Amyloid-induced hyperconnectivity drives connectivity-based tau spreading in Alzheimer's disease
Poster No:
214
Submission Type:
Abstract Submission
Authors:
Sebastian Niclas Roemer1, Fabian Wagner1, Anna Steward2, Davina Biel2, Anna Dewenter2, Jannis Dennecke2, Mattes Gross1, Zeyu Zhu2, Lukai Zheng2, Amir Dehsarvi2, Martin Dichgans2, Michael Ewers2, Matthias Brendel1, Nicolai Franzmeier2
Institutions:
1University Hospital LMU Munich, Munich, Bavaria, 2Institute for Stroke and Dementia Research, Munich, Bavaria
First Author:
Co-Author(s):
Introduction:
In Alzheimer's disease, amyloid-beta (Ab) accumulation triggers tau spreading, which drives neurodegeneration and cognitive decline. Thus, understanding how Ab facilitates tau spread is key to identify treatment targets for attenuating tau spreading. We found previously that tau spreads in an activity-dependent manner across functionally connected brain regions in AD and that stronger inter-regional connectivity and less segregated brain networks accelerate tau spreading (Franzmeier, Rubinski et al. 2019, Frontzkowski, Ewers et al. 2022, Steward, Biel et al. 2023). Ab has been shown to induce neuronal hyperexcitability (Busche, Chen et al. 2012) via different mechanisms, such as an increased glutamate release and reduced glutamate re-uptake (Li, Hong et al. 2009), reduced sensitivity to GABA (Wu, Guo et al. 2014) and increased direct postsynaptic Ca2+-influx (Lam, Sarkis et al. 2020, Horvath, Papp et al. 2021). Congruently, patient studies have reported a higher prevalence of subclinical epileptiform brain activity related to Ab deposition (Lam, Sarkis et al. 2020), as well as Ab-related hyperactivity and hyperconnectivity on EEG and resting-state fMRI (Ying, Najm et al. 2014). Together these preclinical and clinical data provide converging evidence that Ab induces a hyperexcitatory shift in neuronal activity. Since synaptic secretion of hyperphosphorylated tau seeds and subsequent spread to connected neurons is activity-dependent, Ab-related increases in neuronal activity may accelerate tau spreading from local epicenters across connected brain regions.
The key aim of this project was to better understand the cross-link between Ab deposition and connectivity-associated tau spreading in AD. Specifically, we aimed to test whether Ab induces neuronal hyperconnectivity resulting in reduced brain network segregation, therefore accelerating inter-regional tau spreading. Specifically, our key aims were to test
i) Whether regional PET-assessed Ab deposition is associated with regional resting-state fMRI-assessed connectivity increases and reduced brain network segregation in AD
ii) Whether regional Ab-related connectivity increases and reduced brain network segregation are associated with accelerated tau spreading across connected brain regions
iii) Whether reduced brain network segregation mediates the association between Ab deposition and PET-assessed tau accumulation.
The key aim of this project was to better understand the cross-link between Ab deposition and connectivity-associated tau spreading in AD. Specifically, we aimed to test whether Ab induces neuronal hyperconnectivity resulting in reduced brain network segregation, therefore accelerating inter-regional tau spreading. Specifically, our key aims were to test
i) Whether regional PET-assessed Ab deposition is associated with regional resting-state fMRI-assessed connectivity increases and reduced brain network segregation in AD
ii) Whether regional Ab-related connectivity increases and reduced brain network segregation are associated with accelerated tau spreading across connected brain regions
iii) Whether reduced brain network segregation mediates the association between Ab deposition and PET-assessed tau accumulation.
Methods:
We included 116 Ab-positive subjects across the preclinical to clinical AD spectrum plus 52 Ab-negative controls, all with baseline amyloid-PET, 3T resting-state fMRI and longitudinal Flortaucipir tau-PET data. PET data were parceled into 200 cortical ROIs of the Schaefer atlas, longitudinal tau-PET change rates were computed per ROI using linear mixed models. Resting-state fMRI connectivity was computed across the 200 ROIs. Tau epicenters were defined per subject as 5% of brain regions with highest baseline tau-PET SUVRs.
Results:
Higher amyloid-PET (i.e. centiloid) is associated with increased connectivity of temporal-lobe tau epicenters to temporo-occipital and parietal regions (Fig.1), i.e. typical tau vulnerable regions. Higher connectivity of the tau epicenters to these brain regions predicted faster tau-PET increase over time. Mediation analysis revealed that Ab-associated connectivity increase to temporal, parietal and occipital brain regions mediated the association between higher amyloid-PET and faster tau-PET increase over time (Fig.2).
Conclusions:
We demonstrate a close link between Ab-associated connectivity increases and faster tau spread across connected regions in AD. These findings suggest that Ab promotes tau spreading via increasing neuronal activity and connectivity, hence Ab-associated neuronal hyperexcitability may be a promising target for attenuating tau spreading in AD.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Modeling and Analysis Methods:
Classification and Predictive Modeling
Connectivity (eg. functional, effective, structural) 2
PET Modeling and Analysis
Task-Independent and Resting-State Analysis
Keywords:
FUNCTIONAL MRI
Positron Emission Tomography (PET)
Other - Alzheimer's Disease
1|2Indicates the priority used for review
Provide references using author date format
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