"JAMA" sub-issue: Neuron loss causes sleepiness

Sleepiness in many Alzheimer's patients is not caused by sleep deprivation, but by the degeneration of a type of neuron that keeps us awake, according to a study that also confirmed that tau is responsible for neurodegeneration reason

The study's findings contradict the widely held belief that Alzheimer's patients sleep during the day to compensate for sleep deprivation at night, and point to potential treatments to help these patients feel more awake

The data came from study participants at the UCSF Center for Memory and Aging who volunteered to monitor their sleep with electroencephalography (EEG) and donate their brains after they died

Being able to compare sleep data with microscopic views of their postmortem brain tissue is key to answering questions scientists have been pondering for years

"We were able to show what our previous research pointed to -- that in Alzheimer's patients who need to nap all the time, the disease damages the neurons that keep them awake," said neuropathologist Grinberg, who worked with psychiatrists Thomas Neylan, MD, is the senior author of the study, which appears in the April 4, 2022, issue of JAMA Neurology

"It's not that these patients are tired during the day because they don't sleep at night," Grinberg noted.

The opposite phenomenon occurred in patients with other neurodegenerative diseases, such as progressive supranuclear palsy (PSP), who were also included in the study

After discovering a set of neurons that keep us awake, Grinberg's team hypothesized that people with Alzheimer's have a hard time staying awake, and that these neurons are activated at the onset of Alzheimer's been affected

"You can think of this system as a switch between wake-promoting neurons and sleep-promoting neurons, each of which is connected to neurons that control circadian rhythms," said medical student Joseph Oh, one of the study's lead authors

'Extremely smart neurons' destroyed by Tau protein

Oh describes these neurons as "extremely smart" because they produce a range of neurotransmitters and can stimulate, inhibit and modulate other nerve cells

"Although the number of neurons is small, their computational power is incredible," Oh said

To determine what caused the degeneration of these neurons in Alzheimer's disease, the researchers looked at the brains of 33 Alzheimer's patients, 20 PSP patients, and 32 people who had always had healthy brains.

The team measured the levels of two proteins commonly involved in neurodegenerative processes: amyloid and tau

During sleep, the brain clears the amyloid that accumulates during the day

"But it turns out they have nothing," he said

In PSP patients, this understanding has changed the treatment paradigm, Grinberg said

"What we found was that these patients couldn't fall asleep because there was nothing telling the 'awake' neurons to shut down," she said.
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Right now, the idea is not to try to induce sleep in these people, but to shut down the system that keeps them awake
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Clinical trials give patients hope

The idea is currently being tested in clinical trials in patients with PSP, using treatments that specifically target the overactive "wake" system that keeps these patients from falling asleep
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This approach is in stark contrast to the trial-and-error approach of traditional sleep medication
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The study's other lead author, Dr.
Christine Walsh, who led the trial, also worked on the study for a decade
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Noting that PSP and Alzheimer's are two extremes of sleep disorders, she said she hopes this research will lead to new treatments for sleep disorders caused by neurodegeneration
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Alzheimer's treatments can be tailored to the patient's needs, weakening the "sleep" system while strengthening the "wake" system, said Walsh, who along with Grinberg are both at the UCSF Weill Institute for Neuroscience.
member
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The PSP trial is still ongoing, and Walsh is very optimistic that the new approach will work better than current drugs for patients with both conditions
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Based on the findings published today, she said, "We are even more hopeful that we can actually make a difference in the lives of these patients
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Subcortical Neuronal Correlates of Sleep in Neurodegenerative Diseases