Functional network collapse in neurodegenerative disease

Cognitive and behavioral deficits in Alzheimer’s disease (AD) and frontotemporal dementia (FTD) arise alongside gray matter atrophy and altered functional connectivity, yet the structure-function relationship across the dementia spectrum remains unclear. Here we combine structural and functional MRI from 221 patients—AD (n = 82), behavioral variant FTD (n = 41), corticobasal syndrome (n = 27), and nonfluent (n = 34) or semantic (n = 37) variant primary progressive aphasia—and 100 cognitively normal individuals. Partial least-squares regression reveals three structure–function components. Component 1 links cumulative atrophy to sensorimotor hypo-connectivity and hyper-connectivity in association cortical and subcortical brain regions. Components 2 and 3 tie focal, syndrome-specific atrophy to peri-lesional hypo-connectivity and distal hyper-connectivity. Structural and functional component scores explain 34% of the variance in global and domain-specific cognitive deficits on average. The functional connectivity changes reflect alterations of intrinsic activity gradients. Eigenmode analysis shows that atrophy relates to reduced gradient amplitudes and narrowed phase angles between gradients, offering a mechanistic account of network collapse in neurodegeneration.