Mild behavioural impairment-apathy and core Alzheimer’s disease cerebrospinal fluid biomarkers

Apathy is a common neuropsychiatric symptom (NPS) in Alzheimer’s disease (AD) but can emerge earlier in prodromal and even preclinical stages as part of mild behavioural impairment (MBI-apathy), a syndrome defined by emergent and persistent NPS. In dementia, apathy is associated with higher morbidity, mortality, and caregiver distress. However, the significance of MBI-apathy in dementia-free persons, including its associations with AD biomarkers, remains unclear. This study aimed to determine whether MBI-apathy is associated with biomarker evidence of amyloid beta (Aβ) and tau (phosphorylated [p-tau], total [t-tau]) in CSF. Because MBI predicts incident dementia better than NPS without MBI, we aimed to determine the association between apathy and AD biomarkers when it occurred as part of the MBI syndrome and when it did not. Dementia-free participants with mild cognitive impairment (MCI) or normal cognition from the Alzheimer’s Disease Neuroimaging Initiative were stratified by NPS status – MBI-apathy, non-apathy MBI, non-MBI NPS, and no-NPS – based on the Neuropsychiatric Inventory (NPI) or NPI-Questionnaire (NPI-Q). Linear regressions modelled cross-sectional associations between NPS status (predictor) and CSF biomarker ratios (Aβ42/Aβ40, p-tau181/Aβ42, and t-tau/Aβ42; primary outcomes) and levels (Aβ40, Aβ42, p-tau181, t-tau; exploratory outcomes), adjusting for age, sex, Apolipoprotein E4, education, Mini Mental State Examination, and NPI version. Hierarchical linear mixed-effects (LME) models assessed longitudinal associations over two years incorporating random intercepts and slopes to account for repeated measures. Fixed effects included NPS status, all covariates from the linear regression model, as well as an interaction term between NPS status and time. Among 477 participants (176 cognitively normal), 52 had MBI-apathy. Primary cross-sectional analyses showed that, compared to the no-NPS group, MBI-apathy was associated with higher CSF p-tau181/Aβ42 (11.25% [2.56% – 20.68%]; adjusted p = 0.018) and t-tau181/Aβ42 (10.26% [2.42% – 18.70%]; adjusted p = 0.018). Exploratory analyses revealed that MBI-apathy was associated with higher CSF p-tau181 (5.98% [0.50% – 11.77%]; p = 0.032). Primary LMEs showed that MBI-apathy was associated with higher CSF p-tau181/Aβ42 (11.34% [2.55% – 20.88%]; adjusted p = 0.022) and t-tau181/Aβ42 (10.34% [2.41–18.88%]; adjusted p = 0.022) over two years. Exploratory LMEs revealed that MBI-apathy was associated with higher CSF p-tau181 (6.03% [0.56% – 11.81%]; p = 0.032) and t-tau (4.96% [0.07% – 10.09%]; p = 0.049) over two years. MBI-apathy was significantly associated with core AD biomarkers cross-sectionally and longitudinally, over two years, underscoring its relevance as a marker of AD pathological burden. An overall MBI composite score may reflect a broader spectrum of pathology and warrants further investigation.