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

Nicolai Franzmeier (), Amir Dehsarvi, Anna Steward, Davina Biel, Anna Dewenter, Sebastian Niclas Roemer, Fabian Wagner, Mattes Groß, Matthias Brendel, Alexis Moscoso, Prithvi Arunachalam, Kaj Blennow, Henrik Zetterberg, Michael Ewers and Michael Schöll
Additional contact information
Nicolai Franzmeier: University Hospital, LMU Munich
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
Matthias Brendel: Munich Cluster for Systems Neurology (SyNergy)
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
Henrik Zetterberg: University of Gothenburg, The Sahlgrenska Academy, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Michael Ewers: University Hospital, LMU Munich
Michael Schöll: University of Gothenburg, The Sahlgrenska Academy, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-023-44374-w

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