# AD/ADRD Supplement to: Alterations of Sleep and Circadian Timing in Aging P01AG011412 Project 3.

> **NIH NIH P01** · NORTHWESTERN UNIVERSITY · 2021 · $390,776

## Abstract

The goal of the proposed studies in this administrative supplement application is to test the hypothesis that
specific sleep and circadian disturbances characteristic of aging and early-stage Alzheimer’s disease (AD)
contribute to AD and ADRD cognitive disturbances, and targeting these can be used as a countermeasure to
aging- and AD- related dementia. AD is associated with profound disruptions in circadian rhythms and sleep,
which exacerbate neuropathology and dementia via mechanisms involving neurophysiology, synaptic plasticity,
neuroinflammation, and metabolic pathways. In a study of a widely used genetic model of AD, 5xFAD mice, we
found elevated intensity of theta (4-8 Hz) oscillations during rapid-eye-movement (REM) sleep at all times of the
day, blunting the diurnal rhythms of theta intensity that can be observed in wildtype mice. These circadian and
sleep changes were observed at the early symptomatic stage, tightly linked to acetylcholine neurotransmission
and memory consolidation, and with striking resemblance to REM sleep power spectrum changes in patients
with preclinical and mild-to-moderate AD. Remarkably, our current P01AG011412 studies found that aged mice
exhibit the same alternations in REM theta as observed in the young early symptomatic 5xFAD mice. Our
program project studies (Project 3) are designed to test the hypothesis that circadian phase-restricted feeding
as an aging countermeasure to boost circadian amplitude and alignment, sleep, and metabolic homeostasis.
Given our new preliminary observations, we propose to test the hypothesis that circadian phase-restricted
feeding is also a countermeasure to restore disrupted circadian rhythms and abnormally elevated levels of REM
theta oscillations, thereby alleviating aging- and AD- related cognitive disturbances. The proposed studies
complement and extend the Project 3 studies; specifically, we will test whether circadian phase-restricted feeding
restores the diurnal rhythms and proper levels of REM theta activity in aged and 5xFAD mice, and consequently
improves memory performance. These studies build upon the experiments currently described in Aim 1 of Project
3, which focuses on the circadian, sleep, and metabolic benefits of circadian phase-restricted feeding in aged
animals. Completion of these studies is expected to open new avenues to use behavioral approaches to mitigate
the risks of and combat age- and AD -related dementia.

## Key facts

- **NIH application ID:** 10294649
- **Project number:** 3P01AG011412-22S1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Phyllis C. Zee
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $390,776
- **Award type:** 3
- **Project period:** 1997-02-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10294649

## Citation

> US National Institutes of Health, RePORTER application 10294649, AD/ADRD Supplement to: Alterations of Sleep and Circadian Timing in Aging P01AG011412 Project 3. (3P01AG011412-22S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10294649. Licensed CC0.

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