Abstract
Abstract
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.