Targeting Sleep and Slow-Wave Activity to Enhance Cognition in MCI (TASSLE)

Study Description As most clinical trials in Alzheimer's disease (AD) have been unsuccessful to date, it has become increasingly crucial to focus on treating earlier stages of the disease. Compelling evidence indicates that sleep disruption is associated with accumulation of Alzheimer's biomarkers, including amyloid-beta (Aβ) and tau pathology. Slow-wave activity (SWA) during sleep is particularly important for the clearance of Aβ and sleep-dependent memory consolidation, and sleep disturbance could reduce the amount of time spent in slow-wave sleep. Together, these findings suggest that treating sleep disruption in older adults may help reduce the level of adverse brain aging.

The goal of this study is to better understand the effect of sleep interventions on improving sleep and building cognitive resilience in older adults with amnestic mild cognitive impairment (aMCI), and to assess the feasibility of relevant study protocols. Fifty older adults (ages 60-85) with aMCI and sleep disturbance (Insomnia Severity Index score of 8 or greater) will be randomized 1:1 to one of two treatment arms: Cognitive Behavioral Therapy for Insomnia only (CBT-I + Sham), or CBT-I combined with acoustic slow-wave activity enhancement (CBT-I + SWAE). CBT-I is a psychotherapy intervention designed to address maladaptive cognitive and behavioral patterns associated with sleep and bedtime. SWAE is administered through non-invasive earbuds (Smartbuds, NextSense Inc.) that detect and amplify endogenous slow-wave activity using acoustic pulses during sleep.

Each participant will complete 3 visits over approximately 6 months: a baseline visit, a post-treatment visit (approximately 12 weeks after baseline), and a 6-month follow-up visit. Group differences will be compared on changes in cognitive performance and plasma biomarkers of AD (phosphorylated tau [pTau-217]) across these time points. The study will also explore potential mechanisms behind the relationship between sleep and cognition/biomarkers by investigating a range of objectively measured sleep metrics (e.g., sleep architecture, sleep duration, arousals) along with depressive symptoms.

Hypotheses:

CBT-I will be associated with more favorable outcomes (i.e., less decline or greater improvement) in frontal network functioning (sustained attention/target detection, executive functions), while SWAE will be associated with better outcomes in measures of episodic memory (word-list learning and story recall). Improvements in total sleep time and insomnia symptoms at 8 weeks are hypothesized to mediate the relationship between CBT-I and performance on attention and executive functions over 6 months, while improvements in slow-wave non-rapid eye movement (NREM) sleep at 12 weeks are hypothesized to mediate the relationship between SWAE and episodic memory measures. Additionally, CBT-I is hypothesized to be associated with increased scores on the Visuospatial Abilities, Planning, Organization, and Divided Attention subscales of the Everyday Cognition (ECog) questionnaire after 6 months, while SWAE is hypothesized to be associated with a significant increase in the Everyday Memory subscale.

Objectives:

Aim 1: To determine if CBT-I and SWAE have different neuropsychological outcomes in aMCI.

Aim 2: To examine the impact of sleep treatments on cognitively mediated everyday functioning.

Exploratory Aim: To assess whether CBT-I and/or SWAE are associated with changes in plasma pTau and whether pTau moderates the association between sleep and cognition.

Results from this study will determine whether sleep interventions can build brain and cognitive resilience in the context of aging, and will inform the design of a future, larger-scale R01 study rigorously examining the association between targeted sleep modifications and markers of AD pathophysiology as a potentially modifiable risk factor for dementia.