ABSTRACT Total joint arthroplasty (TJA) is the fastest growing elective surgery in the nation. Over 7 million Americans are currently living artificial hip or knee joints and this is expected to reach epidemic proportions as a result of growing demand for improved mobility and quality of life. Although TJA is a safe and effective procedure, there is growing concern about the long-term safety of chronic exposure to TJA implants. Indeed, in a growing number of published case reports, TJA is associated with neurocognitive deficits several years after surgery. Yet, the long-term effects of implant debris from TJA implants on brain structure and cognitive function are unknown. Large scale, population-based studies are needed to assess the potential contribution of chronic exposure to TJA implant debris and subtypes (cobalt/chromium, polyethylene) to the risk of cognitive decline and dementia. We propose to leverage the unique data resources of the Rochester Epidemiology Project (REP, R01-AG034676), the Mayo Clinic Study of Aging (MCSA, U01-AG006786) and the Mayo Alzheimer's Disease Research Center (ADRC; P50 AG016574) as well as the Mayo Clinic TJA registry to elucidate the long-term risk of dementia and cognitive impairment in TJA patients. Using 5-decades of historical data from the REP, we will compare the risk of dementia and subtypes in population-based cohorts of TJA patients and matched non-TJA subjects adjusting for well-known confounders (age, sex, obesity). We will further examine the risk according to implant types. Using cross-sectional and longitudinal cognition and neuroimaging measures collected as part of the MCSA cohort, we will determine whether cognitive status and neuroimaging markers of cognitive function are worse in TJA patients compared with non-TJA subjects. Finally, we will correlate metal ion levels with cognitive function and structural changes on neuroimaging and postmortem tissues. Successful completion of the proposed series of studies will be a key step towards understanding whether chronic exposure to TJA implants is associated with cognitive impairment. Our unique data resources offer a rare opportunity to efficiently address this unknown risk. Potential downstream effects are significant including eligibility criteria for TJA, and monitoring high risk TJA implants and patients who are most likely to suffer from systemic effects. Even negative findings can exert a significant public health impact by providing reassurance about the safety of TJA to millions of current and future TJA patients.