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.