Associations between REM sleep EEG slowing and brain cholinergic denervation in aging and Mild Cognitive Impairment

Cholinergic activity supports cortical activation during REM sleep, while other neurotransmitter systems are almost silent. Here, we tested the long-standing hypothesis that early cholinergic denervation may be associated with REM sleep EEG slowing in older adults. Twenty-four older participants without dementia (mean age: 71.29 ± 4.85 years; 58.33% women; 25% participants with amnestic Mild Cognitive Impairment) underwent a night of in-laboratory polysomnography, comprehensive neuropsychological evaluation, structural MRI and molecular PET imaging with [¹⁸F]-Fluoroethoxybenzovesamicol (FEOBV) to quantify brain cholinergic innervation. Voxel-wise multiple regressions assessed the associations between REM sleep characteristics (i.e., REM sleep percentage, relative theta power and EEG slowing ratios, defined as [delta + theta]/[alpha + beta] power) and FEOBV-PET standard uptake value ratio maps, controlling for sex. Given that FEOBV uptake was higher in women compared to men, we also performed exploratory sex-stratified analyses adjusted for age. Higher REM sleep EEG slowing over frontal (F3-F4), central (C3-C4), parietal (P3-P4), occipital (O1-O2) and temporal (T5-T6) derivations was significantly associated with cortical cholinergic denervation, notably in fronto-parietal areas and the medial temporal lobe. Sex-stratified analyses showed that higher REM sleep EEG slowing ratios were associated with cholinergic denervation mainly in medial temporal regions in women, and neocortical regions in men. These findings suggest that global REM sleep EEG slowing may represent a sensitive marker of cortical cholinergic denervation in older adults without dementia, and may constitute a promising marker for early diagnosis and disease-modifying interventions in Alzheimer's disease.