# Characterization of Orexin/Hypocretin Kinetics in Alzheimer's Disease

> **NIH NIH R21** · WASHINGTON UNIVERSITY · 2022 · $196,875

## Abstract

PROJECT SUMMARY
Alzheimer’s disease (AD) is characterized by deposition of amyloid-β (Aβ) as insoluble plaque, tau aggregation
and hyperphosphorylation, neuronal degeneration, synaptic loss, and eventual cognitive dysfunction and
dementia. Soluble forms of Aβ and tau, proteins critical to Alzheimer’s disease pathogenesis, change in
cerebrospinal fluid (CSF) with sleep-wake activity. CSF Aβ and tau concentrations increase during
wakefulness and decrease during sleep in both mice and humans. Based on these findings, sleep is
hypothesized to be a potential marker for Alzheimer’s disease pathology and/or a modifiable risk factor for
Alzheimer’s disease. Orexin-A and orexin-B (also known as hypocretin-1 and hypocretin-2) are two wake-
promoting neuropeptides encoded by a common precursor polypeptide, prepro-orexin. The orexin system
regulates sleep-wake activity, feeding behavior, energy homeostasis, and the reward system. Orexin
deficiency causes narcolepsy, a sleep disorder resulting in excessive daytime sleepiness. Substantial evidence
supports a role for the orexin system in the development of Alzheimer’s disease pathology. Knocking out the
orexin gene in amyloid precursor protein (APP) transgenic mice that develop amyloid deposition led to a
marked decrease in amyloid pathology in the brain. Studies in APP transgenic mice found that treatment with
almorexant, a drug that blocks orexins at their receptors, decreased Aβ concentrations while administration of
orexin increased them. Further, prolonged treatment with almorexant decreased amyloid deposition. In
humans, CSF orexin-A also correlates with CSF Aβ, tau, phospho-tau, and alpha-synuclein concentrations in
individuals with AD and other dementias. Patients with narcolepsy (i.e., with orexin deficiency) have reduced
CSF Aβ, tau, phospho-tau concentrations, and amyloid deposition on amyloid PET compared to age- and sex-
matched controls. These findings strongly suggest that orexin is a potential Alzheimer’s disease
biomarker and that blocking orexin will modulate amyloid and potentially tau pathology in the brain.
Orexin kinetics (e.g., production and clearance rates) are not understood and CSF orexin remains poorly
characterized at the protein structure and isoform level. The gold standard for measuring CSF orexin-A is a
radioimmunoassay. The overall goal of this proposal is to fully characterize orexin isoforms in CSF
from humans with and without AD pathology using mass spectrometry in order to quantify prepro-
orexin, orexin-A, orexin-B, and 13C6-leucine labeled and unlabeled orexins, and assess the utility of
orexin concentrations and kinetics in quantifying AD neurodegeneration and changes in sleep-wake
activity. This study will aid in identifying disease specific isoforms for future biomarker use, improve
understanding of the pathophysiology of sleep disorders such as primary insomnia, narcolepsy, and other
hypersomnias of central origin, as well as allow for an understanding of how the ore...

## Key facts

- **NIH application ID:** 10491248
- **Project number:** 5R21AG074151-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Brendan Patrick Lucey
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $196,875
- **Award type:** 5
- **Project period:** 2021-09-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10491248

## Citation

> US National Institutes of Health, RePORTER application 10491248, Characterization of Orexin/Hypocretin Kinetics in Alzheimer's Disease (5R21AG074151-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10491248. Licensed CC0.

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