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

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2022 · $733,717

## Abstract

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...

## Key facts

- **NIH application ID:** 10356908
- **Project number:** 5R01AG062673-04
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** NATALIE L DENBURG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $733,717
- **Award type:** 5
- **Project period:** 2019-04-15 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10356908

## Citation

> US National Institutes of Health, RePORTER application 10356908, Evaluating the disease-modifying potential of a sleep intervention for Alzheimer's Disease outcomes (5R01AG062673-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10356908. Licensed CC0.

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