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Elevated CSF GAP-43 is associated with accelerated tau accumulation and spread in Alzheimer’s disease

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  • Nicolai Franzmeier

    (University Hospital, LMU Munich
    Munich Cluster for Systems Neurology (SyNergy)
    University of Gothenburg, The Sahlgrenska Academy, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry)

  • Amir Dehsarvi

    (University Hospital, LMU Munich)

  • Anna Steward

    (University Hospital, LMU Munich)

  • Davina Biel

    (University Hospital, LMU Munich)

  • Anna Dewenter

    (University Hospital, LMU Munich)

  • Sebastian Niclas Roemer

    (University Hospital, LMU Munich)

  • Fabian Wagner

    (University Hospital, LMU Munich)

  • Mattes Groß

    (University Hospital, LMU Munich
    University Hospital, LMU Munich)

  • Matthias Brendel

    (Munich Cluster for Systems Neurology (SyNergy)
    University Hospital, LMU Munich)

  • Alexis Moscoso

    (University of Gothenburg, The Sahlgrenska Academy, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry)

  • Prithvi Arunachalam

    (University of Gothenburg, The Sahlgrenska Academy, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry)

  • Kaj Blennow

    (University of Gothenburg, The Sahlgrenska Academy, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
    Sahlgrenska University Hospital)

  • Henrik Zetterberg

    (University of Gothenburg, The Sahlgrenska Academy, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
    Sahlgrenska University Hospital
    UCL Institute of Neurology
    UK Dementia Research Institute at UCL)

  • Michael Ewers

    (University Hospital, LMU Munich
    German Center for Neurodegenerative Diseases (DZNE))

  • Michael Schöll

    (University of Gothenburg, The Sahlgrenska Academy, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
    University of Gothenburg
    University College London)

Abstract

In Alzheimer’s disease, amyloid-beta (Aβ) triggers the trans-synaptic spread of tau pathology, and aberrant synaptic activity has been shown to promote tau spreading. Aβ induces aberrant synaptic activity, manifesting in increases in the presynaptic growth-associated protein 43 (GAP-43), which is closely involved in synaptic activity and plasticity. We therefore tested whether Aβ-related GAP-43 increases, as a marker of synaptic changes, drive tau spreading in 93 patients across the aging and Alzheimer’s spectrum with available CSF GAP-43, amyloid-PET and longitudinal tau-PET assessments. We found that (1) higher GAP-43 was associated with faster Aβ-related tau accumulation, specifically in brain regions connected closest to subject-specific tau epicenters and (2) that higher GAP-43 strengthened the association between Aβ and connectivity-associated tau spread. This suggests that GAP-43-related synaptic changes are linked to faster Aβ-related tau spread across connected regions and that synapses could be key targets for preventing tau spreading in Alzheimer’s disease.

Suggested Citation

  • Nicolai Franzmeier & Amir Dehsarvi & Anna Steward & Davina Biel & Anna Dewenter & Sebastian Niclas Roemer & Fabian Wagner & Mattes Groß & Matthias Brendel & Alexis Moscoso & Prithvi Arunachalam & Kaj , 2024. "Elevated CSF GAP-43 is associated with accelerated tau accumulation and spread in Alzheimer’s disease," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44374-w
    DOI: 10.1038/s41467-023-44374-w
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    as
    1. Lukas Frontzkowski & Michael Ewers & Matthias Brendel & Davina Biel & Rik Ossenkoppele & Paul Hager & Anna Steward & Anna Dewenter & Sebastian Römer & Anna Rubinski & Katharina Buerger & Daniel Janowi, 2022. "Earlier Alzheimer’s disease onset is associated with tau pathology in brain hub regions and facilitated tau spreading," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Nicolai Franzmeier & Matthias Brendel & Leonie Beyer & Luna Slemann & Gabor G. Kovacs & Thomas Arzberger & Carolin Kurz & Gesine Respondek & Milica J. Lukic & Davina Biel & Anna Rubinski & Lukas Front, 2022. "Tau deposition patterns are associated with functional connectivity in primary tauopathies," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    3. Nicolai Franzmeier & Julia Neitzel & Anna Rubinski & Ruben Smith & Olof Strandberg & Rik Ossenkoppele & Oskar Hansson & Michael Ewers, 2020. "Functional brain architecture is associated with the rate of tau accumulation in Alzheimer’s disease," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    4. Alexa Pichet Binette & Nicolai Franzmeier & Nicola Spotorno & Michael Ewers & Matthias Brendel & Davina Biel & Olof Strandberg & Shorena Janelidze & Sebastian Palmqvist & Niklas Mattsson-Carlgren & Ru, 2022. "Amyloid-associated increases in soluble tau relate to tau aggregation rates and cognitive decline in early Alzheimer’s disease," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
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