Home-Based Closed-Loop Auditory Stimulation to Enhance Slow-Wave Activity in MCI Due to Alzheimer's Disease: A Proof-of-Concept Study

Alzheimer's disease (AD) is characterized by progressive cognitive decline and is preceded by a prodromal stage known as amnestic mild cognitive impairment due to AD (MCI-AD), in which early neurophysiological alterations are detectable. Among these, disruptions in sleep architecture-particularly reductions in slow-wave activity (SWA; \~0.5-4 Hz) and sleep spindle activity (\~11-16 Hz)-have been associated with impaired memory consolidation and the progression of AD-related pathophysiological processes.

Closed-loop auditory stimulation during sleep (CLAS) is a non-invasive neuromodulation approach that delivers precisely timed auditory stimuli phase-locked to endogenous slow oscillations, with the aim of enhancing slow-wave activity and associated thalamocortical spindle dynamics. This targeted entrainment of sleep oscillations may improve sleep-dependent neural processes and represents a potential therapeutic strategy in the early stages of AD.

The present study is an open-label, single-arm investigation designed to evaluate the effects of home-based CLAS in patients with biomarker-confirmed amnestic mild cognitive impairment due to Alzheimer's disease (MCI-AD). The intervention is self-administered in the participants' home environment. All participants complete an initial treatment period of 3 months followed by a one-month off-treatment (washout) period to assess persistence of effects. Participants who elect to continue may then enter an optional extension phase consisting of 3 additional months of treatment, followed by a second one-month off-treatment period. The total study duration is approximately 4 months for participants completing the initial phase only, or approximately 8 months for those completing the extension phase.

The primary objective is to assess target engagement, defined as the modulation of NREM sleep electrophysiological activity, with particular focus on slow-wave sleep. More precisely, sustained increases in slow-wave activity across the intervention period will be quantified using the study EEG device during intervention nights.

Secondary objectives include evaluation of adherence to the intervention, usability of the device in the home environment, and safety and tolerability. Exploratory objectives include evaluation of the intervention's effects on clinical, functional, cognitive, and sleep-related outcomes, as well as blood-based biomarkers. Clinical, functional, and cognitive variables will be assessed at three time points: before intervention (baseline, Month 0), at the end of the initial treatment period (Month 3), and, for participants entering the extension phase, at the end of the extended treatment period (Month 7).

Blood biomarkers will be obtained at the following time points: baseline (Month 0), end of the initial treatment period (Month 3), and end of the first washout period (Month 4). Participants entering the extension phase will have two additional blood draws: at the end of the extended treatment period (Month 7) and at the end of the second washout period (Month 8). Sleep metrics, derived from EEG recordings or subjective responses to digitized questionnaires, will be acquired daily using the home-based study device.

This study does not include randomization or a sham control group; all participants receive active treatment during intervention periods. The results are expected to provide evidence on neurophysiological target engagement, feasibility, safety, and the clinical and biological effects of home-based CLAS as a therapeutic strategy in early-stage AD.

• Sustained Increase in Spindle Activity During N2-N3 Sleep [Срок оценки: Assessed at each intervention night, from baseline through the end of the intervention period (3 months, or up to 7 months for participants entering the extension phase).]
• Adherence to the Intervention [Срок оценки: Computed as a summary measure over each participant's full intervention period (3 months, or up to 7 months for participants entering the extension phase).]
• Usability of the Closed-Loop Auditory Stimulation System [Срок оценки: Computed as a summary measure over each participant's full intervention period (3 months, or up to 7 months for participants entering the extension phase).]
• Safety and Tolerability [Срок оценки: Continuously monitored from enrollment through the end of participation, with summary analyses at 3 months and, for participants entering the extension phase, at 7 months.]