Evaluating the disease-modifying potential of a sleep intervention for Alzheimer's Disease outcomes

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Abstract Treatments that can slow Alzheimer's disease (AD) progression can reduce care burden significantly. Sleep interventions may be among treatments with such disease-modifying potential. Evidence from animal models suggests there is a bi-directional relationship between sleep and AD pathophysiology such that sleep disruptions can facilitate amyloid beta (Aβ) accumulation and its aggregation into plaques and downstream formation of tau-tangles, and conversely, that AD pathophysiology can be reversed with sleep agents. Many key findings from animal models translate to human models of the disease, such as diurnal variation in Aβ (higher in wakefulness, lower in sleep), reduced clearance of Aβ to cerebrospinal fluid (CSF) in sleep deprivation and disruption, and weakening of the Aβ circadian rhythm with both normative aging and those with Aβ plaques. Epidemiologic studies supplement these smaller sample findings to indicate sleep and circadian disruptions can predict incident MCI/AD over 4-6 years. However, other evidence suggests these predictions are consistent with poor aging in general and may not be specific to AD. Experimental studies with efficacious sleep aids can address these questions. Melatonin improves sleep, has a good safety record for long-term use among older adults, and improves cognitive outcomes over a 9-month period in non-randomized studies among MCI patients. However, whether melatonin affects biomarkers in the Aβ-cascade is unknown. The proposed pragmatic trial will test efficacy of 5mg of melatonin on both memory and AD-biomarker outcomes in the spectrum of preclinical to prodromal AD using stratified randomization of MCI+ and MCI- to active and placebo arms using a short-term longitudinal framework. The participants will be observed with actigraphy to objectively track both sleep and circadian rhythm in daily life for a two month period in the sleep-as-usual phase#1, ending with CSF sampling of AD biomarkers and brief cognitive testing. Following stratified randomization, participants will be followed for another two-month period with actigraphic monitoring in the sleep-intervention-phase#2, also ending with CSF sampling of AD biomarkers and brief cognitive testing. Phase#3 long-term follow-up will extend the melatonin treatment to 9 months without actigraphic monitoring, ending with CSF sampling of AD biomarkers and cognitive testing. Dense, repeated, objective sampling of both sleep and circadian function in the real-world and the coupling of those objective assessments with AD biomarker sampling both prior to and after two-months of melatonin treatment will permit a methodologically rigorous evaluation of whether melatonin has disease-modifying treatment potential. Project's specific aims are organized around the central prediction that improvements in episodic memory will lag those seen in biomarkers, and that biomarker improvements will mediate the effects of improved sleep on episodic memory. Findings will address whether previously reported associations of sleep / circadian function with AD outcomes speak to the potential of these interventions to slow disease progression.