Home › Research › Risk factors
Orexinergic system dysregulation, sleep impairment, and cognitive decline in Alzheimer disease
Liguori C, Romigi A, Nuccetelli M, Zannino S, Sancesario G, Martorana A, Albanese M, Mercuri NB et al.. JAMA neurology, 2014-12-01
Topic: Amyloid, tau and blood-test diagnosis
Importance Nocturnal sleep disruption develops in Alzheimer disease (AD) owing to the derangement of the sleep-wake cycle regulation pathways. Orexin contributes to the regulation of the sleep-wake cycle by increasing arousal levels and maintaining wakefulness. Objectives To study cerebrospinal fluid levels of orexin in patients with AD, to evaluate the relationship of orexin cerebrospinal fluid levels with the degree of dementia and the cerebrospinal fluid AD biomarkers (tau proteins and β-amyloid 1-42), and to analyze potentially related sleep architecture changes measured by polysomnography. Design, setting, and participants We conducted a case-control study from August 1, 2012, through May 31, 2013. We included 48 drug-naive AD patients referred to the Neurological Clinic of the University Hospital of Rome Tor Vergata. Based on the Mini-Mental State Examination score, 21 patients were included in mild AD group (score, ≥21), whereas 27 were included in the moderate to severe AD group (score, Exposure Laboratory assessment of cerebrospinal fluid levels of orexin, tau proteins, and β-amyloid 1-42 and polysomnographic assessment of sleep variables. Main outcomes and measures Levels of orexin, tau proteins, and β-amyloid 1-42; macrostructural variables of nocturnal sleep (total sleep time, sleep efficiency, sleep onset and rapid eye movement [REM] sleep latencies, non-REM and REM sleep stages, and wakefulness after sleep onset); and Mini-Mental State Examination scores. Results Patients with moderate to severe AD presented with higher mean (SD) orexin levels compared with controls (154.36 [28.16] vs 131.03 [26.55]; P Conclusions and relevance Our results demonstrate that, in AD, increased cerebrospinal fluid orexin levels are related to a parallel sleep deterioration, which appears to be associated with cognitive decline. Therefore, the orexinergic system seems to be dysregulated in AD, and its output and function appear to be overexpressed along the progression of the neurodegenerative process. This overexpression may result from an imbalance of the neurotransmitter networks regulating the wake-sleep cycle toward the orexinergic system promoting wakefulness.
Key findings
- Results Patients with moderate to severe AD presented with higher mean (SD) orexin levels compared with controls (154.36 [28.16] vs 131.03 [26.55]; P < .01) and with more impaired nocturnal sleep with respect to controls and patients with mild AD.
- This overexpression may result from an imbalance of the neurotransmitter networks regulating the wake-sleep cycle toward the orexinergic system promoting wakefulness.
Why it matters
In this case-control study, patients with moderate to severe Alzheimer's disease had higher cerebrospinal fluid orexin levels than controls, and these higher levels were related to worse sleep. It describes a possible link between the orexin system, sleep disruption, and dementia severity, not a treatment or cure.
New to this subject? Start with our plain-English guide: Risk factors, ranked →
Study details
- Study designcase-control study
- Participants48
- Evidence strengthModerate
How this study scored 61/100
Published in a leading specialty journal, and it is a case-control study. Scored zero for effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (JAMA neurology) |
| Journal's citation record | 2 / 4 | JAMA Neurology: journal h-index 235 (OpenAlex, 2026-10-29) |
| Study design | 6 / 12 | A case-control study |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2014 — within 20 year(s) of the newest study here |
| Sample size | 1 / 4 | 48 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 6 / 7 | Cited 352 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 25.1 citations a year over 14 year(s) since 2014 |
| Impact for its field and year | 4 / 6 | Cited 10.2× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 15 other studies in this library |
| Still being cited | 3 / 4 | Cited 93 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Fabio Placidi: h-index 42 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | University of Rome Tor Vergata: institution h-index 778 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 2 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 25322206) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 61 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
May need a subscription OpenAlex found no free copy of the full text (checked 6 Feb 1020), so the publisher may charge for it. The PubMed abstract is free.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Liguori, C., Romigi, A., Nuccetelli, M., Zannino, S., Sancesario, G., Martorana, A., et al. (2014). Orexinergic system dysregulation, sleep impairment, and cognitive decline in Alzheimer disease. JAMA neurology. https://doi.org/10.1001/jamaneurol.2014.2510
Vancouver
Liguori C, Romigi A, Nuccetelli M, Zannino S, Sancesario G, Martorana A, et al. Orexinergic system dysregulation, sleep impairment, and cognitive decline in Alzheimer disease. JAMA neurology. 2014. doi:10.1001/jamaneurol.2014.2510. PMID: 25322206.
BibTeX
@article{liguori2014-25322206,
author = {Liguori, C. and Romigi, A. and Nuccetelli, M. and Zannino, S. and Sancesario, G. and Martorana, A. and Albanese, M. and Mercuri, N. B. and others},
title = {{Orexinergic system dysregulation, sleep impairment, and cognitive decline in Alzheimer disease}},
journal = {JAMA neurology},
year = {2014},
doi = {10.1001/jamaneurol.2014.2510},
pmid = {25322206},
url = {https://doi.org/10.1001/jamaneurol.2014.2510}
}
Studies this one cites
Referenced by this study and also in the alzhub library, so you can read them here.
Later studies that cite this one
15 studies in the alzhub library list this one in their references. Showing the 8 highest-scoring.
Related studies in Risk factors
Also tagged “amyloid-beta”
1,339 studies in the library carry the topic tag “amyloid-beta”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 1,339 tagged studies.