Summary: Degeneration of neurons associated with wakefulness, and not a lack of sleep, makes Alzheimer’s patients more drowsy. The degeneration of these neurons is caused by the tau protein. In PSP, the damage to the neurons was associated with symptoms of sleep deprivation.
The lethargy that many Alzheimer’s patients experience is caused not by a lack of sleep, but rather by the degeneration of a type of neuron that keeps us awake, according to a study that also confirms the tau protein is behind that neurodegeneration.
The study’s findings contradict the common notion that Alzheimer’s patients sleep during the day to make up for a bad night of sleep and point toward potential therapies to help these patients feel more awake.
The data came from study participants who were patients at UC San Francisco’s Memory and Aging Center and volunteered to have their sleep monitored with electroencephalogram (EEG) and donate their brains after they died.
Being able to compare sleep data with microscopic views of their post-mortem brain tissue was the key to answering a question that scientists have been pondering for years.
“We were able to prove what our previous research had been pointing to—that in Alzheimer’s patients who need to nap all the time, the disease has damaged the neurons that keep them awake,” said Grinberg, a neuropathologist who, along with psychiatrist Thomas Neylan, MD, is a senior author on 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 didn’t sleep at night,” noted Grinberg. “It’s that the system in their brain that would keep them awake is gone.”
The opposite phenomenon occurs in patients with other neurodegenerative conditions, such as progressive supranuclear palsy (PSP), who were also included in the study. Those patients have damage to the neurons that make them feel tired, so they are unable to sleep and become sleep deprived.
Grinberg’s team developed the hypothesis that Alzheimer’s patients were having trouble staying awake, after discovering a set of neurons that keep us awake and that are affected in Alzheimer’s from the onset of the disease.
“You can think of this system as a switch with wake-promoting neurons and sleep-promoting neurons, each tied to neurons controlling circadian rhythms,” said Joseph Oh, a medical student and one of the lead authors.
“Finally, with this post-mortem tissue, we’ve been able to confirm that this switch, which is known to exist in model animals, also exists in humans and governs our sleep and awake cycles.”
“Extremely Smart Neurons” Disrupted by Tau Proteins
Oh describes these neurons as “extremely smart” because they can produce an array of neurotransmitters and can excite, inhibit, and modulate other nerve cells.
“It’s a small number of neurons but their computational capabilities are incredible,” Oh said. “When these cells are affected by disease, it can have a huge effect on sleep.”
To determine what’s contributing to the degradation of these neurons in Alzheimer’s, the researchers looked at the brains of 33 patients with Alzheimer’s, 20 with PSP, and 32 volunteers who’d had healthy brains through the end of life.
The team measured the amounts of two proteins often associated with the neurodegenerative process—beta amyloid and tau. Which of the two is more involved in disrupting sleep has been a long-disputed question, with most researchers crediting the sleep problems to beta-amyloid accumulation.
During sleep, the brain clears out the beta amyloid that accumulates during the day. When we can’t sleep, it builds up. So, Neylan said, since the PSP patients never sleep, she expected to see lots of the protein in their brains.
“But it turns out that they have none,” he said. “These findings confirm with direct evidence that tau is a critical driver of sleep disturbances.”
In patients with PSP, said Grinberg, this understanding turned the treatment paradigm on its head.
“We see that these patients can’t sleep because there is nothing telling the “awake” neurons to shut down,” she said. “Now, rather than trying to induce these people to sleep, the idea is to shut down the system that’s keeping them awake.”
Clinical Trial is Giving Patients Hope
That idea is currently being tested in a clinical trial of patients with PSP, using a treatment that specifically targets the overactive ‘awake’ system that keeps these patients from sleeping. This approach contrasts with the traditional trial-and-error treatment with sleep medications.
At the helm of that trial is Christine Walsh, PhD, the study’s other lead author, who has also worked on the study for a decade. Noting that PSP and Alzheimer’s are at opposite ends of the sleep-disturbance spectrum, she said she expects the research to lead to new ways of treating sleep disturbances driven by neurodegeneration.
Treatments for Alzheimer’s could be adjusted depending on the patient’s needs, bumping up the “awake” system while tamping down the “sleep” system, said Walsh, who along with Grinberg, is a member of the UCSF Weill Institute for Neurosciences.
The PSP trial is still underway, and Walsh is highly optimistic that this new approach will have better results than current medications for people with either condition. Based on the findings of the study published today, she said, “We’re even more hopeful that we can actually make a difference in the lives of these patients.”
