Excitation–inhibition imbalance links amyloid pathophysiology to cognition in non‐demented individuals
INTRODUCTION: Excitation-inhibition (E/I) imbalance has been proposed as an early circuit-level mechanism in Alzheimer's disease (AD), but its relationship to molecular pathology and cognition in humans remains unclear. METHODS: We integrated biophysical modeling of resting-state functional magnetic resonance imaging with cerebrospinal fluid (CSF) and plasma biomarkers to examine whether E/I ratio links amyloid pathophysiology to memory in non-demented individuals across two cohorts from North America (N = 302; CSF amyloid beta 42 [Aβ42]) and Singapore (N = 240; plasma phosphorylated tau 217 [p-tau217]). RESULTS: Elevated E/I ratio was associated with lower CSF Aβ42 and higher plasma p-tau217, with greater sensitivity in sensory-motor regions. In contrast, elevated E/I ratio in association cortices was more strongly related to worse memory function. Mediation analyses indicated E/I ratio partially accounted for the AD biomarker-memory relationship. DISCUSSION: E/I imbalance represents an intermediate, systems-level circuit mechanism that links AD pathophysiology to cognitive impairment, offering novel insight into early neurophysiological changes along the AD continuum.
Authors
- Narayanaswamy Venketasubramanian (ORCID: https://orcid.org/0000-0003-3593-6362)
- B.T. Thomas Yeo (ORCID: https://orcid.org/0000-0002-0119-3276)
- Christopher Chen (ORCID: https://orcid.org/0000-0002-1047-9225)
- Shaoshi Zhang (ORCID: https://orcid.org/0000-0002-6352-9150)
- Juan Helen Zhou (ORCID: https://orcid.org/0000-0002-0180-8648)
- Tianchu Zeng (ORCID: https://orcid.org/0009-0009-0773-4502)
- Gustavo Deco (ORCID: https://orcid.org/0000-0002-8995-7583)
- Sebastian Niclas Roemer (ORCID: https://orcid.org/0000-0003-3423-457X)
- Joyce Ruifen Chong (ORCID: https://orcid.org/0000-0002-2869-0096)
- Nicolai Franzmeier (ORCID: https://orcid.org/0000-0001-9736-2283)
- Mitchell K.P. Lai (ORCID: https://orcid.org/0000-0001-7685-1424)
- Tian Fang (ORCID: https://orcid.org/0009-0004-9549-0694)
- Alzheimer's Disease Neuroimaging Initiative
- Ziwen Wang (ORCID: https://orcid.org/0009-0001-9252-0083)
- Xin Li
- Yan Li (ORCID: https://orcid.org/0009-0000-8905-7799)
Institutions
- Institució Catalana de Recerca i Estudis Avançats (ES)
- University of Wisconsin–Madison (US)
- Stockholm University (SE)
- National University of Singapore (SG)
- Universitat Pompeu Fabra (ES)
- Karolinska Institutet (SE)
- LMU Klinikum (DE)
- Munich Cluster for Systems Neurology (DE)
- Ludwig-Maximilians-Universität München (DE)
- University of Gothenburg (SE)
Publication Details
- Journal
- Alzheimer s & Dementia
- Published
- 2026-09-30
- DOI
- https://doi.org/10.1002/alz.71891
- Primary Topic
- Functional Brain Connectivity Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00