Fixel-Based Analysis Identifies Selective Vulnerability of Non-Dominant Fiber Populations in Aging and Cognitive Decline

Fixel-Based Analysis (FBA) offers a novel framework to disentangle fiber-specific white matter (WM) degeneration, particularly within complex crossing-fiber architecture where conventional diffusion tensor imaging (DTI) falls short. In this study, we leveraged single-shell diffusion MRI data from 297 older adults enrolled in the Vanderbilt Memory & Aging Project to quantify fiber density (FD), cross-section (FC), and their composite (FDC) across primary (N1), secondary (N2), and tertiary (N3) fiber populations. By stratifying white matter into anatomically defined crossing-fiber convergence groups, we examined how fiber dominance and architectural complexity modulate associations with age, cognitive status, and longitudinal cognitive decline. Results revealed that FD and FDC in non-dominant (N2/N3) fibers were the strongest predictors of both baseline and longitudinal cognitive trajectories, particularly in memory and executive domains. These associations persisted across fiber convergence strata, suggesting that fiber population identity, rather than anatomical complexity, may confer greater vulnerability to age- and disease-related degeneration. Our findings position non-dominant fiber metrics as sensitive candidate biomarkers for early white matter disruption in Alzheimer’s disease and support the application of multi-fiber modeling to enhance detection of preclinical neurodegeneration.