Atrophy-driven functional network collapse in neurodegenerative disease

Cognitive deficits in Alzheimer's disease (AD) and frontotemporal dementia (FTD) result from atrophy and altered functional connectivity. However, it is unclear how atrophy and functional connectivity disruptions relate across dementia subtypes and stages. We addressed this question using structural and functional MRI from 221 patients with AD (n=82), behavioral variant FTD (n=41), corticobasal syndrome (n=27), nonfluent (n=34) and semantic (n=37) variant primary progressive aphasia, and 100 cognitively normal individuals. Using partial least squares regression, we identified three principal structure-function components. The first component showed cumulative atrophy correlating with primary cortical hypo-connectivity and subcortical/fronto-parietal association cortical hyper-connectivity. The second and third components linked focal syndrome-specific atrophy patterns to peri-lesional hypo-connectivity and distal hyper-connectivity. Structural and functional component scores collectively predicted global and domain-specific cognitive deficits. Anatomically, functional connectivity decreases and increases reflected alterations in specific brain activity gradients. Eigenmode analysis identified temporal phase and amplitude disruptions as a potential explanation for atrophy-driven functional connectivity changes. ### Competing Interest Statement J.A.B. is a founder of Radiata Inc. J.A.B. has a financial interest in Radiata Inc. and may benefit financially if the company is successful in marketing biomarker software products.