ou can sleep, the saying goes, when you're dead. But the fundamental substance of
nature is irony, and it turns out that not sleeping kills you. And maybe, some
scientists suspect, it can also cause Alzheimer's disease.
As we get older, our sleep patterns change. Ten years ago, I would have laughed at the idea of getting up at four in the morning; now I automatically wake up around 3:50 (check the editing date on this file if you don't believe me).* Sleep is easily disrupted. Sleep apnea can wake you up, and so can pain, tinnitus, nightmares, stress, and of course lights and sounds from the environment, and many kinds of medications.
Time to get up already
The brain also monitors itself during sleep. If it senses something amiss, it will jerk you wide awake.
It might not be surprising, then, that in the late stages of Alzheimer's disease, when almost everything that can go amiss has already done so, patients spend 40% of their time in bed lying awake, and they spend lots of time sleeping during the daytime. Is this simply the result of broken circuits in the brain, or could lack of sleep be a contributing factor, maybe even a cause of the disease?
The importance of sleep
Sleep is essential for the brain to repair itself. Lack of sleep causes apathy, impaired memory, depression, anxiety, inability to multitask, delusions, and hallucinations—all familiar signs in Alzheimer patients. But which is the cause and which is the effect?
Alzheimer delusions can range from accusatory, like the belief that items they've lost were actually stolen or that the doctor is trying to hurt them, to the irrational, such as that cats are sneaking into their house. Or they might only think they believe it. The mind is a hall of mirrors.
What if Alzheimer's happens when the brain's mechanism for creating sleep goes haywire? If it did, you would have trouble concentrating. You might even start having delusions or hallucinations, believing things in the world are different from the way they really are.
These kinds of hallucinations happen to everyone when they are drowsy and deprived of sleep. We forget them almost immediately because the brain can't fit them into its narrative. An important function of the brain during sleep is to try to fit pieces of information together. They don't always fit, and it makes sense that we'd be programmed not to remember that.
For example, in a drowsy state you might have a fleeting thought that the CIA is listening to you through a hidden microphone in your TV. Twenty years ago they'd have come after you with a net if you suggested that. But nowadays, what's really crazy is the idea that the CIA is not doing it. If that idea occurred to you during sleep, you'd have to make a conscious effort to prevent your brain from erasing it. But what if you were permanently sleep-deprived?
Fatal Familial Insomnia
It just so happens that there's a condition, first described in 1986, called fatal familial insomnia, or FFI, which does exactly that. Patients come in to their doctor's office looking hypersomnolent, but in fact they're badly sleep deprived. The disease causes severe fragmentation and reduction of sleep time, progressing to dementia, exhaustion, hallucinations, somatomotor and gait abnormalities, coma, and death.
FFI is a hereditary prion disease[1]. Prions are proteins that are normally found in the brain. They're needed for memory, but some mutations cause prion protein to become misfolded. As in other prion diseases, such as Creutzfeldt-Jakob disease (CJD) and mad cow disease, the misfolded protein acts as a template to misfold normal prion proteins. In fact, the culprit in FFI is the same as in one hereditary form of CJD: an aspartate (D) at position 178 is changed to an asparagine (N), so the mutation is called D178N.
But in a cruel piece of really bad luck, a second polymorphism at codon 129, which is normally (mostly) harmless, changes the patients' fate from death by CJD into death by FFI. Those who have a valine at position 129 get CJD; those with a methionine at that spot get FFI.[2] This double whammy causes patients to lose up to 90% of the neurons in their thalamic nuclei, which are information relay centers in the brain that play important roles in wakefulness. Damage to this region causes you to lose slow-wave sleep and sleep spindles in your EEG, and FFI patients either die while fully conscious or they fall into a vegetative state and die from systemic or respiratory infection.[3]
Those all-important sleep spindles are actually generated by the reticular nuclei, which connect to the thalamus. Sometimes the reticular nuclei are lesioned in FFI, and this makes it even worse: the victims get profound insomnia and death.[4] It's not a fun way to go.
In the past, that same polymorphism in prion protein at position 129 was thought to be involved in other diseases, such as Alzheimer's disease, multiple sclerosis, schizophrenia, migraine, and even cancer. Most of these reports haven't held up. Nevertheless, there's a whole theory that Alzheimer's might be a prion disease. It hasn't caught on with the wider scientific community yet, but it's a very respectable theory.
Could lack of sleep cause Alzheimer's?
So it's clear how Alzheimer's disease could cause a change in sleep patterns. But could a change in sleep patterns cause Alzheimer's disease? Well, a study showed how that might work. (Well, I say “a” study, but in fact there are actually over 1400 papers on this topic. Anyone who has trouble sleeping is invited to read them.)
