You may ask whether I have changed my own educational practice and assessment. I have. There are no “final” exams at the end of the semester in my classes. Instead, I split my courses up into thirds so that students only have to study a handful of lectures at a time. Furthermore, none of the exams are cumulative. It’s a tried-and-true effect in the psychology of memory, described as mass versus spaced learning. As with a fine-dining experience, it is far more preferable to separate the educational meal into smaller courses, with breaks in between to allow for digestion, rather than attempt to cram all of those informational calories down in one go.
In chapter 6 I described the crucial role for sleep after learning in the offline cementing, or consolidating, of recently learned memories. My friend and longtime collaborator at Harvard Medical School, Dr. Robert Stickgold, conducted a clever study with wide-reaching implications. He had a total of 133 undergraduates learn a visual memory task through repetition. Participants then returned to his laboratory and were tested to see how much they had retained. Some subjects returned the next day after a full night of sleep. Others returned two days later after two full nights of sleep, and still others after three days with three nights of sleep in between.
As you would predict by now, a night of sleep strengthened the newly learned memories, boosting their retention. Additionally, the more nights of sleep participants had before they were tested, the better their memory was. All except another sub-group of participants. Like the subjects in the third group, these participants learned the task on the first day, and learned it just as well. They were then tested three nights later, just like the third group above. The difference was that they were deprived of sleep the first night after learning and were not tested the following day. Instead, Stickgold gave them two full recovery nights of sleep before testing them. They showed absolutely no evidence of a memory consolidation improvement. In other words, if you don’t sleep the very first night after learning, you lose the chance to consolidate those memories, even if you get lots of “catch-up” sleep thereafter. In terms of memory, then, sleep is not like the bank. You cannot accumulate a debt and hope to pay it off at a later point in time. Sleep for memory consolidation is an all-or-nothing event. It is a concerning result in our 24/7, hurry-up, don’t-wait society. I feel another op-ed coming on …
SLEEP AND ALZHEIMER’S DISEASE
The two most feared diseases throughout developed nations are dementia and cancer. Both are related to inadequate sleep. We will address the latter in the next chapter regarding sleep deprivation and the body. Regarding the former, which centers on the brain, a lack of sleep is fast becoming recognized as a key lifestyle factor determining whether or not you will develop Alzheimer’s disease.
The condition, originally identified in 1901 by German physician Dr. Aloysius Alzheimer, has become one of the largest public health and economic challenges of the twenty-first century. More than 40 million people suffer from the debilitating disease. That number has accelerated as the human life span has stretched, but also, importantly, as total sleep time has decreased. One in ten adults over the age of sixty-five now suffers from Alzheimer’s disease. Without advances in diagnosis, prevention, and therapeutics, the escalation will continue.
Sleep represents a new candidate for hope on all three of these fronts: diagnosis, prevention, and therapeutics. Before discussing why, let me first describe how sleep disruption and Alzheimer’s disease are causally linked.
As we learned in chapter 5, sleep quality—especially that of deep NREM sleep—deteriorates as we age. This is linked to a decline in memory. However, if you assess a patient with Alzheimer’s disease, the disruption of deep sleep is far more exaggerated. More telling, perhaps, is the fact that sleep disturbance precedes the onset of Alzheimer’s disease by several years, suggesting that it may be an early-warning sign of the condition, or even a contributor to it. Following diagnosis, the magnitude of sleep disruption will then progress in unison with the symptom severity of the Alzheimer’s patient, further suggesting a link between the two. Making matters worse, over 60 percent of patients with Alzheimer’s disease have at least one clinical sleep disorder. Insomnia is especially common, as caregivers of a loved one with Alzheimer’s disease will know all too well.
It was not until relatively recently, however, that the association between disturbed sleep and Alzheimer’s disease was realized to be more than just an association. While much remains to be understood, we now recognize that sleep disruption and Alzheimer’s disease interact in a self-fulfilling, negative spiral that can initiate and/or accelerate the condition.
Alzheimer’s disease is associated with the buildup of a toxic form of protein called beta-amyloid, which aggregates in sticky clumps, or plaques, within the brain. Amyloid plaques are poisonous to neurons, killing the surrounding brain cells. What is strange, however, is that amyloid plaques only affect some parts of the brain and not others, the reasons for which remain unclear.
What struck me about this unexplained pattern was the location in the brain where amyloid accumulates early in the course of Alzheimer’s disease, and most severely in the late stages of the condition. That area is the middle part of the frontal lobe—which, as you will remember, is the same brain region essential for the electrical generation of deep NREM sleep in healthy young individuals. At that time, we did not understand if or why Alzheimer’s disease caused sleep disruption, but simply knew that they always co-occurred. I wondered whether the reason patients with Alzheimer’s disease have such impaired deep NREM sleep was, in part, because the disease erodes the very region of the brain that normally generates this key stage of slumber.
I joined forces with Dr. William Jagust, a leading authority on Alzheimer’s disease, at the University of California, Berkeley. Together, our research teams set about testing this hypothesis. Several years later, having assessed the sleep of many older adults with varying degrees of amyloid buildup in the brain that we quantified with a special type of PET scan, we arrived at the answer. The more amyloid deposits there were in the middle regions of the frontal lobe, the more impaired the deep-sleep quality was in that older individual. And it was not just a general loss of deep sleep, which is common as we get older, but the very deepest of the powerful slow brainwaves of NREM sleep that the disease was ruthlessly eroding. This distinction was important, since it meant that the sleep impairment caused by amyloid buildup in the brain was more than just “normal aging.” It was unique—a departure from what is otherwise the signature of sleep decline as we get older.
