A study headed by researchers at the University of California, San Francisco (UCSF) Memory and Aging Center has found that 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, or wake-promoting neurons (WPNs). The study results, reported in JAMA Neurologyalso implicated tau protein in that neurodegeneration.
The findings contradict the common notion that Alzheimer’s patients sleep during the day to make up for a bad night of sleep, and may reveal options for potential therapies to help these patients feel more awake.
“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 Lea T Grinberg, MD, PhD, a neuropathologist who, along with psychiatrist Thomas Neylan, MD, is a senior author of the study, titled, “Subcortical neuronal correlates of sleep in neurodegenerative diseases.”
Sleep disturbance is common in neurodegenerative diseases, the authors explained. “For instance, patients with Alzheimer’s disease (AD) experience excessive daytime sleepiness and sundowning,” they wrote. “Progressive supranuclear palsy (PSP) features hyperarousal and decreased homeostatic sleep drive.” Sleep disturbance generally precedes symptoms that are characteristic of the disease, often by decades, the team continues. This suggests that dysregulation of sleep is important in the early pathogenesis of neurodegeneration. However, the investigators noted, while sleep disturbances and early neurodegenerative processes have a “bidirectional relationship,” it remains unclear which is the initial driver. “Identifying neural substrates of specific sleep-wake patterns may inform novel treatments to address early symptoms of neurodegenerative diseases and help to slow overall disease progression.”
The team looked to answer the question, “Are the numbers of subcortical neurons, which often start degenerating early in neurodegenerative diseases, correlated with clinical sleep phenotypes in patients with AD or PSP?” To help answer this, the team examined the correlation between the number of important subcortical wake-promoting neurons (assessed using quantitative postmortem neuronal analysis) and clinical sleep phenotypes (assessed using objective sleep measurements) in patients with AD and PSP.
For their study, they enrolled 33 patients with AD, 20 patients with PSP, and 32 healthy individuals. The participants were patients at UCSF’s Memory and Aging Center, and had all volunteered to have their sleep monitored with electroencephalogram (EEG), and to donate their brains after they died. The participants received EEG and polysomnographic (PSG) sleep assessments. Subsequently, postmortem neuronal analysis of brainstem hypothalamic wake-promoting neurons was performed for 10 patients with AD and 9 patients with PSP.
Grinberg’s team had developed the hypothesis that Alzheimer’s patients were having trouble awake staying after discovering a set of neurons that keep us awake and that are affected in Alzheimer’s from the onset of the disease. Being able to compare sleep data with microscopic views of postmortem brain tissue was the key to the investigation.
The results of their analyses, Grinberg said, showed that, “It’s not that these patients are tired during the day because they didn’t sleep at night. It’s that the system in their brain that would keep them awake is gone.” The opposite phenomenon occurred in patients with progressive supranuclear palsy PSP. These patients demonstrate damage to the neurons that make them feel tired, so they are unable to sleep and become sleep deprived.
The authors further noted, “Altogether, our study suggests that subcortical WPNs have a strong influence in driving sleep-wake physiology in humans by decreasing sleep promotion. Under neurodegenerative conditions, loss of WPNs at the disease’s early stages may be sufficient to diminish regulation of sleep-wake homeostasis.
“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 study’s 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.”
Oh described 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 team measured the amounts of beta amyloid and tau, two proteins commonly associated with the neurodegenerative process. Which of the two proteins might be 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.”
The authors further stated, “Individuals with AD and PSP, while harboring pathological tau lesions, exhibit sleep-wake disturbances differently. From a clinical perspective, patients with AD exhibit increasing severity of arousal deficiencies. In contrast, those with PSP, a 4-repeat tauopathy, exhibit sleep deficiencies that are characterized by hyperarousal and difficulty falling and remaining asleep.”
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.”
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.
The trial is being led by Christine Walsh, PhD, co-lead author of the newly released report, 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.”
Reporting on their newly released study data, the authors concluded: “The study’s findings suggest that loss of subcortical wake-promoting neurons in the early stages of neurodegenerative disease may be sufficient to reduce regulation of sleep-wake homeostasis in patients with AD and PSP … Further research on the specific patterns of neurodegeneration within the subcortical network, including sleep-promoting nuclei and the circadian system, may inform tailored treatment strategies for sleep disturbances and early symptoms of neurodegenerative diseases, which may help to slow overall disease progression.”