Rapid Eye Movement Sleep, Neurodegeneration, and Amyloid Deposition in Aging

Abstract

Rapid eye movement (REM) sleep is markedly altered in Alzheimer's disease (AD), and its reduction in older populations is associated with AD risk. However, little is known about the underlying brain mechanisms. Our objective was to investigate the relationships between REM sleep integrity and amyloid deposition, gray matter volume, and perfusion in aging. Methods: We included 121 cognitively unimpaired older adults (76 women, mean age 68.96 AE 3.82 years), who underwent a polysomnography, T1-weighted magnetic resonance imaging, early and late Florbetapir positron emission tomography scans to evaluate gray matter volume, perfusion, and amyloid deposition. We computed indices reflecting REM sleep macro-and microstructural integrity (ie, normalized electroencephalographic spectral power values). Voxelwise multiple regression analyses were conducted between REM sleep indices and neuroimaging data, controlling for age, sex, education, the apnea-hypopnea index, and the apolipoprotein E ε4 status. Results: Lower perfusion in frontal, anterior and posterior cingulate, and precuneus areas was associated with decreased delta power and electroencephalographic slowing (slow/fast frequencies ratio), and increased alpha and beta power. To a lower extent, similar results were obtained between gray matter volume and delta, alpha, and beta power. In addition, lower REM sleep theta power was more marginally associated with greater diffuse amyloid deposition and lower gray matter volume in fronto-temporal and parieto-occipital areas. Interpretation: These results suggest that alterations of REM sleep microstructure are associated with greater neurodegeneration and neocortical amyloid deposition in older adults. Further studies are warranted to replicate these findings, and determine whether older adults exhibiting REM sleep alterations are more at risk of cognitive decline and belonging to the Alzheimer's continuum.

Suvorexant Acutely Decreases Tau Phosphorylation and Aβ in the Human CNS

“…24,25 Alternatively, REM sleep may be an important regulator of Alzheimer pathology and neurodegeneration. 26 DORAs increase REM sleep more than other hypnotics, 27 although we did not find an increase in REM sleep in the groups treated with suvorexant. Based on these prior results, our findings, and the observation that the effect of suvorexant persisted for > 18 hours after drug administration, we hypothesize that suvorexant's effect on p-tau and Aβ may be due to mechanisms other than sleep involving orexin receptor signaling pathways, although further studies are needed.…”

“…A potential explanation of these findings is that previous studies in a diurnal species of monkeys found that the administration of GHB at night did not change CSF orexin levels, 24 whereas sleep deprivation increased CSF orexin levels 24,25 . Alternatively, REM sleep may be an important regulator of Alzheimer pathology and neurodegeneration 26 . DORAs increase REM sleep more than other hypnotics, 27 although we did not find an increase in REM sleep in the groups treated with suvorexant.…”

“…Starting from a baseline of 23% to 26%, the pT181/T181 ratio decreased 2% to 4% (a relative reduction of 10-15%) over the first 7 hours after receiving suvorexant 20 mg at 21:00 (hour 1) and remained lower for hours from 10:00-12:00 (hours 14- ). The ratio then increased to approximately the level of the placebo group at hour 24 and then decreased again after participants received the second dose of suvorexant 20 mg from 22:00 to 08:00 (hours [26][27][28][29][30][31][32][33][34][35][36]. The area under the curve (AUC) of percent change from hour 0 for pT181/T181 across hours 0 to 36 was also significantly reduced in the suvorexant 20 mg group compared to placebo.…”

Association Between Slow-Wave Sleep Loss and Incident Dementia

“…[21][22][23] Further, 1 study linked REM sleep microstructure to amyloid deposition in older adults. 24 Studies, including ours, have failed to demonstrate an association between SWS percentage measured at a single time point and risk of cognitive decline or dementia. 25,26 Thus, it may be the decline in SWS percentage, rather than individual differences at a given time, that are important for determining dementia risk.…”

“…Some studies have shown associations between slow-wave activity and amyloid burden in humans whereas others suggest that sleep spindle–slow wave coupling, rather than the quantity of overnight slow waves per se, is associated with amyloid accumulation . Further, 1 study linked REM sleep microstructure to amyloid deposition in older adults . Studies, including ours, have failed to demonstrate an association between SWS percentage measured at a single time point and risk of cognitive decline or dementia .…”