# RCT Targeting Cognition in Early Alzheimer's Disease by Improving Sleep with Trazodone (Rest)

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2022 · $748,283

## Abstract

PROJECT SUMMARY
It is estimated that 5.8 million people are afflicted by dementia in the US, a number projected to increase to 14
million by 2050 unless effective therapies are available that prevent or significantly slow the disease process.
Sleep complaints are common throughout the AD continuum beginning with prodromal stages. In
observational studies, disturbed sleep has been linked to AD pathogenesis and subsequent development of
mild cognitive impairment (MCI) and dementia. Co-investigator Dr. Bakker has studied pattern separation (PS;
a memory task involved with the earliest stages of encoding that is essential to formation of new memories) in
a task related functional MRI (fMRI) paradigm, determining that impaired PS is associated with increased
hippocampal activation in amnestic MCI (aMCI). Because poor sleep may be associated with increased
hippocampal activation, improving sleep is a potential target for positively affecting cognition and disease
progression in AD. Trazodone is a generic antidepressant widely used off-label to treat sleep disturbance,
particularly enhancing slow wave sleep (SWS) that is evidenced to be a critical sleep phase influencing
pathogenic mechanisms. While it has been demonstrated to improve sleep in AD and potentially mitigate the
risk of developing MCI, its effect on sleep has not been rigorously studied in MCI. Supported by its benign
safety profile, we propose a rigorous double-blind, placebo-controlled, randomized crossover trial of
trazodone in 100 subjects with prodromal AD/aMCI and sleep complaints. Each treatment phase will last
four weeks with a two-week washout between phases. Sleep will be measured by home sleep testing
including polysomnography, actigraphy, and self-report. Hippocampal function and excitability will be
assessed by task-related fMRI employing PS. The primary outcome will be to examine the association of
trazodone with sleep parameters. We hypothesize that trazodone will improve total sleep time and proportion
of time in SWS. Secondary outcomes include assessment of trazodone's effect on 1) PS and hippocampal
activation by task-related fMRI, with the hypothesis that trazodone will improve PS performance and decrease
hippocampal activation; 2) a broader range of cognitive domains, with the hypothesis that trazodone will
improve performance on other memory tasks, executive function, and processing speed; 3) neuropsychiatric
symptoms with the hypothesis that they will improve with trazodone treatment. We will also assess blood-
based biomarkers of amyloid and tau, as exploratory outcomes to assess their association with sleep and
cognitive responses to trazodone.

## Key facts

- **NIH application ID:** 10477205
- **Project number:** 5R01AG071522-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Barry David Greenberg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $748,283
- **Award type:** 5
- **Project period:** 2021-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10477205

## Citation

> US National Institutes of Health, RePORTER application 10477205, RCT Targeting Cognition in Early Alzheimer's Disease by Improving Sleep with Trazodone (Rest) (5R01AG071522-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10477205. Licensed CC0.

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