White Matter Tract Vulnerability to Amyloid Pathology on the Alzheimer’s Disease Continuum

Alzheimer’s disease (AD) is marked by progressive cognitive decline and memory loss, due to the abnormal accumulation of amyloid-beta (Aβ) plaques, followed by tau pathology, and a gradually spreading pattern of neuronal loss. Understanding how amyloid positivity affects the brain’s neural pathways is critical for understanding how the brain changes with AD pathology. Tractometry offers a powerful approach for the in vivo, 3D quantitative assessment of white matter tracts, enabling the localization of microstructural abnormalities in diseased populations and those at risk. In this study, we applied BUAN (Bundle Analytics) tractometry to multi-cohort diffusion MRI data from a total of 1,908 participants: 606 participants in ADNI3 (Alzheimer’s Disease Neuroimaging Initiative Phase 3) and 1,302 participants from the HABS-HD (Health and Aging Brain Study–Healthy Diversity). Using BUAN and along-tract statistical analysis, we assessed the localized effects of amyloid positivity, potentially mediated by tau, on white matter pathways, with amyloid positivity quantified via amyloid-sensitive positron emission tomography (PET). BUAN enables tract-specific quantification of white matter microstructure and supports statistical testing along the full length of fiber bundles to detect subtle, spatially localized associations. We present 3D visualizations of tract-wise amyloid associations, highlighting distinct patterns of white matter degeneration in AD.