Mapping Sleep’s Oscillatory Events as a Biomarker of Alzheimer’s Disease

Objective Memory-associated neural circuits produce oscillatory events within single-channel sleep electroencephalography (EEG), including theta bursts (TBs), sleep spindles (SPs) and multiple subtypes of slow waves (SWs). Changes in the temporal “coupling” of these events are proposed to serve as a biomarker for early stages of Alzheimer’s disease (AD) pathogenesis. Methods We analyzed data from 205 aging adults, including single-channel sleep EEG, cerebrospinal fluid (CSF) AD-associated biomarkers, and Clinical Dementia Rating® (CDR®) scale. Individual SW events were sorted into high and low transition frequencies (TF) subtypes. We utilized time-frequency spectrogram locations within sleep EEG to “map” the precision of SW-TB and SW-SP neural circuit coupling in relation to amyloid positivity (by CSF Aβ42/Aβ40 threshold), cognitive impairment (by CDR), and CSF levels of AD-associated biomarkers. Results Cognitive impairment was associated with lower TB spectral power in both high and low TF SW-TB coupling (p<0.001, p=0.001). Cognitively unimpaired, amyloid positive aging adults demonstrated lower precision of the neural circuits propagating high TF SW-TB (p<0.05) and low TF SW-SP (p<0.005) event coupling, compared to cognitively unimpaired amyloid negative individuals. Biomarker correlations were significant for high TF SW-TB coupling with CSF Aβ42/Aβ40 (p=0.005), phosphorylated-tau181 (p<0.005), and total-tau (p<0.05). Low TF SW-SP coupling was also correlated with CSF Aβ42/Aβ40 (p<0.01). Interpretation Loss of integrity in neural circuits underlying sleep-dependent memory processing can be measured for both SW-TB and SW-SP coupling in spectral time-frequency space. Breakdown of sleep’s memory circuit integrity is associated with amyloid positivity, higher levels of AD-associated pathology, and cognitive impairment. ### Competing Interest Statement R.L.P. is employed by Google; V.O.K. consults for Garmin; D.M.H. co-founded and is on the scientific advisory board of C2N Diagnostics. D.M.H. consults for Genentech, Denali., Cajal Neurosciences, and Alector. Washington University receives research grants to the laboratory of D.M.H. from C2N Diagnostics and NextCure. J.C.M. is funded by NIH grants P30 AG066444; P01AG003991; P01AG026276 and U19 AG032438. Neither J.C.M. nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. B.P.L. consults for Eli Lilly, has funding from Eisai, and is a member of the scientific advisory board for Beacon Biosignals; E.K., L.M.M., A.R.R., C.D.T., S.H.S., B.M.B., and B.V.M., declare that they have no competing interests.