Total Shoulder Replacement Does Not Confer Neuroprotection: A Propensity-Matched Negative Control Analysis Using a National Real-World Database

Background/Objectives: Lower-limb total joint arthroplasty (TJA) has been associated with neuroprotective effects, including reduced incidence of dementia and Parkinson disease. Whether these effects are mediated by restored ambulation (specific to lower-limb surgery) or by the systemic anti-inflammatory consequences of arthroplasty (shared by all joint replacement procedures) remains undetermined. We used total shoulder replacement (TSR) as a negative control comparator to interrogate this mechanistic question. Methods: Using the TriNetX US Collaborative Network (114 million patients), we constructed propensity score-matched cohorts comparing TSR patients to total knee arthroplasty (TKA) patients (66,038 per group) following a 730-day lag period. Five pre-specified outcomes were tracked: incident dementia, sarcopenia, Parkinson disease, cataract (active positive control), and elevated C-reactive protein (CRP). Matching balanced 18 demographic and comorbidity covariates. Kaplan–Meier survival analysis with log-rank testing and Cox proportional hazards regression were performed. Results: After propensity matching, TSR and TKA groups were balanced on all covariates (standardized mean differences < 0.10 for all 18 variables). Compared to TKA, TSR patients showed no significant reduction in incident dementia (HR = 1.63, 95% CI: 0.75–3.55, p = 0.217) or sarcopenia (HR = 1.32, 95% CI: 0.72–2.45, p = 0.369). Notably, TSR patients had significantly higher rates of incident Parkinson disease (HR = 1.24, 95% CI: 1.08–1.41, p = 0.002) and more frequent CRP elevation (HR = 1.13, 95% CI: 1.06–1.21, p < 0.001) than TKA patients. The cataract control outcome did not differ between groups (HR = 0.98, 95% CI: 0.89–1.08, p = 0.698). Conclusions: TSR does not replicate the neuroprotective effects associated with lower-limb TJA, and is associated with greater inflammatory burden and higher Parkinson disease incidence than TKA after careful propensity matching. These findings support the hypothesis that restored ambulation—rather than surgical anti-inflammatory effects alone—is the primary mediator of neuroprotection following lower-limb arthroplasty, with important implications for understanding the biology of exercise-dependent neuroprotection.