The Alzheimer’s continuum was biologically characterized by beta-amyloid accumulation, which, in its initial stages, was overlaid on white matter degradation associated with aging. For a study, researchers sought to combine diffusional kurtosis imaging (DKI) and biophysical modeling to detect and characterize amyloid-related white matter alterations in preclinical Alzheimer’s disease. In cohort research, cognitively normal adults aged 45 to 85 years conducted brain magnetic resonance imaging, amyloid positron emission tomography (florbetapir), neuropsychological testing, and other baseline clinical assessments. Investigators examined whether beta-amyloid-negative (AB−) and -positive (AB+) participants differed on DKI-based conventional (i.e., fractional anisotropy [FA], mean diffusivity [MD], mean kurtosis) and modeling (i.e., axonal water fraction [AWF], extra-axonal radial diffusivity [De,⊥]) metrics, as well as whether these metrics were associated with other biomarkers. The study group discovered considerably stronger diffusion restriction (higher FA/AWF, lower MD/De,⊥) in white matter in AB+ than in AB (partial η2=0.08–0.19), particularly in the extra-axonal area of mostly late myelinating fibers. AWF (a marker of axonal density) is linked with speed/executive functions and neurodegeneration. In contrast, De, ⊥(a marker of gliosis/myelin repair) is correlated with amyloid deposition and white matter hyperintensity volume. The outcomes supported preliminary evidence of a nonmonotonic change in diffusion behavior. An early increase in diffusion restriction was hypothesized to reflect inflammation and myelin repair, followed by a subsequent decrease in diffusion restriction, which indicated glial and neuronal degeneration.