Behavioral Complexity in Alzheimer's Disease: A Diversity-Based Analysis of Neuropsychiatric Symptoms

Background and Objectives: To quantify behavioral complexity in probable Alzheimer's disease (AD), compare complexity phenotypes, and determine whether behavioral complexity provides clinically meaningful information beyond total neuropsychiatric burden. We also explored whether global amyloid extent and lobar amyloid topography added explanatory value. Methods: In this cross-sectional retrospective study, we analyzed 245 psychotropic drug-naïve patients with probable AD, positive ¹⁸F-FC119S amyloid positron emission tomography (PET), and complete neuropsychiatric, cognitive, functional, and regional PET data. Behavioral complexity was derived from 12 Korean Neuropsychiatric Inventory domains using symptom count, normalized Shannon entropy of the frequency × severity profile, and a composite index. Patients were classified into tertiles. Multivariable regression and burden-stratified analyses examined associations with cognition, dementia severity, function, and amyloid measures. Results: Higher behavioral complexity was associated with lower Korean Mini-Mental State Examination (K-MMSE) scores and higher Clinical Dementia Rating (CDR) and Global Deterioration Scale (GDS) stages. In multivariable analysis, higher CDR, higher GDS, and lower Barthel Index independently predicted greater complexity, whereas amyloid extent did not. After adjustment for total neuropsychiatric burden, higher CDR remained independently associated with the composite complexity index and normalized entropy, while amyloid extent remained non-significant. Complexity-related clinical differences were most evident in the lowest burden stratum and attenuated at higher burden levels. Regional amyloid analyses yielded only selective signals. Conclusions: Behavioral complexity is a clinically meaningful neuropsychiatric phenotype in AD. Although strongly related to total neuropsychiatric burden, it is not fully reducible to it, with its clearest independent association seen for global dementia severity, particularly at lower overall burden.