Authors: Additional authors on the study include Kamalini Ranashinge, Mihovil Mladinov, Felipe L. Pereira, Catherine Petersen, Neus Falgàs, Tia Lamore, Rakin Nasar, Caroline Lew, Song Li, Quentin Coppola, Natalie Pandher, Hilary Heuer, Salvatore Spina, William Seeley, Joel Kramer, Gil Rabinovici, Adam L. Boxer, and Bruce L. Miller, all of UCSF. For other authors, please see the study.
Funding: This work was supported by NIH grants R01AG060477, R01 AG064314, R01 AG038791, U54NS092089, K24 AG053435, K08AG058749 and K23AG038357 and the Rainwater Charity Foundation.
About this Alzheimer’s disease and sleep research news
Author: Robin Marks Source: UCSF Contact: Robin Marks – UCSF Image: The image is in the public domain
Subcortical Neuronal Correlates of Sleep in Neurodegenerative Diseases
Sleep disturbance is common among patients with neurodegenerative diseases. Examining the subcortical neuronal correlates of sleep disturbances is important to understanding the early-stage sleep neurodegenerative phenomena.
To examine the correlation between the number of important subcortical wake-promoting neurons and clinical sleep phenotypes in patients with Alzheimer disease (AD) or progressive supranuclear palsy (PSP).
Design, Setting, and Participants
This longitudinal cohort study enrolled 33 patients with AD, 20 patients with PSP, and 32 healthy individuals from the Memory and Aging Center of the University of California, San Francisco, between August 22, 2008, and December 31, 2020. Participants received electroencephalographic and polysomnographic sleep assessments. Postmortem neuronal analyses of brainstem hypothalamic wake-promoting neurons were performed and were included in the clinicopathological correlation analysis. No eligible participants were excluded from the study.
Electroencephalographic and polysomnographic assessment of sleep and postmortem immunohistological stereological analysis of 3 wake-promoting nuclei (noradrenergic locus coeruleus [LC], orexinergic lateral hypothalamic area [LHA], and histaminergic tuberomammillary nucleus [TMN]).
Main Outcomes and Measures
Nocturnal sleep variables, including total sleep time, sleep maintenance, rapid eye movement (REM) latency, and time spent in REM sleep and stages 1, 2, and 3 of non-REM (NREM1, NREM2, and NREM3, respectively) sleep, and wake after sleep onset. Neurotransmitter, tau, and total neuronal counts of LC, LHA, and TMN.
Among 19 patients included in the clinicopathological correlation analysis, the mean (SD) age at death was 70.53 (7.75) years; 10 patients (52.6%) were female; and all patients were White.
After adjusting for primary diagnosis, age, sex, and time between sleep analyses and death, greater numbers of LHA and TMN neurons were correlated with decreased homeostatic sleep drive, as observed by less total sleep time (LHA: r = −0.63; P = .009; TMN: r = −0.62; P = .008), lower sleep maintenance (LHA: r = −0.85; P < .001; TMN: r = −0.78; P < .001), and greater percentage of wake after sleep onset (LHA: r = 0.85; P < .001; TMN: r = 0.78; P < .001).
In addition, greater numbers of LHA and TMN neurons were correlated with less NREM2 sleep (LHA: r = −0.76; P < .001; TMN: r = −0.73; P < .001). A greater number of TMN neurons was also correlated with less REM sleep (r = −0.61; P = .01). A greater number of LC neurons was mainly correlated with less total sleep time (r = −0.68; P = .008) and greater REM latency (r = 0.71; P = .006). The AD-predominant group had significantly greater sleep drive, including higher total sleep time (mean [SD], 0.49 [1.18] vs −1.09 [1.37]; P = .03), higher sleep maintenance (mean [SD], 0.18 [1.22] vs −1.53 [1.78]; P = .02), and lower percentage of wake after sleep onset during sleep period time (mean [SD], −0.18 [1.20] vs 1.49 [1.72]; P = .02) than the PSP-predominant group based on unbiased k-means clustering and principal component analyses.
Conclusions and Relevance
In this cohort study, subcortical wake-promoting neurons were significantly correlated with sleep phenotypes in patients with AD and PSP, suggesting that the loss of wake-promoting neurons among patients with neurodegenerative conditions may disturb the control of sleep-wake homeostasis. These findings suggest that the subcortical system is a primary mechanism associated with sleep disturbances in the early stages of neurodegenerative diseases.