Transcriptomic, cellular, and functional signatures of white matter damage in Alzheimer’s disease

Anatomical white matter (WM) alterations in Alzheimer’s disease (AD) have been widely reported, but functional WM dysregulation in AD has been rarely investigated. The current study focuses on characterizing WM functional and network properties alterations in participants with AD and mild cognitive impairment (MCI), and on further describing their spatially overlapping gene expression patterns. Both AD and MCI shared decreased functional connectivity, clustering coefficient and local efficiency within WM regions involved in impaired sensory-motor, visual-spatial, language or memory function. Notably, observed AD-specific dysfunction (i.e., AD vs. MCI and cognitively unimpaired participants) was predominantly located in WM, including anterior and posterior limb of internal capsule, corona radiata and left tapetum. This WM dysfunction spatially correlates with gene expression of BCHE and SLC24A4 , enriched in multiple biological processes such as brain development and behavior, and mostly active in endothelial cells. These findings may represent a substantial contribution to the understanding of molecular, cellular, and functional signatures associated with WM damage in AD.