Different functional connectivity gradients reflect aging and Alzheimer’s disease
Year: 2026
Type: article
Study design: Observational Study
Abstract: Aging and Alzheimer's disease (AD) are associated with alterations in functional connectivity (FC), yet their spatial and temporal characteristics remain debated. Whole-cortex functional gradients, which organize regions along axes of functional similarity, are positioned here as a framework for understanding such alterations. Across two independent cohorts (BioFINDER-2, N=973; ADNI, N=129), we demonstrate that hyper- and hypoconnectivity in both healthy aging and biomarker-confirmed AD progression coexist systematically, forming consistent spatial patterns that align with two distinct axes of brain organization. Using a combination of longitudinal and non-linear analyses, we show that the early (but not late) stages of AD pathology accumulation is associated with functional alteration along the sensory-association axis, a pattern that vanishes in later stages of AD. However, functional alteration along the sensory-association axis is associated with worse cognition throughout the AD spectrum, and even in older adults without AD pathology, suggesting that these FC patterns may reflect a general neural response to cognitive strain. Independently of AD, older age was associated with alterations instead along the executive-nonexecutive axis, a finding that was consistent throughout the adult lifespan. These findings highlight the fundamental role of intrinsic functional organization in shaping how the brain responds to aging and to AD, helping to resolve previously reported discrepancies.
Source: Nature Neuroscience
Authors: Jonathan Rittmo, Nicolai Franzmeier, Olof Strandberg, Léa Chauveau, Theodore D. Satterthwaite, Laura E. M. Wisse, Nicola Spotorno, Harry H. Behjat, Amir Dehsarvi, Danielle van Westen, Toomas Erik Anijärv, The Alzheimer’s Disease Neuroimaging Initiative, Susan M. Landau, Sebastian Palmqvist, Shorena Janelidze, Erik Stomrud, Rik Ossenkoppele, Niklas Mattsson-Carlgren, Oskar Hansson, Jacob W. Vogel
Institutions: Lund University, Science for Life Laboratory, Munich Cluster for Systems Neurology, Institut für Schlaganfall- und Demenzforschung, Ludwig-Maximilians-Universität München, University of Gothenburg, Children's Hospital of Philadelphia, University of Pennsylvania, Skåne University Hospital, University of California, Berkeley, Amsterdam Neuroscience, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam
Language: English
Subfield: Cognitive Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Funders: Alzheimer's Association, BrightFocus Foundation, Cure Alzheimer's Fund, Hjärnfonden, Knut och Alice Wallenbergs Stiftelse, Vetenskapsrådet, Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, Fondation Philippe Chatrier, National Institutes of Health, GE Healthcare, National Institute on Aging, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Institute of Biomedical Imaging and Bioengineering
Awards: G1457535256, G1858921230, Novel biomarkers for improving diagnostics, prognostics, and treatments of Alzheimer’s disease, G3955935609, G4038479886, Reproducible imaging-based brain growth charts for psychiatry, Prospective validation of high-performing blood biomarkers and digital cognitive tests in both specialist memory clinic and general primary care settings, The role of brain connectivity as a mechanistic link between Amyloid and Tau pathology spread in Alzheimer’s disease, A precision medicine approach for the diagnosis and prognosis of preclinical Alzheimer´s disease with implications for clinical trials, Precision mapping of individualized executive networks in youth, The Neuroimaging Brain Chart Software Suite, Alzheimer's Disease Neuroimaging Initiative (ADNI4), Inter-modal Coupling Image Analytics, Interpretable Deep Learning for Analyzing Brain Development Heterogeneity with Personalized Functional Networks Across Multi-Site Data
OpenAlex ID: W7215067935