Sleep disorders and Alzheimer’s disease: relationship and mechanisms involving neuroinflammation, orexin and Aβ

Jun 20, 2025Fluids and barriers of the CNS

How Sleep Problems and Alzheimer's Disease Are Linked Through Brain Inflammation, Wakefulness Control, and Amyloid Beta

AI simplified

Circadian Biology on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

AD patients with (SSD) exhibited poorer cognitive performance and higher A levels compared to those without SSD.

AD-SSD patients showed significantly lower scores in cognitive assessments compared to AD-nSSD patients.
Increased orexin A levels were found in the cerebrospinal fluid of AD-SSD patients.
AD-SSD patients had lower levels of β amyloid (Aβ) 42 in cerebrospinal fluid.
In 5XFAD mice, elevated levels of glial activation and hypothalamic orexin A were observed prior to cognitive impairment.
Colocalization of orexinergic fibers with β amyloid was noted in the cerebral cortex of 5XFAD mice.

AI simplified

AIMS: Sleep disorders are common in Alzheimer's disease (AD), but the underlying mechanisms are unknown. This study aimed to specifically investigate the relationship between a specific sleep disorder of (SSD) and AD, and related mechanisms involving neuroinflammation, and AD biomarkers in both AD patients and mice.

METHODS: In part I, total 247 AD patients were consecutively recruited and categorized into AD with SSD (AD-SSD, < 6 h) and AD with no SSD (AD-nSSD, 7-8 h). Comparisons were made between the two groups in cognitive function, neuroinflammatory factors, orexinergic factors and AD biomarkers in cerebrospinal fluid (CSF). The correlations of orexinergic factors with the neuroinflammatory factors and AD biomarkers in CSF from AD-SSD group were investigated. In part II, the spatiotemporal relationships among glial activation, orexin expression, AD pathology, sleep architecture disturbance and cognitive function in 5XFAD mice were dynamically explored and the potential mechanisms underlying their relationships were analyzed.

RESULTS: In part I, compared to AD-nSSD group, AD-SSD group exhibited significantly poorer cognitive performance on the Montreal Cognitive Assessment and the Auditory Verbal Learning Test-delayed recall scales, higher orexin A level in CSF and lower β amyloid (Aβ) 42 level in CSF (all P < 0.05). Furthermore, orexin A had a positive correlation with prostaglandin E(PGE) (r = 0.322, P = 0.002) and a negative correlation with Aβ42 (r = -0.223, P = 0.027) levels in CSF from AD-SSD group. In part II, compared with WT mice, 5XFAD mice displayed elevated hippocampal glial fibrillary acidic protein level at 3.5 months, increased hippocampal/cortical Chitinase-3-like protein 1 level, hypothalamic orexin A level and sleep architecture disturbance at 4.5 months, elevated insoluble Aβ42 deposition in hippocampus, orexinergic neuronal numbers in lateral hypothalamus, colocalization of their fibers with Aβ in cerebral cortex and cognitive impairment at 5.5 months old (all P < 0.05). 2 2

CONCLUSION: SSD in AD is associated with significant cognitive impairment, neuroinflammation, orexin elevation and Aβ deposition. Hippocampal astroglial activation, hypothalamic orexin elevation and sleep architecture disturbance precede Aβ deposition in hippocampus and cognitive impairment in 5XFAD mice.

Key numbers

118 of 247 patients

Cognitive Function Decrease

Patients with out of total enrolled AD patients.

210.94 pg/mL

A Level Increase

A levels in AD- group.

0.42 ng/mL

Aβ42 Level Decrease

Aβ42 levels in AD- group.

Full Text

We can’t show the full text here under this license. Use the link below to read it at the source.

View full text (PDF) ↗View full text (HTML) ↗

Sleep disorders and Alzheimer’s disease: relationship and mechanisms involving neuroinflammation, orexin and Aβ

Abstract

Key numbers

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief

Abstract

Key numbers

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief