Phase-Amplitude Coupling of Theta and Gamma Rhythms During Rapid Eye Movement Sleep Predicts Verbal Memory in Alzheimer’s Disease

Background: Phase–amplitude coupling (PAC) is a fundamental neurophysiological mechanism underlying memory consolidation and is disrupted in Alzheimer’s disease (AD). While non-rapid eye movement (non-REM) PAC and wake theta–gamma coupling have been associated with aging and AD, theta–gamma coupling during rapid eye movement (REM) sleep has not previously been characterized in humans. Given the important role of REM sleep in memory processing, we investigated whether REM theta–gamma coupling (REM-TGC) is associated with cognitive performance in persons with mild-to-moderate AD.

Methods: Sixty persons with mild-to-moderate AD (30 women) enrolled in a prospective cohort study in Lleida, Spain underwent overnight polysomnography and cerebrospinal fluid (CSF) sampling at baseline. REM-TGC was quantified using theta (5–7 Hz) phase and gamma (30–65 Hz) amplitude recorded from frontal (F3, F4) and central (C3, C4) EEG channels. Cognitive assessments (MMSE, ADAS-Cog, CVLT, and ROCF) were completed at baseline and during follow-up over 36 months. Sine/cosine linear regression models with false discovery rate correction examined associations between REM-TGC preferred coupling phase and cognitive performance while adjusting for age, sex, apnea–hypopnea index, CSF Aβ42, and orexin-A.

Results: Across frontal and central EEG channels, gamma amplitude was consistently coupled to the theta trough during REM sleep, demonstrating stable REM oscillatory coupling. REM-TGC at the theta trough significantly predicted episodic verbal memory performance (CVLT) at both baseline and 12-month follow-up. Trend-level associations were also observed for global cognition (MMSE) at baseline and 12 months. Importantly, these associations remained significant after adjustment for CSF Aβ42 and orexin-A, indicating that REM-TGC provides information beyond established Alzheimer’s disease biomarkers.

Conclusions: This study is the first to characterize REM theta–gamma coupling in humans and in Alzheimer’s disease. Our findings demonstrate that temporally precise REM oscillatory coupling is associated with episodic verbal memory in persons with mild-to-moderate AD and may represent a novel electrophysiological biomarker of cognitive function. These results support further investigation of REM oscillatory coupling as a potential biomarker of disease progression and as a therapeutic target for interventions aimed at preserving memory in Alzheimer’s disease.