Neuropsychiatric symptoms trajectories preceding incident mild cognitive impairment and dementia

To characterize nonlinear neuropsychiatric symptoms (NPS) trajectories preceding mild cognitive impairment (MCI) and dementia and examine their associations with neuropathology and cerebrospinal fluid (CSF) biomarkers. We analyzed 11,781 cognitively normal participants aged 60 years or older from the National Alzheimer’s Coordinating Center. NPS were assessed using the Neuropsychiatric Inventory Questionnaire and Mild Behavioral Impairment–derived domains. Event-anchored models evaluated the normal-to-MCI and MCI-to-dementia transitions. Among 11,781 participants, 2,865 developed MCI and 731 subsequently developed dementia. Overall NPS separation was already present at the earliest evaluated time point, 12 years before MCI diagnosis (RR = 1.42, 95% CI 1.09–1.84), and first became significant 5 years before dementia diagnosis (RR = 1.41, 95% CI 1.15–1.74). These time points also met the prespecified acceleration criteria, although the 12-year estimate was located at the boundary of the observation window. Emotional dysregulation showed the earliest sustained separation before MCI, whereas domain-specific acceleration preceding dementia was staggered from 5 to 1 years before diagnosis. Autopsy analyses showed heterogeneous associations across Alzheimer Disease–Related Neuropathologic Measures, Lewy Body Pathology, and Cerebrovascular Pathologies. In CSF analyses, only p-tau status was associated with a significant trajectory difference. Distinct nonlinear NPS trajectories preceded MCI and dementia and showed heterogeneous neuropathological correlates. Longitudinal NPS assessment may provide complementary information about behavioral progression, although its individual predictive value requires validation.