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 in | Nature communications Vol. 16; no. 1; pp. 7957 - 14 |
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Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
26.08.2025
Nature Publishing Group Nature Portfolio |
Subjects | |
Online Access | Get full text |
ISSN | 2041-1723 2041-1723 |
DOI | 10.1038/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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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 |
ISSN: | 2041-1723 2041-1723 |
DOI: | 10.1038/s41467-025-62798-4 |