Exploring Brain and Ventricular Boundary Shift Integral Associations with Beta Amyloid and Neurofilament Light in Alzheimer’s Disease

Background Alzheimer’s disease (AD) pathology develops over decades, creating a prolonged preclinical phase. Sensitive biomarkers are needed to detect neurodegeneration early. We aimed to determine whether baseline cerebrospinal fluid Aβ1–42 (CSF Aβ1–42) and plasma neurofilament light chain (NfL) levels are associated with brain atrophy rates in early AD. Methods We analyzed data from 76 participants in the ADNI cohort (30 cognitively normal [CN], 32 with mild cognitive impairment [MCI], 14 with AD). Baseline CSF Aβ1–42 and plasma NfL levels were measured. Whole-brain, ventricular, and hippocampal volume changes over 12 months were quantified with the Boundary Shift Integral (BSI) on serial T1-weighted MRIs. Linear regression models tested associations between each biomarker and 12-month brain atrophy, adjusting for age, sex, and education (significance threshold p < 0.05). Results Lower baseline CSF Aβ1–42 was significantly associated with greater whole-brain, ventricular, and hippocampal volume loss over 12 months in the MCI and AD groups (p < 0.05). No significant association was found between CSF Aβ1–42 and atrophy in CN. Baseline plasma NfL showed no significant relationship with 12-month atrophy in any group. Conclusion These findings help clarify the differential relationship between key pathological markers (Aβ accumulation vs. axonal injury reflected by NfL) and longitudinal structural brain changes by directly comparing these associations using multiple BSI metrics across the AD spectrum. The results highlight that BSI is sensitive to Aβ-related neurodegeneration but may capture different aspects of pathology than plasma NfL, significantly impacting our understanding of biomarker dynamics and supporting BSI's potential for tracking early AD changes. This warrants further longitudinal validation to establish its clinical utility.