Functional network collapse in neurodegenerative disease

Jesse A. Brown (), Alex J. Lee, Kristen Fernhoff, Taylor Pistone, Lorenzo Pasquini, Amy B. Wise, Adam M. Staffaroni, Maria Luisa Mandelli, Suzee E. Lee, Adam L. Boxer, Katherine P. Rankin, Gil D. Rabinovici, Maria Luisa Gorno Tempini, Howard J. Rosen, Joel H. Kramer, Bruce L. Miller and William W. Seeley ()
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Jesse A. Brown: Weill Institute for Neurosciences, University of California, San Francisco, Memory and Aging Center, Department of Neurology
Alex J. Lee: Weill Institute for Neurosciences, University of California, San Francisco, Memory and Aging Center, Department of Neurology
Kristen Fernhoff: Weill Institute for Neurosciences, University of California, San Francisco, Memory and Aging Center, Department of Neurology
Taylor Pistone: Weill Institute for Neurosciences, University of California, San Francisco, Memory and Aging Center, Department of Neurology
Lorenzo Pasquini: Weill Institute for Neurosciences, University of California, San Francisco, Memory and Aging Center, Department of Neurology
Amy B. Wise: Weill Institute for Neurosciences, University of California, San Francisco, Memory and Aging Center, Department of Neurology
Adam M. Staffaroni: Weill Institute for Neurosciences, University of California, San Francisco, Memory and Aging Center, Department of Neurology
Maria Luisa Mandelli: Weill Institute for Neurosciences, University of California, San Francisco, Memory and Aging Center, Department of Neurology
Suzee E. Lee: Weill Institute for Neurosciences, University of California, San Francisco, Memory and Aging Center, Department of Neurology
Adam L. Boxer: Weill Institute for Neurosciences, University of California, San Francisco, Memory and Aging Center, Department of Neurology
Katherine P. Rankin: Weill Institute for Neurosciences, University of California, San Francisco, Memory and Aging Center, Department of Neurology
Gil D. Rabinovici: Weill Institute for Neurosciences, University of California, San Francisco, Memory and Aging Center, Department of Neurology
Maria Luisa Gorno Tempini: Weill Institute for Neurosciences, University of California, San Francisco, Memory and Aging Center, Department of Neurology
Howard J. Rosen: Weill Institute for Neurosciences, University of California, San Francisco, Memory and Aging Center, Department of Neurology
Joel H. Kramer: Weill Institute for Neurosciences, University of California, San Francisco, Memory and Aging Center, Department of Neurology
Bruce L. Miller: Weill Institute for Neurosciences, University of California, San Francisco, Memory and Aging Center, Department of Neurology
William W. Seeley: Weill Institute for Neurosciences, University of California, San Francisco, Memory and Aging Center, Department of Neurology

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-65156-6

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