MAPPING EXCITATION/INHIBITION WITH MEG IN EARLY ALZHEIMER’S DISEASE

Characterizing the preclinical stages of Alzheimer's Disease (AD) is essential for developing preventive strategies and early interventions. Early AD is characterized by disruptions in the excitation/inhibition (E/I) balance, involving hyperexcitability, GABAergic hypofunction, hypersynchronization, and large-scale network dysfunction. Recent advances in human electrophysiology allow indirect estimation of E/I balance using proxies such as the aperiodic component of the power spectrum. However, their relationship with the underlying neurochemical architecture remains unclear. Here, we investigated alterations in E/I balance using magnetoencephalography (MEG) in a large cohort (N=579) spanning the AD continuum, including healthy individuals, participants with a family history of AD, subjective cognitive decline, mild cognitive impairment, and AD. Resting-state MEG recordings were source reconstructed, and E/I balance was characterized by the aperiodic exponent across 74 cortical regions. Spatial patterns of MEG-derived E/I were then correlated with open-access normative glutamatergic and GABAergic receptor density maps obtained from PET. We assessed whether macroscale neurotransmitter distributions predict the spatial organization of electrophysiological E/I in healthy individuals, and whether this coupling is disrupted in at-risk and clinical populations. Preliminary findings in healthy participants reveal a hierarchical cortical gradient, with higher E/I ratios in transmodal regions such as the prefrontal cortex and lower ratios in occipital and temporal areas. With disease progression, we anticipate increased E/I imbalance alongside a reduced correspondence between MEG-derived metrics and neurotransmitter distributions. This multimodal approach provides a novel mechanistic link between non-invasive electrophysiological markers of E/I and neurochemical organization, offering a promising avenue for early detection and risk stratification in AD.