HAI Book 2025 - Flipbook - Page 598
Roemer-Cassiano, Sebastian Niclas
139
Amyloid-associated hyperconnectivity drives tau spreading across
connected brain regions in Alzheimer9s disease
Sebastian Niclas Roemer-Cassiano1,14, Fabian Wagner2, Lisa Evangelista2, Amir Dehsarvi2,
Anna Steward2, Anna Dewenter2, Davina Biel2, Zeyu Zhu2, Maura Malpetti9, Günter U.
Höglinger1,5,6, Matthias Brendel5,6,13, Sarah Jäkel2, Michael Scholl10,11, Nicolai Franzmeier2,10,11
1
Department of Neurology, University Hospital, LMU Munich, Germany, Munich, DE
Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Germany, Munich, DE
3
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany, Munich, DE
4
German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany, Munich, DE
5
Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK, Cambridge, GB
6
University of Gothenburg, The Sahlgrenska Academy, Institute of Neuroscience and Physiology, Department of
Psychiatry and Neurochemistry, Mölndal and Gothenburg, Sweden, Gothenburg, SE
7
Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Sweden, Gothenburg, SE
8
Department of Nuclear Medicine, University Hospital, LMU Munich, Germany, Munich, DE
9
Max Planck School of Cognition, 04103 Leipzig, Germany, Leipzig, DE
2
Background: In Alzheimer9s disease, A´ triggers tau spreading which drives neurodegeneration and cognitive
decline. Preclinical research found that tau spreads across connected neurons in an activity-dependent manner,
and A´ was shown to trigger neuronal hyperactivity and hyperconnectivity. Therefore, we hypothesized that A´
induces neuronal hyperactivity and hyperconnectivity, thereby promoting tau spreading from initial epicenters
across connected brain regions.
Methods: From ADNI, we included 140 A´-positive subjects across the AD spectrum plus 69 A´-negative controls,
all with baseline amyloid-PET, 3T resting-state fMRI and longitudinal Flortaucipir tau-PET. For validation, we
included cross-sectional data of 345 preclinical AD patients from the A4 study. PET and fMRI data were parceled
into 200 cortical ROIs and ROI-wise longitudinal tau-PET change rates were computed using linear-mixed models.
Further, we included post-mortem brain tissue from 5 AD patients vs. 4 controls stained for A´ and c-Fos, i.e. a
marker of ante-mortem neuronal activity.
Results: In the AD spectrum cohort, we confirmed that A´ induces hyperconnectivity of temporal lobe tau
epicenters to posterior brain regions that are highly vulnerable to tau accumulation in AD (Fig.1A-C). This was
replicated in the validation cohort of preclinical AD patients with low cortical tau-PET, suggesting that the
emergence of A´-related hyperconnectivity precedes neocortical tau spreading (Fig.1D). Supporting that A´associated fMRI-based hyperconnectivity may mirror neuronal hyperactivity, we found that neurons in AD postmortem tissue expressed higher levels of c-Fos compared to controls, i.e. a marker of ante-mortem neuronal
activity (Fig.2). Lastly, using longitudinal tau-PET, we confirmed that A´-related connectivity increases of the tau
epicenters to posterior brain regions mediated the effect of A´ on tau accumulation and triggered faster tau
spreading (Fig.3).
Conclusions: Our translational results suggest that A´ promotes tau spreading via increasing neuronal activity
and connectivity. Therefore, A´-associated neuronal hyperexcitability may be a promising target for attenuating
tau spreading in AD.
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