Tau tangles appeared to selectively destroy wake-promoting neurons in Alzheimer's disease patients, a small post-mortem study found, potentially explaining the excessive daytime napping that precedes clinical disease.
Compared with healthy brains, those from Alzheimer's patients showed significant tau buildup in three areas promoting wakefulness -- the locus coeruleus, lateral hypothalamic area, and tuberomammillary nucleus -- and these regions had lost as many as 75% of their neurons, reported Lea Grinberg, MD, PhD, of the University of California San Francisco, and co-authors.
Wake-promoting neurons appeared to be extremely vulnerable to Alzheimer's but not other tauopathies: more were lost in Alzheimer's disease than in corticobasal degeneration or progressive supranuclear palsy (PSP), the researchers wrote in Alzheimer's & Dementia.
This study shows "in a very rigorous and systematic way that tau pathology in Alzheimer's disease destroys the whole network of neurons that keep us awake," Grinberg said.
It supports the idea that sleep dysfunction is a manifestation of Alzheimer's pathology rather than a risk factor, "opening the door to opportunities to treat the cause, rather than the symptoms," Grinberg told MedPage Today. "It also supports the idea that early Alzheimer's disease-like changes in the brainstem are an integral part of the disease and do have clinical consequences and should not be ignored if we want to treat the disease early."
The research adds to the growing evidence linking sleep and Alzheimer's disease pathology, noted Brendan Lucey, MD, of Washington University in St. Louis, who was not involved with the study.
"This is a very interesting paper," said Lucey, who recently published work linking cortical tau and sleep quality in cognitively normal and mildly impaired individuals. "By looking at brain regions important for regulating sleep-wake activity, this new paper was able to examine regions of the brain not visualized with tau PET scans and reinforces the potential importance of tau driving sleep-wake disturbances in individuals with Alzheimer's disease or at risk for Alzheimer's disease."
"If there is increased tau in brain regions such as the lateral hypothalamus or locus coeruleus at the very earliest stages of Alzheimer's disease, then this could explain the disturbed sleep-wake activity observed in these patients," he told MedPage Today.
In their research, Grinberg and colleagues performed design-based stereology -- a way of estimating quantities in a three-dimensional space, such as the number of cells in a region -- in post-mortem brains from 13 Alzheimer's patients and seven healthy controls. They also studied brain samples from seven patients who had PSP and seven with corticobasal degeneration as disease-specific controls. They excluded people with mixed pathology from the study.
Mean age at death was 65 and 76.5% were male, with no important differences between groups.
Compared with healthy controls, Alzheimer's patients had significant tau buildup in all three wakefulness-promoting centers. They also had 74.84% (P=0.001) fewer locus coeruleus neurons and more than 60% loss of lateral hypothalamic area and tuberomammillary nucleus neurons.
Neuronal loss in corticobasal degeneration and PSP was milder in the locus coeruleus and undetectable in the lateral hypothalamic area and tuberomammillary nucleus. Despite neuronal loss being spared, the percentage of neurons synthesizing their corresponding neurotransmitter (tyrosine hydroxylase, orexin, or histidine decarboxylase) was reduced in PSP and corticobasal degeneration relative to healthy controls, similar to the Alzheimer brains.
These findings "support the idea that even symptomatic treatment for Alzheimer's disease can expand from the current ones tackling the cholinergic system to ones tackling other neurotransmitters such as orexin, noradrenaline, and histamine," Grinberg observed. "Such drugs exist, but they haven't been systematically tested in Alzheimer's disease yet."
The study has several limitations, the authors noted. The sample size was small. Participants were relatively young, and results may not apply to older Alzheimer's patients. Sex-related bias may have occurred since men outnumbered women, and whether people had sleep apnea before they died was unknown.
Last Updated August 12, 2019
This study was supported by the Tau Consortium/Rainwater Charity Foundation and grants from the National Institutes of Health, the Global Brain Health Institute, and the São Paulo Research Foundation.
The researchers declared no conflicts of interest.
Alzheimer's & Dementia
Source Reference: Oh J, et al "Profound degeneration of wake-promoting neurons in Alzheimer's disease" Alzheimers Dement 2019; DOI: 10.1016/j.jalz.2019.06.3916.