Macroscale connectome topographical structure reveals the biomechanisms of brain dysfunction in Alzheimer’s disease

The intricate spatial configurations of brain networks offer essential insights into understanding the specific patterns of brain abnormalities and the underlying biological mechanisms associated with Alzheimer’s disease (AD), normal aging, and other neurodegenerative disorders. This study investigated alterations in the topographical structure of the brain related to aging and neurodegenerative diseases by analyzing brain gradients derived from structural MRI data across multiple cohorts ( n = 7323). The analysis identified distinct gradient patterns in AD, aging, and other neurodegenerative conditions. Gene enrichment analysis indicated that inorganic ion transmembrane transport was the most significant term in normal aging, while chemical synaptic transmission is a common enrichment term across various neurodegenerative diseases. Moreover, the findings show that each disorder exhibits unique dysfunctional neurophysiological characteristics. These insights are pivotal for elucidating the distinct biological mechanisms underlying AD, thereby enhancing our understanding of its unique clinical phenotypes in contrast to normal aging and other neurodegenerative disorders.