Surrogates of glymphatic metrics decline and coupled sleep rhythms disruption in Alzheimer’s disease

Abstract Background Sleep is essential for brain homeostasis, in part by supporting glymphatic clearance through sleep-related oscillations. However, the relationship between putative glymphatic metrics and coupled sleep rhythm disruption, and their combined role in Alzheimer’s disease (AD) progression, remains poorly understood. Methods We analyzed data from 75 individuals, 54 with AD and 21 cognitively normal (CN) controls, including sleep electroencephalography (EEG), magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) AD biomarkers, and two-year longitudinal cognitive assessments. Putative glymphatic metrics was evaluated using choroid plexus (CP) volume, perivascular spaces (PVSs), diffusion tensor imaging along the perivascular space (DTI-ALPS) index, and blood oxygen level-dependent signal coupled to CSF signal (BOLD-CSF coupling). Coupled sleep rhythm was assessed via slow oscillation (SO)-theta and SO-spindle couplings. Correlation and mediation analyses explored associations between these MRI-derived indices and coupled sleep oscillations, and least absolute shrinkage and selection operator (LASSO) regression was used to predict AD progression. Results Compared to CN controls, individuals with AD had reduced DTI-ALPS index and BOLD-CSF coupling (p < 0.05), along with disrupted SO-spindle coupling (p = 0.029). Across all participants, lower global BOLD-CSF coupling correlated with misaligned SO-theta burst coupling (r = 0.311, p = 0.018), and reduced DTI-ALPS was associated with misaligned SO-spindle coupling (r = 0.370, p = 0.008). In the AD group, DTI-ALPS remained correlated with SO-spindle misalignment (r = 0.376, p = 0.028). Mediation analysis revealed that SO-spindle misalignment contributed to cognitive decline through its effect on DTI-ALPS. Importantly, combining putative glymphatic and sleep EEG metrics effectively predicted AD progression. Conclusions Our findings suggest that disruptions in surrogates marker of glymphatic clearance and coupled sleep rhythms are jointly associated with AD-related cognitive decline. These metrics offer a promising framework for predicting disease progression and understanding neurodegenerative mechanisms in AD. Graphical Abstract