Sleep-like slow waves: early sentinels of Alzheimer’s disease?

Sleep and wakefulness are not all-or-nothing states; they can overlap. That is the case in certain cetaceans, such as the dolphin, half of whose brain sleeps while the other half stays awake. The phenomenon does not occur in humans; yet when we are awake, small regions of the brain can, for a fraction of a second, slip into a state resembling deep sleep. The electroencephalogram then picks up small slow waves at the surface of the scalp.

A clinical use for waking slow waves?

The origin of these sleep-like slow waves remains poorly understood. Researchers have nonetheless observed, in animals as in humans, that they proliferate under sleep deprivation. They also coincide with fluctuations in attention and with errors on cognitive tasks, and occur more frequently in people living with attention-deficit/hyperactivity disorder (ADHD). 

That makes it worth examining how they behave in patients with Alzheimer’s disease, who present memory problems and attentional deficits but also, very often, sleep badly (night-time awakenings, difficulty falling asleep, daytime sleepiness…). 

As it happens, sleep is precisely what helps clear waste from the brain – toxic proteins included – largely through the glymphatic system.

An invaluable cohort 

To better understand the relationship between slow brain waves and the onset of Alzheimer’s disease, the researchers drew on a rare resource: the INSIGHT-preAD cohort, assembled at the Pitié-Salpêtrière hospital and comprising 318 people aged 70 to 85 with memory complaints.

“When they enter the cohort, participants score normally on cognitive tests. But they also report subjective cognitive decline – that is, a complaint about their mental performance slipping. Some of them will go on to develop dementia; others will not. That is exactly why it is worth following them at this tipping point, to work out who is genuinely at risk,” says the researcher. 

Participants selected for the study were assessed at inclusion and again two years later: PET and MRI brain scans measuring amyloid plaque load and neurodegeneration, cognitive testing, and high-density EEG recordings from sensors placed on the scalp. 

Reading the disease’s subtle signals

The team finds that people carrying the biological markers of the disease – amyloid plaques and neurodegeneration – produce higher-amplitude slow waves, chiefly over the centro-parietal region at the top of the head. 

“It is a kind of brain signature of cognitive fatigue, the sort you normally see after sustained mental effort. And yet the participants were at rest throughout the recording! It chimes with the drowsiness that patients with Alzheimer’s report,” adds Pierre Champetier.

The most striking result comes two years on. Among participants with very little amyloid at baseline, high-amplitude slow waves at rest proved to be a warning signal: these were the people who later went on to accumulate the most toxic protein deposits.   

Predicting the clinical course

These new data show that slow-wave amplitude predicts with reasonable accuracy which individuals are at high risk of developing the disease – and, just as usefully, rules out those whose symptoms are not an early sign of dementia, which matters just as much. 

PET and MRI remain the most reliable ways to spot future cases; but, unlike EEG, they are expensive and hard to access, and PET involves injecting a radioactive tracer. If these findings hold up in further studies, an EEG – available almost anywhere – could serve as a first pass, flagging early on the patients worth investigating further. 

Early detection would, in turn, help clinicians weigh the benefit–risk balance of the new anti-amyloid therapies more finely and decide, case by case, whether they suit a given patient.

Mechanisms still to be elucidated

While there is little doubt that waking slow waves are worth observing in Alzheimer’s, researchers cannot yet explain exactly how they relate to the disease. Are they a sign that the cerebral cortex, weakened by inflammation and by the accumulation of amyloid plaques, “drops out” over the course of the day? Or do they reflect a compensatory mechanism, in which the brain is continually trying to rest and to flush out toxic proteins?

“We will need to take this work further, both to understand sleep dysregulation in Alzheimer’s disease – particularly in patients with established dementia – and to get a better grip on where waking slow waves come from in the first place,” concludes Pierre Champetier.