White matter dysfunction in Alzheimer’s disease is associated with disease-related transcriptomic signatures

While anatomical white matter (WM) alterations in Alzheimer’s disease (AD) are well-established, functional WM dysregulation remains rarely investigated. The current study examines WM functional connectivity and network properties alterations in AD and mild cognitive impairment (MCI) and further describes their spatially correlated genes. 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 functions. 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 specific genes, which are enriched in multiple biological processes related to synaptic function and development, and are mostly active in neurons and astrocytes. These findings may contribute to understanding molecular, cellular, and functional signatures associated with WM damage in AD.