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White matter (WM) microstructure characterized with diffusion tensor imaging (DTI) can indicate underlying architectural changes in longitudinal studies, suggestive of neurodegeneration. This study investigated relationships between DTI and A\u03b2 in DS along the AD continuum.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>Using longitudinal amyloid Pittsburgh compound B positron emission tomography, Centiloid (CL) and DTI parameters were examined in 35 adults with DS ages 25 to 57. DTI measures of anisotropy and diffusivity were analyzed using tract\u2010based spatial statistics and permutation analysis of linear models, testing for significant correlation between the rates of change for CL and DTI.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>All rates of DTI and A\u03b2 changes were significantly related. Significant regions included the corpus callosum, corona radiata, and long\u2010association fibers.<\/jats:p><\/jats:sec><jats:sec><jats:title>DISCUSSION<\/jats:title><jats:p>A\u03b2 burden is associated with widespread longitudinal WM changes in DS. This suggests WM microstructure alterations accompany amyloid accumulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>A Down syndrome\u2013specific template was created.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Longitudinal diffusion tensor imaging (DTI) and amyloid burden rates of change correlate.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Longitudinal results show more significant regions than cross\u2010sectional results.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>DTI and amyloid changes were found over two timepoints, 3.7 years apart on average.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>DTI and amyloid\u2010PET offer greater sensitivity when tracking microstructural 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