Neuropsychiatric Symptom Clusters and Their Association With Brain Structure in Alzheimer Disease.

Objective: Neuropsychiatric symptoms (NPS) constitute a major challenge in Alzheimer disease (AD). We applied a component-based symptom paradigm by deriving Neuropsychiatric Inventory Questionnaire (NPI-Q) clusters and evaluating their longitudinal associations with regional brain volumes and functional outcomes (instrumental activities of daily living, activities of daily living [ADLs]). Methods: Participants with AD (N=111) were from the Ontario Neurodegenerative Disease Research Initiative. NPS were assessed using the NPI-Q. Symptom clusters were identified via principal components analysis at baseline. Magnetic resonance imaging-derived volumes for 34 cortical and 9 subcortical regions were obtained annually over 3 years. Longitudinal associations between NPS clusters and functional outcomes were examined using linear mixed-effects models adjusting for age, sex, Montreal Cognitive Assessment (MoCA), education, visit number, and cholinesterase inhibitor use. Results: Four clusters explained 62% of variance: hyperactivity (disinhibition, irritability, motor disturbance, agitation), psychosis (hallucinations, delusions, euphoria), neurovegetative (apathy, appetite), and affective (depression, anxiety, nighttime behavior). The hyperactivity cluster was associated with the left middle temporal (β=-0.24, P=.025) and right nucleus accumbens (β=-0.28, P=.007). The neurovegetative cluster was associated with the left middle temporal (β=-0.50, P<.001) and right nucleus accumbens (β=-0.55, P<.001). The affective cluster showed the strongest associations with the left rostral anterior cingulate (β=-0.42, P=.002) and right medial orbitofrontal cortex (β=-0.47, P=.001). All clusters predicted iADL outcomes; clusters 1, 3, and 4 also predicted ADL outcomes. Greater NPS burden, male sex, age, lower MoCA, and later visits predicted worse function. Conclusion: NPS in AD separate into hyperactivity, psychosis, neurovegetative, and affective clusters, supporting a cluster-based paradigm linking co-occurring behavioral symptoms with brain structure and functional decline.