Sleep Signals and Orexin May Shape Alzheimer's Disease Progression

Sleep and Alzheimer's disease are known to have a close relationship.

A newly published study in Neurology examined links between specific forms of electrical activity during deep sleep, the peptide neurotransmitter orexin, and the progression of Alzheimer's disease.

Sleep monitoring and cerebrospinal fluid samples

The researchers enrolled 60 people aged 60 or over who had recently received a diagnosis of mild to moderate Alzheimer's disease. None were using medicines known to affect brain-wave activity.

Each participant underwent overnight monitoring using sleep-study equipment. The following morning, researchers took a sample of cerebrospinal fluid (CSF) from every participant. CSF is the colourless fluid surrounding the brain and spinal cord, transporting molecules to and from the nervous system.

The team then followed up with the participants to track changes in their Alzheimer's symptoms over the subsequent three years.

Within the CSF samples, they measured levels of orexin, a chemical messenger involved in regulating sleep and wakefulness. For example, in type 1 narcolepsy, low levels of orexin in the brain contribute to extreme sleepiness and abrupt bouts of muscle weakness known as cataplexy.

Researchers are interested in whether orexin has a role in Alzheimer's disease, particularly because medicines that act on orexin already exist.

A number of small studies have suggested that orexin levels may be dysregulated in people with Alzheimer's disease.

Orexin-targeting medicines might potentially aid Alzheimer's treatment. They could perhaps indirectly support the brain's removal of amyloid beta and tau proteins, which laboratory animal experiments and observational studies in people suggest build up more readily in the brain when sleep is disturbed.

If that is the case, such drugs might slow the disease's progression. At present, however, the nature of this relationship, if there is one, remains highly uncertain.

"Dysregulated orexin signaling is associated with apathy, depression, and anxiety and may contribute to neuropsychiatric symptoms in dementia," the study's authors write.

"However, few studies have examined whether orexinergic activity relates to cognitive decline or neuropsychiatric symptom severity in people with Alzheimer's disease."

Orexin, sleep spindles and slow oscillations

To investigate further, the scientists compared orexin levels with sleep-study data measuring participants' sleep spindles and slow oscillations during non-rapid eye movement (NREM) sleep.

In healthy brains, these electrical signals reflect processes that help consolidate memories and stabilise the cortical network.

Sleep is frequently disrupted in people with Alzheimer's disease, and their sleep spindles and slow oscillations commonly reflect this disturbance.

Greater concentrations of orexin in participants' CSF were associated with poorer disease progression over the next three years.

However, the association between higher orexin and worse outcomes was less pronounced among participants with comparatively 'stronger' sleep-spindle and slow-oscillation activity.

These NREM signals were more robust in people with lower CSF orexin concentrations: their spindles were denser and their slow oscillations lasted longer.

The researchers also found that orexin concentrations in CSF were significantly higher in women than in men.

Limits of the Alzheimer's disease study

With just 60 participants, this was a very small study. It also lacked a control group, making it difficult to establish whether its findings identify anything specific to Alzheimer's disease.

Furthermore, the long-term findings were interpreted using only one overnight sleep assessment and one CSF sample collected the following morning, which is not ideal.

As many people will know from experience, sleep on one night can differ completely from sleep on another, particularly when that night involves being connected to unfamiliar equipment.

The results may therefore be of interest, but they should be regarded only as a starting point for additional research.

To properly clarify what is happening, future research would need far more participants, more detailed information about their sleep at baseline, and a control group of cognitively healthy patients.

The research was published in Neurology.

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