It’s clear that dementia and sleep disorders are closely linked, but the relationship remains murky.
Although poor sleep can increase the risk of cognitive decline, dementia can also increase the risk of sleep problems. Many of the mechanisms involved are not yet fully understood.
In a new research review, scientists investigated this association using information from another seemingly unrelated disease: narcolepsy.
Narcolepsy is a chronic neurological disorder that impairs the brain’s ability to regulate sleep-wake cycles. People with narcolepsy often experience fragmented sleep at night as well as excessive sleepiness during the day, among other sleep-related symptoms.
Despite potentially serious sleep problems, the brains of narcolepsy patients generally do not exhibit the premature aging otherwise associated with chronic sleep disruptions, the review authors write.
Could narcolepsy help slow down the biological aging of the brain?
There are two main forms of narcolepsy, called type 1 and type 2. Both involve excessive daytime sleepiness, but type 2 tends to have milder symptoms. Unlike type 1, it does not include cataplexy or sudden episodes of muscle weakness triggered by strong emotions.
Narcolepsy type 1 (NT1) involves severe disturbances in sleep and wakefulness as well as a loss of hypocretin (also known as orexin), a neuropeptide that helps regulate various important physiological processes, including wakefulness and arousal, which are also associated with age-related brain changes.
Given the established link between sleep disturbances and dementia, NT1 “should therefore predispose individuals to premature brain aging,” the authors write.
“Yet available biomarker and neuroimaging results do not consistently support this possibility,” they add, “raising questions about the role of hypocretin in the mechanisms linking sleep to neurodegeneration.”
In addition to regulating arousal and arousal, hypocretin is also involved in several other key determinants of neuronal resilience, the authors explain, including inflammatory circuits, metabolic regulation, synaptic plasticity, and circadian timing.
Some evidence suggests that loss of hypocretin could change the way sleep disorders affect a person’s brain.
“Selective loss of hypocretin in NT1 could alter how age-related stressors are integrated into neuronal systems that are particularly susceptible to disease processes,” the authors write.
Further research will be needed to investigate this possibility, but the review identifies some ideas for how it could work.
In animal models, for example, experiments have indicated that hypocretin signaling influences the production and accumulation of beta-amyloid – the main component of amyloid plaques in Alzheimer’s disease – and that inhibition of hypocretin reduces amyloid burden.
In another study of transgenic mice lacking the hypocretin gene, researchers reported a decline in beta-amyloid pathology as sleep time increased.
“These results suggest that the relationship between orexin and β-amyloid may be mediated, at least in part, by changes in the sleep-wake state rather than by a direct effect of orexin, although the underlying mechanisms remain unclear,” the review authors write.
It is also important to consider the “structure of arousal,” they add, and to distinguish the total duration of arousal from the ability to maintain it. Many narcolepsy patients do not spend less time awake overall, they note, due to fragmented nighttime sleep compensating for daytime sleep.
Total waking time was similar for hypocretin-deficient mice and wild-type controls, one study showed, but the results suggested that hypocretin was key to the rodents’ ability to maintain a prolonged wakeful state.
In humans with NT1, disrupted wakefulness “could therefore limit cumulative β-amyloid production and activity-dependent tau release, even when total wake time is preserved,” the authors write, noting that this could be a valuable topic for future studies.
If narcolepsy patients have younger-looking brains, at least compared to the premature aging that typically accompanies sleep disorders in other contexts, what can this tell us about sleep and dementia?
“We are not suggesting that narcolepsy confers protection against dementia,” they write. “Cases of Alzheimer’s disease, although rare, have been described in narcoleptic patients.”
Instead, the researchers say, they suggest that our emerging knowledge about narcolepsy should be more integrated with modern studies of neuronal integrity, or structural and functional brain health.
“The most important question may not be whether narcolepsy increases or decreases the risk of dementia, but what this apparent paradox can reveal about how hypocretin and the organization of sleep and wakefulness influence brain aging,” they write.
The research was published in Reviews of Aging Research.
This article was fact-checked by Rachel Garner and edited by Peter Dockrill. Although we are proud of our process, we are only human. If you spot an error, please let us know.
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