Neurodegenerative diseases such as Parkinson's (PD) and Alzheimer's (AD) exhibit considerable heterogeneity of functional brain features within patient populations, complicating diagnosis, treatment, prognosis, and drug discovery. Here, we use electroencephalography (EEG) and normative modeling to investigate neurophysiological oscillatory mechanisms underpinning this heterogeneity. To this aim, we use resting-state EEG activity collected by 14 clinical units, in healthy older persons (n=499) and patients with PD (n=237) and AD (n=197), aged over 40 years old. Spectral and source connectivity analyses of EEG activity provided EEG features for normative modeling and deviation measures in the PD and AD patients. Normative models confirmed significant deviations of the EEG features in PD and AD patients over population norms, characterized by high heterogeneity and frequency-dependence. The percentage of patients with at least one deviating EEG feature was ~30% for spectral measures and ~80% for functional source connectivity. Notably, the spatial overlap of the deviant EEG features did not exceed 60% for spectral analysis and 25% for functional source connectivity analysis. Furthermore, the patient-specific deviations were correlated with relevant clinical measures, such as the UPDRS for PD (⍴=0.24, p=0.025) and the MMSE for AD (⍴=-0.26, p=0.01), indicating that greater deviations from normative EEG features are associated with worsening score values. These results suggest that the deviation percentage from EEG norms may enrich clinical assessment in PD and AD patients at individual levels in the framework of Precision Neurology.

Characterizing the heterogeneity of neurodegenerative diseases through EEG normative modeling