Recently, scientists showed just how important brain waves are in Alzheimer's disease. They induced a high-frequency EEG pattern known as gamma oscillations in mice, and they found that gamma waves, which are related to attentive focus, can activate our microglia, which are the immune cells of the brain. Once activated, these microglia reduce the amounts of beta-amyloid, a protein that's greatly increased in Alzheimer's[5].
How is this relevant? Well, one of the things beta-amyloid might do is to act as a natural tranquilizer. It blocks NMDA receptors and, according to one report, AMPA receptors. These receptors are big protein molecules on the surface of our neurons that send excitatory signals when they're exposed to the neurotransmitter glutamate. We need just the right amount of this signaling: too much, and our neurons burn out; not enough, and we lose consciousness.
We might need such a tranquilizer, for instance, when we get a brain injury. And so it would not be surprising that beta-amyloid gets produced after brain injury. It's even been suggested that we need small amounts of beta-amyloid to remain healthy.
This is most definitely not a majoritarian view. Most people still subscribe to the idea that beta-amyloid is a toxin that must be removed. But the role of beta-amyloid is starting to be questioned, due to the failures of industry to get the immunotherapy program to work. And there's no controversy about the correlation between sleep deprivation and late-onset Alzheimer's disease, which is by far the most common form. (I will call it AD from here on, so I don't wear out my motoneurons.)
A great article in August 2016 Trends in Neurosciences[6] (trigger warning: paywall) summarizes what we know so far. Here are the main points:
- Sleep problems occur in patients before the onset of AD symptoms; sleep disruption gets progressively worse in AD patients.
- Lack of sleep causes increased beta-amyloid in the cerebrospinal fluid, or CSF. The reason for this seems to be that glial cells shrink by up to 60% while we're in NREM (non-rapid eye movement) sleep, creating more space for junk to be cleared out of the brain by other means besides the CSF. The amount of beta-amyloid in the CSF increases by about 30% during the daytime and decreases at night.
- Lack of sleep also increases beta-amyloid plaques in AD transgenic mice, which suggests it's not just that clearance is increased; the amount in the brain is also up (although people argue about this a lot).
- The amount of NREM slow wave sleep decreases with age; by age 75, only 10% of it remains. This causes the elderly person to lie awake for long periods at night.
- Sleep abnormalities are greatly increased in patients with mild cognitive impairment, and in patients who carry the APOE4 allele, which are risk factors for AD. 60% of patients with mild cognitive impairment or AD have sleep apnea and insomnia. Some researchers think that sleep apnea may cause hypoxia, which can be another risk factor for AD.
- ApoE4 (the strongest risk factor for late-onset AD) increases the risk of of sleep apnea.
- Sleep is important for hippocampus-dependent memory consolidation. The hippocampus is one of the brain areas most affected in AD.
- AD transgenic mice spend less time sleeping than normal mice and spend less time in REM sleep.
As you can see, the evidence is mostly circumstantial. A good lawyer could get insomnia released on a technicality: the lawyer could say that, of course, a person with AD or cognitive impairment would have trouble sleeping. Who wouldn't? But a bookie would say it couldn't hurt to do whatever it takes to get a good night's sleep. Even if it means reading highly technical blog posts about the brain. You're welcome.
* I have to discipline myself not to eat lunch before 9:00 a.m. My internal clock tends to speed up, as if reverting to the time 850 million years ago when the Earth rotated once every 19.5 hours. Those were the days.
References
1. Lugaresi E, Medori R, Montagna P, et al. Fatal familial insomnia and dysautonomia with selective degeneration of thalamic nuclei. N Engl J Med 1986; 315: 997–1003.
2. Goldfarb LG, Petersen RB, Tabaton M, et al. Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease phenotype determined by a DNA polymorphism. Science 1992; 258: 806–808.
3. Lancet Neurol. 2003 Mar;2(3):167–176. Familial and sporadic fatal insomnia. Montagna P, Gambetti P, Cortelli P, Lugaresi E.
4. Steriade M, McCormick DA, Sejnowski TJ. Thalamocortical oscillations in the sleeping and aroused brain. Science 1993; 262: 679–685.
5. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Iaccarino HF, Singer AC, Martorell AJ, Rudenko A, Gao F, Gillingham TZ, Mathys H, Seo J, Kritskiy O, Abdurrob F, Adaikkan C, Canter RG, Rueda R, Brown EN, Boyden ES, Tsai LH. Nature. 2016 Dec 7;540(7632):230–235. doi: 10.1038/nature20587. Link
6. Trends Neurosci. 2016 Aug;39(8):552–566. doi: 10.1016/j.tins.2016.05.002. Sleep: A Novel Mechanistic Pathway, Biomarker, and Treatment Target in the Pathology of Alzheimer's Disease? Mander BA, Winer JR, Jagust WJ, Walker MP. Link
Last edited mar 12 2017, 5:28 am
