[Apr. 22, 2023: Staff Writer, The Brighter Side of News]
Individuals who develop Alzheimer’s often encounter difficulty falling and remaining asleep long before cognitive issues surface. (CREDIT: Creative Commons)
Alzheimer’s disease may manifest as sleep disturbances in its early stages. Individuals who develop Alzheimer’s often encounter difficulty falling and remaining asleep long before cognitive issues such as memory loss and confusion surface. A harmful cycle occurs where Alzheimer’s-induced changes to the brain disrupt sleep, and poor sleep exacerbates detrimental changes to the brain.
In an attempt to break this cycle, researchers from Washington University School of Medicine in St. Louis have discovered a possible solution. In a small two-night study, participants who ingested a sleeping pill before bed displayed reduced levels of crucial Alzheimer’s proteins. This is a positive sign because elevated levels of such proteins are indicative of a worsening disease.
The study utilized a sleeping aid named suvorexant, which has already been sanctioned by the Food and Drug Administration (FDA) for insomnia. Although the results imply that sleep medications might decelerate or halt the progression of Alzheimer’s, significantly more research is necessary to confirm the feasibility of this approach.
The Annals of Neurology recently published a small-scale proof-of-concept study. Although the study showed promising results regarding the use of suvorexant in reducing the levels of proteins linked to Alzheimer's disease, senior author Brendan Lucey, MD, advises against people using it as a preventive measure without further research.
Lucey, who is an associate professor of neurology and the director of Washington University's Sleep Medicine Center, emphasized that the long-term effectiveness and dosage of the drug in staving off cognitive decline remain uncertain. Nonetheless, he remains optimistic about the drug's potential as it has already been proven safe and effective in affecting the levels of critical Alzheimer's disease-driving proteins.
The class of insomnia medications called dual orexin receptor antagonists includes Suvorexant. Orexin is a biomolecule that naturally promotes wakefulness, and its inhibition induces sleep. The FDA has already approved three orexin inhibitors, and more are under development.
Amyloid beta plaques accumulate in the brain to start the onset of Alzheimer's disease. After prolonged amyloid accumulation, toxic tangles of the brain protein tau begin to form, damaging neurons and causing cognitive symptoms like memory loss in patients. Detectable tau tangles usually mark the beginning of Alzheimer's.
The ratio of phosphorylated-tau-threonine-181 to unphosphorylated-tau-threonine-181, a measure of phosphorylation at this tau phosphosite, decreased ~10% to 15% in participants treated with suvorexant 20 mg compared to placebo. (CREDIT: Annals of Neurology)
Poor sleep can lead to higher amyloid and tau levels in the brain, as demonstrated in studies by Lucey and colleagues. It remains uncertain whether good sleep can reduce the accumulation of amyloid and tau and potentially halt or reverse Alzheimer's progress. However, promising results have been obtained from mouse studies with orexin inhibitors.
Lucey and colleagues conducted a sleep study to investigate the effect of orexin inhibitors on people. The study included 38 participants between the ages of 45 and 65, with no cognitive impairments. The participants were divided into three groups, with 13 receiving a lower dose of suvorexant (10mg), 12 receiving a higher dose of suvorexant (20mg), and 13 receiving a placebo.
The participants were given the sleeping aid or placebo at 9 p.m. and then slept in a clinical research unit at Washington University for two nights. Researchers performed spinal taps every two hours for 36 hours, starting one hour before the administration of the sleeping aid or placebo, to measure changes in amyloid and tau levels.
Phosphorylation at tau-serine-202 and tau-threonine-217 were not decreased by suvorexant. Suvorexant decreased amyloid-β ~10% to 20% compared to placebo starting 5 hours after drug administration. (CREDIT: Annals of Neurology)
The study found that the high dose of suvorexant reduced amyloid levels by 10% to 20% and hyperphosphorylated tau levels by 10% to 15% compared to the placebo group, which was a statistically significant difference. However, there was no significant difference between the group that received a low dose of suvorexant and the placebo group.
After 24 hours, the hyperphosphorylated tau levels increased in the high-dose group, while amyloid levels remained low compared to the placebo group. However, a second dose of suvorexant, administered on the second night, reduced the levels of both proteins for people in the high-dose group.
According to Lucey, if amyloid is reduced daily, it may lead to a decrease in the accumulation of amyloid plaques in the brain over time. He also explained that hyperphosphorylated tau is significant in the development of Alzheimer's disease since it is linked to the formation of tau tangles, which cause neuronal death. Therefore, reducing tau phosphorylation could result in less tangle formation and less neuronal death.
Thirty-eight cognitively unimpaired participants aged 45 to 65 years were randomized to placebo (N = 13), suvorexant 10 mg (N = 13), and suvorexant 20 mg (N = 12). (CREDIT: Annals of Neurology)
Although the study only examined the effects of two doses of the drug on a small group of participants, Lucey has ongoing research to determine the longer-term impact of orexin inhibitors in people with a higher risk of dementia. He stressed that future studies should observe the effects of the drug for several months and measure the impact on amyloid and tau over time.
Additionally, he plans to investigate older participants who may still be cognitively healthy but have some amyloid plaques in their brains. Notably, the study involved healthy middle-aged participants, and the results may vary in older populations.
Lucey expressed hope that researchers would eventually develop drugs that use the link between sleep and Alzheimer's to prevent cognitive decline. However, he acknowledged that such drugs are yet to be developed. For now, he recommended getting adequate sleep, seeking help from a sleep specialist if necessary, and treating any sleep-related issues.
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