Distinct manifestations of excitatory-inhibitory imbalance associated with amyloid-β and tau in patients with Alzheimer’s disease

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...

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Published inNature communications Vol. 16; no. 1; pp. 7957 - 14
Main Authors Ranasinghe, Kamalini G., Kudo, Kiwamu, Syed, Faatimah, Yballa, Claire, Kramer, Joel H., Miller, Bruce L., Rankin, Katherine P., Garcia, Paul A., Kirsch, Heidi E., Vossel, Keith, Jagust, William, Rabinovici, Gil D., Nagarajan, Srikantan S.
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 26.08.2025
Nature Publishing Group
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ISSN2041-1723
2041-1723
DOI10.1038/s41467-025-62798-4

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Summary: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. This study reveals that excitatory–inhibitory imbalance in Alzheimer’s disease is diverse including both impaired long-range synaptic integration and altered local excitability, with distinct links to β-amyloid and tau pathology.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-025-62798-4