# Sleep and Orexin: Potential Markers of Progression from Preclinical to Mildly Symptomatic Alzheimer's Disease

> **NIH NIH P01** · WASHINGTON UNIVERSITY · 2021 · $212,554

## Abstract

Project 2 Project Summary
Amyloid-β (Aβ) deposition in the brain is a key early step in the development of Alzheimer disease and is
followed by tauopathy, neuronal and synaptic loss, and cognitive impairment. The presence of Alzheimer
disease pathology in the brain without clinical symptoms is called “preclinical” Alzheimer disease and begins to
develop at least 10-15 years prior to symptom onset. Once cognitive impairment begins, there is already
marked neuronal loss. Therefore, a major goal of Alzheimer disease research is to identify the transition from
Aβ deposition without evidence of neuronal injury to the early stages of tauopathy when neuronal loss and then
cognitive deficts begin to develop. Reliably differentiating this transition in individuals with and without
cognitive impairment is critical to: 1) predict prognosis; 2) screen and monitor response of individuals in
Alzheimer disease clinical trials; and 3) guide Alzheimer disease clinical trial design. Current biomarkers of
Alzheimer disease pathology are either invasive (lumbar puncture) and/or expensive (amyloid PET). Based on
our data in both animals and humans, we propose that changes in sleep can serve as an informative
biomarker of preclinical and symptomatic Alzheimer disease. Changes in sleep associated with Alzheimer
disease pathology may provide a minimally invasive way to assess the transition from preclinical to
symptomatic Alzheimer disease as well as be a functional marker that is responsive to new therapies. Work in
both rodents and humans strongly suggests a bidirectional relationship between sleep and Alzheimer disease:
the amount and quality of sleep may regulate Aβ deposition and/or changes in sleep parameters may indicate
progression of Alzheimer disease pathology. Changes in sleep mediated by Alzheimer disease may also
involve the orexinergic system. Orexin is a wake-promoting neurotransmitter and orexin deficiency results in
narcolepsy. Recent cross-sectional studies associated higher CSF orexin levels with mild cognitive impairment
as well as moderate and severe Alzheimer disease compared to controls. These findings suggest that orexin
could be used for early detection of Alzheimer disease, however the relationship of orexin to different sleep
parameters, CSF Alzheimer disease biomarkers, and neuropsychological testing is unknown. In this study, we
hypothesize that longitudinally measuring sleep parameters and CSF orexin in cognitively normal and mildly
demented individuals will serve to detect changes in global sleep markers and the orexinergic system as
markers of brain injury at the very early progression from preclinical Alzheimer disease to mildly symptomatic
Alzheimer disease.

## Key facts

- **NIH application ID:** 10131745
- **Project number:** 5P01AG003991-38
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Brendan Patrick Lucey
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $212,554
- **Award type:** 5
- **Project period:** 1997-01-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10131745

## Citation

> US National Institutes of Health, RePORTER application 10131745, Sleep and Orexin: Potential Markers of Progression from Preclinical to Mildly Symptomatic Alzheimer's Disease (5P01AG003991-38). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10131745. Licensed CC0.

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