Enhancing slow-wave sleep via non-invasive brain stimulation modulates brain-to-blood clearance of Alzheimer’s disease biomarkers

Sleep disturbances and neurodegeneration form a bidirectional vicious cycle. During slow-wave sleep, glymphatic processes are thought to facilitate the clearance of metabolic waste, including proteins implicated in Alzheimer’s disease (AD). Aging, and more prominently neurodegeneration, is associated with reductions in slow-wave activity (SWA), which may impair these processes. Within SWA, slow oscillations (SO, <1 Hz) and their coupling to sleep spindles capture key aspects of sleep microstructure. Non-invasive brain stimulation during sleep has emerged as a potential approach to modulate these dynamics; however, human evidence linking such modulation to AD biomarkers remains scarce.

In this exploratory mechanistic study, ten healthy older adults underwent one night of slow-oscillatory transcranial current stimulation (so-tDCS) and one sham night in a randomized crossover design, followed by five consecutive stimulation nights. Stimulation was applied during NREM sleep (N2/N3) in the first half of the night. Plasma phosphorylated tau (p-tau)181, β-amyloid (Aβ)42, Aβ40, and total tau were assessed overnight and longitudinally. EEG analyses quantified SO power and SO-spindle coupling. Due to the exploratory character of the study, analyses emphasized effect size estimation and explained variance.

So-tDCS induced small-to-moderate increases in SO power and SO-spindle coupling. Overnight increases in plasma p-tau181 were observed following stimulation relative to sham. Increases in SO power were strongly and positively associated with p-tau181 changes, explaining a substantial proportion of inter-individual variance. In contrast, shifts in SO-spindle coupling phase toward the SO up-state were associated with overnight increases in Aβ42 and Aβ40 and with longitudinal decreases in Aβ42 and the Aβ42/40 ratio.

Enhancing slow oscillatory dynamics during sleep is associated with changes in peripheral AD biomarkers. Differential associations for SO power and SO-spindle coupling timing suggest partially distinct links to tau and Aβ dynamics. These findings support sleep microstructure as a potential intervention target, and should be confirmed in larger cohorts.