Neuropsychiatric symptom phenotypes for early detection of risk in older adults

INTRODUCTION: We examined whether early neuropsychiatric symptom (NPS) patterns were associated with cognitive and neuropathologic changes. METHODS: Latent class analysis within 20,599 cognitively unimpaired older adults in the National Alzheimer's Coordinating Center dataset identified NPS phenotypes. Progression to cognitive impairment, cognitive trajectories, and neuropathology across phenotypes were assessed. RESULTS: Four NPS phenotypes were identified: (1) Low-All, (2) High-Depression, (3) High-Agitation/Anxiety/Irritability (hAAI), and (4) High-All. Risk of progression to mild cognitive impairment (MCI)/dementia differed across phenotypes (Low-All < High-Depression < hAAI < High-All, p < 0.001). High-All and hAAI showed the lowest baseline performance and lower practice effects on cognitive tests, while High-Depression had persistently lower attention scores. The hAAI group had greater amyloid and neuritic plaque burden and higher arteriosclerosis severity compared to other groups (p < 0.01). DISCUSSION: Higher global NPS, and those with high agitation, anxiety, and irritability, showed greater odds of cognitive decline than depressive symptoms alone, underscoring the potential prognostic utility of early NPS patterns in predicting cognitive decline. Highlights: Identified four, data-driven neuropsychiatric symptoms (NPS) phenotypes in cognitively unimpaired older adults NPS phenotypes were differentially linked to progression, cognition, and pathology High-all and high-anxiety, agitation, and irritability had poorer baseline cognition NPS phenotypes may serve as early indicators of neurodegenerative disease risk.