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<p>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&#xa0;epileptic activity. We used two metrics to quantify regional excitatory-inhibitory imbalance distinguishing between local hyperexcitability (<i>Neural excitability, quantified by&#xa0;regional aperiodic spectral slope</i>) and aberrant long-range synaptic input&#xa0;integration (<i>Neural fragility, quantified by regional&#xa0;linear dynamic instability</i>). 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月26日

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  • 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

摘要

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.