Abstract Objective We explored the course of neuropsychiatric symptoms (NPS) in autopsy-confirmed Alzheimer’s disease (ad) subjects with and without a history of TBI (TBI+ vs. TBI-), expecting that TBI history may be associated with NPS severity over time. Method Data from 1532 individuals (age 50+) with autopsy-confirmed ad were obtained from the National Alzheimer’s Coordinating Center (Mean visits = 3.69). Those with other tau pathology and significant Lewy pathology were removed. Neuropsychiatric Inventory Questionnaire (NPI-Q) and the 15-item Geriatric Depression Scale (GDS) scores were used to examine NPS. Multilevel zero-inflated binomial regression models assessed if NPS severity differed between TBI+ (N = 154) and TBI- (N = 1378) groups over time. Covariates included: years from baseline visit, demographics, MMSE, Functional Activities Questionnaire score, and psychotropic treatment. Results The groups did not differ at baseline in NPI-Q (p = 0.36) or GDS (p = 0.07) scores. NPI-Q scores mildly decreased in the TBI+ group (trend = −0.03), whereas the TBI- group remained stable over time (trend = 0.001), 95% CI for the trend [0.01, 0.07]. GDS scores increased more rapidly in the TBI+ group (trend = 0.08) than the TBI- group (trend = 0.02), 95% CI for the trend [0.02, 0.10]. Conclusions This preliminary study suggests that NPS course in ad may differ depending on TBI history, though effect sizes were small. Over the course of ad, individuals with a history of TBI may experience less NPS overall (as measured by NPI-Q scores) but may experience marginally more depressive symptoms (as measured by GDS scores). Future investigations evaluating the relationship between TBI and the course of neurodegenerative disease are needed.