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The goal of this study was to use diffusional kurtosis imaging (DKI) and biophysical modeling to detect and describe amyloid\u2010related white matter changes in preclinical Alzheimer disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Cognitively unimpaired participants ages 45 to 85\u2009years completed brain magnetic resonance imaging, amyloid positron emission tomography (florbetapir), neuropsychological testing, and other clinical measures at baseline in a cohort study. We tested whether beta\u2010amyloid\u2010negative (AB\u2212) and \u2010positive (AB+) participants differed on DKI\u2010based conventional (ie, fractional anisotropy [FA], mean diffusivity [MD], mean kurtosis) and modeling (ie, axonal water fraction [AWF], extra\u2010axonal radial diffusivity [<jats:italic>D<\/jats:italic><jats:sub>e,\u22a5<\/jats:sub>]) metrics, and whether these metrics were associated with other biomarkers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found significantly greater diffusion restriction (higher FA\/AWF, lower MD\/<jats:italic>D<\/jats:italic><jats:sub>e,\u22a5<\/jats:sub>) in white matter in AB+ than AB\u2212 (partial <jats:italic>\u03b7<\/jats:italic><jats:sup>2<\/jats:sup>\u2009=0.08\u20130.19), more notably in the extra\u2010axonal space within primarily late myelinating tracts. Diffusion metrics predicted amyloid status incrementally over age (area under the curve\u00a0=\u00a00.84) with modest yet selective associations, where AWF (a marker of axonal density) correlated with speed\/executive functions and neurodegeneration, whereas <jats:italic>D<\/jats:italic><jats:sub>e,\u22a5<\/jats:sub> (a marker of gliosis\/myelin repair) correlated with amyloid deposition and white matter hyperintensity volume.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>These results support prior evidence of a nonmonotonic change in diffusion behavior, where an early increase in diffusion restriction is hypothesized to reflect inflammation and myelin repair prior to an ensuing decrease in diffusion restriction, indicating glial and neuronal degeneration. 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