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bioRxiv · 10.1101/2025.09.02.673734

The cellular associates of late life changes in white matter microstructure

Chin, R.·Zhang, X.-H.·Anderson, K. M.·Yendiki, A.·Holmes, A. J.
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Abstract

The microstructural architecture of white matter supporting information flow across local circuits and large-scale networks changes throughout the lifespan. However, the genetic and cellular factors underlying age-related variations in white matter microstructure have yet to be established. Here, we examined the genetic associates of individual differences in diffusion-based measures of white matter in a population-based cohort (N=29,862) from the UK Biobank. Estimates of heritability from Genome-Wide Association Study (GWAS) data revealed that genetic factors are linked to population variability in 96.1% of 432 tract microstructural measures. The presence of shared genetic influences was observed to be greater within, relative to between, broad tract classes (commissural, association, projection, and complex cerebellar). Age associations with microstructural changes were estimated across diffusivity measures, with association class tracts showing the greatest vulnerability to age-related decline in older adults. Analyses of imputed cellular associates of age-related changes in white matter revealed a preferential relationship with cell gene markers of oligodendrocytes and other glial cell types, with sparse relationships observed for inhibitory and excitatory cells. These data indicate that white matter tract microstructure is shaped by genetic factors and suggest a role for glial cell-related transcripts in late-life changes in the structural wiring properties of the human brain. Significance StatementThe structural wiring of the human brain supports interregional communication and is essential for cognition, yet the genetic and cellular drivers underlying age-related changes are not well understood. Here, we characterize the extent to which genetic factors follow the major organizational patterns of white matter connectivity and associated age-related changes in late life. Age-related changes were most pronounced in late-developing association tracts, key pathways for higher cognitive functions. By integrating genetic and transcriptomic data, we show that genetic variation linked to glial cell markers accounts for a substantial proportion of age-related white matter changes. These findings provide a mechanistic framework for understanding genetic and cellular determinants of structural brain aging.

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Chin, R., Zhang, X.-H., Anderson, K. M., Yendiki, A., Holmes, A. J.. 2025-09-03. The cellular associates of late life changes in white matter microstructure. https://doi.org/10.1101/2025.09.02.673734

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