New research at UC San Francisco shows that Alzheimer's disease directly attacks brain regions responsible for wakefulness during the day.
Both researchers and caregivers have noted that Alzheimer's patients can develop excessive daytime napping long before showing the memory problems associated with the disease, the paper reads. Prior studies have considered that this is just a symptom of poor nighttime sleep caused by Alzheimer's-related disruptions in the brain regions that govern sleep, while others have argued that the sleep problems themselves contribute to the progression of the disease.
However, the new study comes to show that this is in fact caused by Alzheimer's itself.
Sleepy brain
"Our work shows definitive evidence that the brain areas promoting wakefulness degenerate due to accumulation of tau -- not amyloid -- protein from the very earliest stages of the disease," said study senior author Lea T. Grinberg, MD, Ph.D., an associate professor of neurology and pathology at the UCSF Memory and Aging Center.
The brain regions that govern sleep (including the part of the brain impacted by narcolepsy) are among the first to degrade at the onset of Alzheimer's disease, the team reports. Therefore, excessive daytime napping, particularly when it occurs in the absence of significant nighttime sleep problems, could serve as an early warning sign of the disease.
The findings also add to the body of evidence suggesting that tau proteins contribute more directly to the brain degeneration that drives Alzheimer's symptoms than the more extensively studied amyloid protein.
Led by lead author Jun Oh, a Grinberg lab research associate, the team measured Alzheimer's pathology, tau protein levels, and neuron numbers in three brain regions involved in promoting wakefulness. The team used a sample of 13 deceased Alzheimer's patients and seven healthy control subjects, which were obtained from the UCSF Neurodegenerative Disease Brain Bank.
The brains of Alzheimer's patients had significant tau buildup in all three wakefulness-promoting brain centers compared to the healthy controls, the team reports. These three areas were the locus coeruleus (LC), lateral hypothalamic area (LHA), and tuberomammillary nucleus (TMN). The same regions had lost as many as 75% of their neurons, the team adds.
"It's remarkable because it's not just a single brain nucleus that's degenerating, but the whole wakefulness-promoting network," Oh said. "Crucially this means that the brain has no way to compensate because all of these functionally related cell types are being destroyed at the same time."
Oh's team also studied brain samples from seven patients with progressive supranuclear palsy (PSP) and corticobasal disease (CBD), two distinct forms of neurodegenerative dementia caused by tau accumulation. These brains didn't show any loss of neurons in the same three areas despite showing significant tau protein build-ups.
"It seems that the wakefulness-promoting network is particularly vulnerable in Alzheimer's disease," Oh said. "Understanding why this is the case is something we need to follow up in future research."
The work also ties in with previous research by Grinberg's team, which showed that people who died with elevated levels of tau protein in their brainstem -- i.e. in the earliest stages of Alzheimer's disease onset -- had already begun to experience changes in mood, such as anxiety and depression, as well as increased sleep disturbances.
"Our new evidence for tau-linked degeneration of the brain's wakefulness centers provides a compelling neurobiological explanation for those findings," Grinberg said. "It suggests we need to be much more focused on understanding the early stages of tau accumulation in these brain areas in our ongoing search for Alzheimer's treatments."
The paper "Profound degeneration of wake-promoting neurons in Alzheimer's disease" has been published in the journal Alzheimer's and Dementia.
