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 and Srikantan S. Nagarajan
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Kamalini G. Ranasinghe: University of California San Francisco
Kiwamu Kudo: University of California San Francisco
Faatimah Syed: University of California San Francisco
Claire Yballa: University of California San Francisco
Joel H. Kramer: University of California San Francisco
Bruce L. Miller: University of California San Francisco
Katherine P. Rankin: University of California San Francisco
Paul A. Garcia: University of California San Francisco
Heidi E. Kirsch: University of California San Francisco
Keith Vossel: University of California San Francisco
William Jagust: UC Berkeley
Gil D. Rabinovici: University of California San Francisco
Srikantan S. Nagarajan: University of California San Francisco

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-62798-4

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