Degeneration of neurons, not sleep deprivation, makes Alzheimer's patients drowsy

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 had pointed out -- that in Alzheimer's patients who need to nap all the time, the disease damages the neurons that keep them awake," says neuropathologist Grinberg, who works with psychiatrists J.

"It's not that these patients are tired during the day because they don't sleep at night," Greenberg 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 group of neurons that keep us awake, Greenberg's team hypothesized that people with Alzheimer's struggle to stay awake, and that these neurons play a role in Alzheimer's disease onset.

"You can think of this system as a switch between wake-promoting neurons and sleep-promoting neurons, each of which connects 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 the neurodegenerative process - 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, Greenberg said

"We found that these patients couldn't sleep because there was nothing telling the 'awake' neurons to shut down," she said

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
.
This approach is in stark contrast to the trial-and-error approach of traditional sleep medication
.

The study's other lead author, Dr.
Christine Walsh, who led the trial, also worked on the study for a decade
.
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
.

Alzheimer's treatments can be tailored to the patient's needs, weakening the "sleep" system while strengthening the "wake" system, said Walsh, who and Greenberg are both UCSF Weill Neuroscientists.
Member of the Institute of Science
.

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
.
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
.
"

Journal Reference :

1. Jun Y.
   Oh, Christine M.
   Walsh, Kamalini Ranasinghe, Mihovil Mladinov, Felipe L.
   Pereira, Cathrine Petersen, Neus Falgàs, Leslie Yack, Tia Lamore, Rakin Nasar, Caroline Lew, Song Li, Thomas Metzler, Quentin Coppola, Natalie Pandher, Michael Le, Hilary W.
   Heuer, Helmut Heinsen, Salvatore Spina, William W.
   Seeley, Joel Kramer, Gil D.
   Rabinovici, Adam L.
   Boxer, Bruce L.
   Miller, Keith Vossel, Thomas C.
   Neylan, Lea T .
   Grinberg.
   Subcortical Neuronal Correlates of Sleep in Neurodegenerative Diseases .
   JAMA Neurology , 2022; DOI: 10.
   1001/jamaneurol.
   2022.
   0429