Functional impairment statistically mediates the association between hyperarousal neuropsychiatric symptoms and cognitive decline: a prospective cohort study

Introduction Neuropsychiatric symptoms (NPS) are prevalent in older adults and are associated with cognitive decline. This study investigated the association between hyperarousal NPS (HNPS) and cognitive progression, focusing on the mediating role of functional impairment and its link to Alzheimer’s disease (AD) pathology. Methods Using data from 1,657 non-demented participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we evaluated the Hyperarousal Neuropsychiatric Inventory Questionnaire (HNPI-Q, comprising agitation, anxiety, and irritability), the Functional Activities Questionnaire (FAQ), APOE ε4 status, Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 (ADAS13) scores, regional brain volumes, and amyloid-β (Aβ) positron emission tomography (PET) Centiloid values. Analyses included Cox and linear regression, mediation analysis, and nomogram development. Results HNPS predicted 5-year cognitive decline (HR = 1.14, p = 2.7 × 10 –4 ), an association attenuated after adjusting for FAQ. HNPI-Q scores were longitudinally associated with functional and cognitive decline. Mediation analyses indicated that functional impairment statistically mediated the association between HNPS and cognition. Notably, the rate of functional decline was strongly correlated with the rate of Aβ accumulation, a coupling that was also evident in participants who progressed to cognitive deterioration. Predictive models based on HNPI-Q and FAQ showed excellent discrimination (AUC: 0.838 and 0.845) and calibration. Conclusion HNPS was associated with cognitive decline, an association that was statistically mediated by functional impairment, which itself co-varies with Aβ pathology. The HNPI-Q stratified the 5-year risk of cognitive deterioration in this cohort, and whether intervening on these symptoms or on functional decline alters the clinical course remains to be further investigated.