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Dysfunction of the episodic memory network in the Alzheimer's disease cascade.

Nature communications

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

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.

© 2026. The Author(s).

PMID: 41997924

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