The Alzheimer's Pathways Sleep Study (ALPS): an experimental randomized controlled trial to improve cognition and Alzheimer's pathophysiology through slow-wave sleep.

BACKGROUND: Slow-wave activity (0.5-4 Hz electroencephalographic activity) during non-rapid eye movement sleep is consistently associated with better cognitive performance in older adults. Slow-wave activity is known to regulate synaptic plasticity and may thereby mitigate excitotoxicity and accumulation of Alzheimer's pathology. Paradoxically, longer total sleep times in older adults are often associated with poorer cognition and general health. Conventional behavioral sleep treatments robustly increase sleep efficiency and sleep time, but do not consistently enhance slow-wave activity and have shown only subtle effects on cognition. Thus, enhancement of slow-wave activity may be a critical target for sleep-based cognitive enhancement. The Alzheimer's Pathways Sleep Study (ALPS) uses a novel time-in-bed (TiB) restriction intervention designed to increase slow-wave activity through homeostatic sleep drive and assesses improvements in measures of excitotoxic hippocampal hyperactivation, plasma levels of amyloid beta (Aβ), and overnight memory retention. METHODS: ALPS is a randomized controlled trial designed to increase slow-wave activity behaviorally in older adults with poor sleep. Target enrollment is 116 participants aged 65-85. Participants are randomized to a TiB restriction intervention or an attention-matched control intervention. Participants randomized to TiB restriction follow a sleep schedule restricting their TiB to 85% of their habitual TiB for 4 weeks. The control group follows their habitual TiB for 4 weeks. Both groups are monitored with diary, actigraphy, check-in calls, and sleepiness ratings over the 4 weeks. The primary outcomes for four specific aims are (1) absolute power in the slow oscillation (0.5-1 Hz) range during non-rapid eye movement sleep, (2) hippocampal activation during memory encoding, (3) plasma Aβ1-42, and (4) overnight word pair memory retention. Here we describe how the ALPS intervention is administered, the protocols and scripts implemented to maximize adherence and safety, and outcomes measured to test the proposed conceptual model linking slow-wave activity with excitotoxic hyperactivation, Alzheimer's pathophysiology, and memory performance. DISCUSSION: Behavioral enhancement of homeostatic sleep drive through TiB restriction is a promising approach to improve memory performance and Alzheimer's pathophysiology. Safety measures, as described here, should be implemented to minimize risks associated with TiB restriction. TRIAL REGISTRATION: ClinicalTrials.gov NCT05138848. Registered on December 1, 2021.