ETD

• AD
• Alzheimer's Disease
• Amyloid-beta
• Functional connectivty
• Modeling
• Power spectral density
• Tau
• The Virtual Brain
• TMS
• Transcranial Magnetic Stimulation
• TVB

Alzheimer’s Disease (AD) progression severely alters neural activity, yet how microscopic neurodegeneration links to macroscopic functional alterations remains poorly understood. Concurrently, Transcranial Magnetic Stimulation (TMS) shows promise in alleviating cognitive decline, but its underlying biophysical mechanisms lack a clear explanation.

To bridge these gaps, we developed a whole-brain digital twin composed of 86 Jansen-Rit neural masses, tuned to replicate healthy electroencephalogram (EEG) baselines. To simulate neuropathology progression, we incorporated the toxic accumulation of Amyloid-beta (A$\beta$) and tau ($\tau$) proteins. By discretizing this progression into a novel six-stage framework based on structural protein burden, we systematically varied local parameters and long-range coupling, monitoring the emerging alterations through functional connectivity and power spectral density (PSD).

Subsequently, departing from standard local stimulation approaches, we simulated the network-mediated consequences of focal TMS, introducing a framework that captures how whole-brain connectivity scales and redistributes the perturbation. Therapeutic efficacy was quantified via the spectral ratio between high and low-frequency peaks, evaluating the protocols' capacity to restore healthier activity.

Our results demonstrate that while the least and most severe stages exhibit resilience to external neuromodulation, middle-severity stages show a significant, target-specific spectral recovery. These findings validate our biophysical framework as a robust predictive pipeline for individualized TMS protocol design.