo and TiAlV implant alloy particles and other corrosion products located within the brain of TJA patients, yet the frequency of this occurrence, associ- ated tissue responses, and its impact on cognition or Alzheimer's neuropathologies remain unknown. It is the long-term goal of our research to determine the effect of normal and excessive concentrations of im- plant debris on cognitive abilities of patients and its implications on neurological disorders. It is the objective of this proposal to determine if TJAs are associated with increased implant metal levels in the brain and AD neu- ropathology (Specific Aim 1), to characterize implant debris within different brain regions and associated tissue responses (Specific Aim 2), and to gain an understanding of how debris crosses the blood-brain barrier (Spe- cific Aim 3). It is our hypothesis that implant metal particles and ions are actively or passively transported across the blood-brain barrier, settle within the brain, and are capable of causing local pathology such as in- flammation and may be associated with Alzheimer's neuropathology and cognitive decline. We will leverage 1) an existing unique data set on the concentration of different metals within four brain regions of 544 patients from a NIA funded neuropathologic study of deceased participants with known neuropathology, 2) availability of high resolution imaging techniques to characterize metal particles within brain tissue of patients with TJA history, and 3) an existing murine model of implant debris induced osteolysis in aged mice to establish the mechanism of particle dissemination acr...