Dysfunction of the episodic memory network in the Alzheimer’s disease cascade

Alzheimer's disease (AD) is a major cause of dementia and cognitive decline. Here, we assessed how episodic memory (EM) network dysfunction, a hallmark of AD, is related to the longitudinal progression of AD biomarkers, neurodegeneration and cognition using data from the DZNE DELCODE study. This data set includes over 1000 longitudinal functional magnetic resonance imaging measurements of EM network function. We related activation and deactivation of EM to individual disease progression scores from a disease progression model. Voxel-wise analyses revealed widespread loss of deactivation and activation with disease progression. Trajectories for the loss of deactivation were nonlinear, associated with amyloid- and tau-positivity and visually preceded trajectories of cognitive decline. The relationship between deactivation and cognitive decline was partly independent of neurodegeneration. Our results provide evidence that synaptic dysfunction and neurodegeneration are independent drivers of cognitive decline, providing a rationale for targeting synaptic dysfunction along the AD cascade.

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Journal
Nature Communications
Published
2026-04-17
DOI
https://doi.org/10.1038/s41467-026-71831-z
Primary Topic
Dementia and Cognitive Impairment Research
Type
article
Field-Weighted Citation Impact
0.00

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article

Dysfunction of the episodic memory network in the Alzheimer’s disease cascade

Andrea Lohse, Hartmut Schütze, Ayda Rostamzadeh, Oliver Peters et al.
Nature Communications
Dementia and Cognitive Impairment Research
article

Dysfunction of the episodic memory network in the Alzheimer’s disease cascade

Andrea Lohse, Hartmut Schütze, Ayda Rostamzadeh, Oliver Peters, Gabriel Ziegler, Frederic Brosseron, Yanin Suksangkharn, Anne Maaß, Niklas Vockert, Alfredo Ramı́rez, Renat Yakupov, Luca Kleineidam, Daria Gref, Michael Wagner, Michaela Butryn, Luisa‐Sophie Schneider, Marie Coenjaerts, Melina Stark, Sebastian Sodenkamp, José Bernal, Falk Lüsebrink, Peter Dechent, Eike Jakob Spruth, René Lattmann, Judith Wesenberg, Enise Incesoy, Stefan Teipel, Doreen Goerss, Anja Schneider, Ingo Kilimann, Klaus Scheffler, Frank Jessen, Christoph Laske, Klaus Fliessbach, Björn H. Schott, Matthias Schmid, Wenzel Glanz, Stefan Hetzer, Slawek Altenstein, Julian Hellmann-Regen, Josef Priller, Emrah Düzel, Annika Spottke, Jens Wiltfang
article en

Abstract

Alzheimer's disease (AD) is a major cause of dementia and cognitive decline. Here, we assessed how episodic memory (EM) network dysfunction, a hallmark of AD, is related to the longitudinal progression of AD biomarkers, neurodegeneration and cognition using data from the DZNE DELCODE study. This data set includes over 1000 longitudinal functional magnetic resonance imaging measurements of EM network function. We related activation and deactivation of EM to individual disease progression scores from a disease progression model. Voxel-wise analyses revealed widespread loss of deactivation and activation with disease progression. Trajectories for the loss of deactivation were nonlinear, associated with amyloid- and tau-positivity and visually preceded trajectories of cognitive decline. The relationship between deactivation and cognitive decline was partly independent of neurodegeneration. Our results provide evidence that synaptic dysfunction and neurodegeneration are independent drivers of cognitive decline, providing a rationale for targeting synaptic dysfunction along the AD cascade.

Nature CommunicationsVol. 17(1)
University of Cologne (DE), Friedrich-Alexander-Universität Erlangen-Nürnberg (DE), University Hospital Bonn (DE), German Center for Neurodegenerative Diseases (DE), Wellcome Centre for Integrative Neuroimaging (GB), Institute for Neurodegenerative Disorders (US), Universitätsmedizin Göttingen (DE), European Neuroscience Institute Göttingen (DE), UK Dementia Research Institute (GB), Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE), University Hospital Magdeburg (DE), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), Hertie Institute for Clinical Brain Research (DE), University Hospital Cologne (DE), University College London (GB), University of Rostock (DE), University of Aveiro (PT), Technical University of Munich (DE), University of Göttingen (DE), Charité - Universitätsmedizin Berlin (DE), University of Tübingen (DE), Otto-von-Guericke-Universität Magdeburg (DE), Leibniz Institute for Neurobiology (DE), University of Edinburgh (GB)
Universitätsmedizin Göttingen, Deutsche Forschungsgemeinschaft, Eberhard Karls Universität Tübingen, Deutsches Zentrum für Neurodegenerative Erkrankungen, Rheinische Friedrich-Wilhelms-Universität Bonn, Otto von Guericke University Magdeburg, Department of Artificial Intelligence, Korea University
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