Functional connectome hierarchy dysfunction in Alzheimer's disease and its relationship with cognition and gene expression profiling

Abstract Numerous researches have shown that the human brain organizes as a continuum axis crossing from sensory motor to transmodal cortex. Functional network alterations were commonly found in Alzheimer's disease (AD). Whether the hierarchy of AD brain networks has changed and how these changes related to gene expression profiling and cognition is unclear. Using resting‐state functional magnetic resonance imaging data from 233 subjects (185 AD patients and 48 healthy controls), we studied the changes in the functional network gradients in AD. Moreover, we investigated the relationships between gradient alterations and cognition, and gene expression profiling, respectively. We found that the second gradient organizes as a continuum axis crossing from the sensory motor to the transmodal cortex. Compared to the healthy controls, the secondary gradient scores of the visual and somatomotor network (SOM) increased significantly in AD, and the secondary gradient scores of default mode and frontoparietal network decreased significantly in AD. The secondary gradient scores of SOM and salience network (SAL) significantly positively correlated with memory function in AD. The secondary gradient in SAL also significantly positively correlated with language function. The AD‐related second gradient alterations were spatially associated with the gene expression and the relevant genes enriched in neurobiology‐related pathways, specially expressed in various tissues, cell types, and developmental stages. These findings suggested the changes in the functional network gradients in AD and deepened our understanding of the correlation between macroscopic gradient structure and microscopic gene expression profiling in AD.