Abnormal hippocampo-cortical theta-gamma phase-amplitude coupling in Alzheimer’s disease

INTRODUCTION: Cognitive decline in Alzheimer's disease (AD) may arise not only from neuronal loss but also from disrupted temporal coordination across distributed networks. Prior works in healthy individuals has shown memory-related modulation of hippocampal-cortical phase-amplitude coupling (PAC). We hypothesized alteration of resting-state hippocampo-cortical PAC in AD which relates to cognitive impairment. METHODS: Resting-state magnetoencephalography (MEG) data were obtained from 78 AD patients and 70 healthy controls. Source-reconstructed hippocampal and cortical signals were analysed using antisymmetrized bispectral methods to quantify non-linear across-site PAC. RESULTS: AD patients showed significant disruptions of hippocampo-cortical PAC, particularly involving frontal, parahippocampal, and posterior-cingulate cortices. PAC measures were significantly associated with Mini-Mental State Examination scores within the AD group, with higher PAC corresponding to greater cognitive impairment in regions showing increased coupling relative to controls. DISCUSSION: These findings demonstrate altered hippocampo-cortical temporal coordination in AD and suggest PAC as a potential electrophysiological marker of disease-related network dysfunction.