# Sleep Disruption and Alzheimer's Disease Pathology

> **NIH NIH RF1** · UNIVERSITY OF COLORADO · 2022 · $390,259

## Abstract

ABSTRACT
(Parent R01 Abstract) Alzheimer’s disease (AD) is a disease of aging. AD is the most common form of
dementia, afflicting more than 5 million Americans aged 65 and older. By 2050 it is estimated that more than
14 million Americans will suffer this disease, and that its direct financial impact will exceed $1.1 trillion. AD is
particularly burdensome because it impairs memory; it worsens with time; and there is no cure. Sleep
disruption in AD is highly prevalent, and changes in sleep architecture and circadian rhythmicity that result in
excessive daytime sleepiness and nighttime insomnia are well documented. Less well known is the impact of
sleep or circadian disruption on the etiology of the disease. Sleep facilitates Aβ clearance from brain, and
sleep disruption increases Aβ in cerebrospinal fluid. Aβ pathology impairs core clock genes and exacerbates
neuroinflammation. Collectively, these data suggest that sleep and circadian disruption induce responses that
feed forward and contribute to or exacerbate AD pathology and accelerate disease progression. However, to
our knowledge definitive studies to determine the extent to which sleep disruption per se contributes to AD
pathology have not been conducted. We will use mice expressing an inducible mutant amyloid precursor
protein (APP) transgene to temporally dissociate sleep disruption and mutant APP expression from
subsequent Aβ deposition and AD-like pathology. Specifically, we will: 1) determine how chronic sleep
disruption of transgenic mice alters the course of pathology induced by expression of mutant APP; 2)
determine if sleep disruption accelerates AD onset; and 3) target a key mediator of innate immune activation
and determine effects on responses to sleep disruption and/or mutant APP expression. Outcome measures for
each aim include assessments of cognitive performance; synaptic plasticity; differential gene expression; glial
activation; cytokine production; neuroinflammatory signaling; and proteinopathy. Our multidisciplinary research
team has demonstrated expertise and possesses all requisite skills to successfully complete the proposed
project. Successful completion of this project will have a sustained impact on the field because we will
elucidate the extent to which, and potential mechanisms by which, chronic sleep disruption alters the
progression of AD-like pathology.
(Administrative Supplement) The INCLUDE project focuses on critical health and quality-of-life needs for
individuals with Down syndrome. Links between AD and DS are well-documented, but mechanisms underlying
them are little understood. NIA is prioritizing research that aims “to understand the molecular mechanism(s)
underlying the interplay between aging and neurodegeneration in DS”. A strong candidate for the DS-AD link is
the triplication of the Amyloid Precursor Protein (APP) and Regulator of calcineurin1 (RCAN1) genes in trisomy
21. The cleavage product of APP, Aβ, is a defining histopathological marker of A...

## Key facts

- **NIH application ID:** 10455975
- **Project number:** 3RF1AG064465-01S2
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** CHARLES A HOEFFER
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $390,259
- **Award type:** 3
- **Project period:** 2019-08-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10455975

## Citation

> US National Institutes of Health, RePORTER application 10455975, Sleep Disruption and Alzheimer's Disease Pathology (3RF1AG064465-01S2). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10455975. Licensed CC0.

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