Microstructural heterogeneity of white-matter aging and its age-dependent coupling to cognition

Abstract

Brain white matter (WM) microstructure undergoes extensive changes with age, yet the regional and cellular heterogeneity of age-related WM alterations and their impact on cognition remain unclear. Leveraging Neurite Orientation Dispersion and Density Imaging (NODDI), an advanced microstructural modelling to capture specific WM cellular properties, we investigated age-dependent relationships between advanced microstructural markers and cognitive performance, indexed by six cognitive domains derived from principal component analysis. Using a suite of standard diffusion tensor imaging (DTI) and NODDI techniques in eighty-six cognitively normal adults (Young: n=33, Older: n=53), we show that age group differences are widespread across whole brain white matter, with converging region-based and voxel-level evidence implicating commissural, association, and limbic pathways. Older adults exhibited significant and widespread reductions in global fractional anisotropy (FA) and neurite density index (NDI), concomitant with increases in mean diffusivity (MD), orientation density index (ODI), and free water fraction (FWF). Critically, age moderated WM-cognition associations in a domain- and tract-specific manner: younger adults exhibited stronger coupling between commissural and association tract microstructure and language and visual memory, whereas older adults showed greater dependence on projection and limbic tracts for executive and language function. The observed age-dependent coupling between specific microstructural metrics and cognition underscores the value of advanced diffusion models for capturing heterogeneity in brain aging, reveals age-specific biomarkers of cognitive health. These patterns align with phylogenetic and ontogenetic patterns of white matter vulnerability in callosal, long-range association, and limbic pathways, and suggest cellular specificity in white matter changes associated with cognitive decline. Significance Statement Aging affects brain white matter in complex and regionally specific ways, yet the biological bases of these changes and their relevance to cognition remain challenging to disentangle. Using multi-parameter diffusion MRI modeling, we found that age-related decline follows organized spatial patterns, with the greatest vulnerability in long-range association, callosal, and limbic pathways. These regional effects arise from distinct microstructural processes, including widespread extracellular alterations and more localized changes in neurite density and fiber organization. The strength and direction of white matter–cognition relationships differ between younger and older adults, revealing age-dependent shifts in how brain structural connections support behavior. Together, these findings identify biologically meaningful dimensions of white-matter vulnerability that may explain individual differences in cognitive aging.