Personalized brain models link cognitive decline progression to underlying synaptic and connectivity degeneration.

Cognitive decline is a condition affecting almost one sixth of the elder population and is widely regarded as one of the first manifestations of Alzheimer's disease. Despite the extensive body of knowledge on the condition, there is no clear consensus on the structural defects and neurodegeneration processes determining cognitive decline evolution. Here, we introduce a Brain Network Model (BNM) simulating the effects of neurodegeneration on neural activity during cognitive processing. The model incorporates two key parameters accounting for distinct pathological mechanisms: synaptic degeneration, primarily leading to hyperexcitation, and brain disconnection. Through parameter optimization, we successfully replicated individual electroencephalography (EEG) responses recorded during task execution from 145 participants spanning different stages of cognitive decline. The cohort included healthy controls, patients with subjective cognitive decline (SCD), and those with mild cognitive impairment (MCI) of the Alzheimer type. Through model inversion, we generated personalized BNMs for each participant based on individual EEG recordings. These models revealed distinct network configurations corresponding to the patient's cognitive condition, with virtual neurodegeneration levels directly proportional to the severity of cognitive decline. Strikingly, the model uncovered a neurodegeneration-driven phase transition leading to two distinct regimes of neural activity underlying task execution. On either side of this phase transition, increasing synaptic degeneration induced changes in neural activity that closely mirrored experimental observations across cognitive decline stages. This enabled the model to directly link synaptic degeneration and hyperexcitation to cognitive decline severity. Furthermore, the model pinpointed posterior cingulum fiber degeneration as the structural driver of this phase transition. Our findings highlight the potential of BNMs to account for the evolution of neural activity across stages of cognitive decline while elucidating the underlying neurodegenerative mechanisms. This approach provides a novel framework for understanding how structural and functional brain alterations contribute to cognitive deterioration along the Alzheimer's continuum.