Mild behavioral impairment-apathy and Alzheimer's disease plasma phosphorylated tau biomarker levels
Background Mild behavioral impairment (MBI), characterized by later-life emergence of persistent neuropsychiatric symptoms (NPS), is an early clinical indicator of dementia risk. Global MBI has been associated with Alzheimer's disease (AD) pathology; studies have also explored MBI domains. Prior work has linked MBI-apathy to AD cerebrospinal fluid (CSF) biomarkers, but whether associations are detectable using plasma-based biomarkers such as phosphorylated tau (p-tau) is unknown. Establishing such relationships is critical, as plasma biomarkers are more accessible than CSF. Objective To explore cross-sectional and longitudinal associations between MBI-apathy and plasma p-tau181 levels using Alzheimer's Disease Neuroimaging Initiative data. Methods Older adults with normal cognition or mild cognitive impairment were categorized as MBI-apathy (n = 69), non-MBI NPS (n = 112), and no-NPS (n = 215) based on Neuropsychiatric Inventory scores and symptom persistence over one year. Linear regression modelled cross-sectional associations between NPS group and plasma p-tau181, adjusting for age, sex, education, apolipoprotein E4 status, and Mini-Mental State Examination score. Hierarchical linear mixed-effects modelling assessed associations over two and three years, including time-by-NPS group interactions. Results MBI-apathy was associated with significantly higher plasma p-tau181 levels at baseline (24.05% [6.06–45.08%]; adjusted p = 0.014), and over two (26.46% [7.24–49.12%]; adjusted p = 0.012) and three years (29.28% [10.17–51.72%]; adjusted p = 0.004) compared to no-NPS. No significant associations were observed for non-MBI NPS. In sensitivity analyses, non-MBI apathy was not associated with plasma p-tau181 at baseline (−9.96% [−32.69–20.44%]; unadjusted p = 0.478). Conclusions MBI-apathy is associated with elevated plasma p-tau181 cross-sectionally and longitudinally, supporting MBI-apathy as a potential proxy marker of tau pathology for early AD detection.