Plasma NfL, P-tau181, and P-tau181/Aβ42 Ratio in Predicting Mild Behavioral Impairment in Dementia-Free Multiethnic Asian Older Adults With Mixed Pathology in a 5-Year Clinical Cohort

Objective: The underlying mechanisms of mild behavioral impairment (MBI), a marker for cognitive impairment and dementia, have remained unclear especially in a multiethnic Asian population. The study aimed to examine whether baseline Alzheimer disease biomarkers, including plasma neurofilament light (NfL) chain, phosphorylated tau-181 (p-tau181), and the p-tau181-to-amyloid-β42 (p-tau181/Aβ42) ratio, could predict MBI incidence in dementia-free Asian older adults. Methods: Participants were recruited from the community and memory clinics from August 2010 to April 2022. All participants underwent cognitive, neuropsychiatric, and clinical assessments annually and neuroimaging scans biennially at baseline and over a maximum of 5 years. Neuropsychiatric symptoms (NPS) and incident MBI were examined using Neuropsychiatric Inventory. Plasma NfL, p-tau181, and Aβ42 were measured using single molecule array assays. Neuroimaging measures of hippocampal volume (HV) and white matter hyperintensities (WMH) were obtained. Results: A total of 305 dementia-free participants were included (age 72.1 ± 7.8 years, 52.5% female, 27.9% no cognitive impairment). Among 248 MBI-free participants at baseline, 55 (25.3%) participants developed incident MBI in 5 years. Higher baseline p-tau181, p-tau181/Aβ42 ratio, and NfL were predictive of increased NPS severity longitudinally and MBI incidence (P < .05). Higher p-tau181 levels (hazard ratio [HR] [95% CI], 2.40 [1.00-5.75], P = .05) were independently associated with an increased likelihood of incident MBI after accounting for incident dementia and plasma NfL. This relationship remained significant when controlling for HV and WMH (HR [95% CI], 2.69 [1.08-6.70], P = .03). Conclusions: Our findings highlighted the relationship between amyloid burden and neuroaxonal degeneration with neurobehavioral changes in multiethnic Asian older adults with underlying mixed pathology.