Distinct manifestations of excitatory-inhibitory imbalance associated with amyloid-β and tau in patients with Alzheimer’s disease
- Kamalini G. Ranasinghe
- Kiwamu Kudo
- Faatimah Syed
- Claire Yballa
- Joel H. Kramer
- Bruce L. Miller
- Katherine P. Rankin
- Paul A. Garcia
- Heidi E. Kirsch
- Keith Vossel
- William Jagust
- Gil D. Rabinovici
- Srikantan S. Nagarajan
2025-08-26
A growing body of evidence shows that epileptic activity is frequently observed in patients with Alzheimer’s disease (AD), implicating underlying excitatory-inhibitory imbalance. The distinction of whether the AD-epileptic phenotype represents a subset of patients or an underdiagnosed manifestation holds major therapeutic implications. Here, we quantified the excitatory-inhibitory imbalance in AD patients using magnetoencephalography and examined the relationships to AD pathophysiology—amyloid-beta and tau, and to epileptic activity. We used two metrics to quantify regional excitatory-inhibitory imbalance distinguishing between local hyperexcitability ( Neural excitability, quantified by regional aperiodic spectral slope ) and aberrant long-range synaptic input integration ( Neural fragility, quantified by regional linear dynamic instability ). We found that amyloid-beta correlated with higher neural fragility and higher neural excitability, while tau and hypometabolism uniquely correlated with higher neural excitability. Importantly, the AD-epileptic phenotype showed a distinctive increase in neural fragility. Our findings demonstrate that AD pathophysiology is associated with diverse mechanisms of excitatory-inhibitory imbalance and that AD-epileptic phenotype represents a distinct group of patients with greater impairments in long-range synaptic input integration.