We are now examining whether this very particular “dent” in sleeping brainwave activity represents an early identifier of those who are at greatest risk of developing Alzheimer’s disease, years in advance. If sleep does prove to be an early diagnostic measure—especially one that is relatively cheap, noninvasive, and can be easily obtained in a large number of individuals, unlike costly MRI or PET scans—then early intervention becomes possible.
Building on these findings, our recent work has added a key piece in the jigsaw puzzle of Alzheimer’s disease. We have discovered a new pathway through which amyloid plaques may contribute to memory decline later in life: something that has been largely missing in our understanding of how Alzheimer’s disease works. I mentioned that the toxic amyloid deposits only accumulate in some parts of the brain and not others. Despite Alzheimer’s disease being typified by memory loss, the hippocampus—that key memory reservoir in the brain—is mysteriously unaffected by amyloid protein. This question has so far baffled scientists: How does amyloid cause memory loss in Alzheimer’s disease patients when amyloid itself does not affect memory areas of the brain? While other aspects of the disease may be at play, it seemed plausible to me that there was a missing intermediary factor—one that was transacting the influence of amyloid in one part of the brain on memory, which depended on a different region of the brain. Was sleep disruption the missing factor?
To test this theory, we had elderly patient
s with varying levels of amyloid—low to high—in their brains learn a list of new facts in the evening. The next morning, after recording their sleep in the laboratory that night, we tested them to see how effective their sleep had been at cementing and thus holding on to those new memories. We discovered a chain-reaction effect. Those individuals with the highest levels of amyloid deposits in the frontal regions of the brain had the most severe loss of deep sleep and, as a knock-on consequence, failed to successfully consolidate those new memories. Overnight forgetting, rather than remembering, had taken place. The disruption of deep NREM sleep was therefore a hidden middleman brokering the bad deal between amyloid and memory impairment in Alzheimer’s disease. A missing link.
These findings, however, were only half of the story, and admittedly the less important half. Our work had shown that the amyloid plaques of Alzheimer’s disease may be associated with the loss of deep sleep, but does it work both ways? Can a lack of sleep actually cause amyloid to build up in your brain to begin with? If so, insufficient sleep across an individual’s life would significantly raise their risk of developing Alzheimer’s disease.
Around the same time that we were conducting our studies, Dr. Maiken Nedergaard at the University of Rochester made one of the most spectacular discoveries in the field of sleep research in recent decades. Working with mice, Nedergaard found that a kind of sewage network called the glymphatic system exists within the brain. Its name is derived from the body’s equivalent lymphatic system, but it’s composed of cells called glia (from the Greek root word for “glue”).
Glial cells are distributed throughout your entire brain, situated side by side with the neurons that generate the electrical impulses of your brain. Just as the lymphatic system drains contaminants from your body, the glymphatic system collects and removes dangerous metabolic contaminants generated by the hard work performed by neurons in your brain, rather like a support team surrounding an elite athlete.
Although the glymphatic system—the support team—is somewhat active during the day, Nedergaard and her team discovered that it is during sleep that this neural sanitization work kicks into high gear. Associated with the pulsing rhythm of deep NREM sleep comes a ten- to twentyfold increase in effluent expulsion from the brain. In what can be described as a nighttime power cleanse, the purifying work of the glymphatic system is accomplished by cerebrospinal fluid that bathes the brain.
Nedergaard made a second astonishing discovery, which explained why the cerebrospinal fluid is so effective in flushing out metabolic debris at night. The glial cells of the brain were shrinking in size by up to 60 percent during NREM sleep, enlarging the space around the neurons and allowing the cerebrospinal fluid to proficiently clean out the metabolic refuse left by the day’s neural activity. Think of the buildings of a large metropolitan city physically shrinking at night, allowing municipal cleaning crews easy access to pick up garbage strewn in the streets, followed by a good pressure-jet treatment of every nook and cranny. When we wake each morning, our brains can once again function efficiently thanks to this deep cleansing.
So what does this have to do with Alzheimer’s disease? One piece of toxic debris evacuated by the glymphatic system during sleep is amyloid protein—the poisonous element associated with Alzheimer’s disease. Other dangerous metabolic waste elements that have links to Alzheimer’s disease are also removed by the cleaning process during sleep, including a protein called tau, as well as stress molecules produced by neurons when they combust energy and oxygen during the day. Should you experimentally prevent a mouse from getting NREM sleep, keeping it awake instead, there is an immediate increase in amyloid deposits within the brain. Without sleep, an escalation of poisonous Alzheimer’s-related protein accumulated in the brains of the mice, together with several other toxic metabolites. Phrased differently, and perhaps more simply, wakefulness is low-level brain damage, while sleep is neurological sanitation.
Nedergaard’s findings completed the circle of knowledge that our findings had left unanswered. Inadequate sleep and the pathology of Alzheimer’s disease interact in a vicious cycle. Without sufficient sleep, amyloid plaques build up in the brain, especially in deep-sleep-generating regions, attacking and degrading them. The loss of deep NREM sleep caused by this assault therefore lessens the ability to remove amyloid from the brain at night, resulting in greater amyloid deposition. More amyloid, less deep sleep, less deep sleep, more amyloid, and so on and so forth.
From this cascade comes a prediction: getting too little sleep across the adult life span will significantly raise your risk of developing Alzheimer’s disease. Precisely this relationship has now been reported in numerous epidemiological studies, including those individuals suffering from sleep disorders such as insomnia and sleep apnea.fn8 Parenthetically, and unscientifically, I have always found it curious that Margaret Thatcher and Ronald Reagan—two heads of state that were very vocal, if not proud, about sleeping only four to five hours a night—both went on to develop the ruthless disease. The current US president, Donald Trump—also a vociferous proclaimer of sleeping just a few hours each night—may want to take note.
A more radical and converse prediction that emerges from these findings is that, by improving someone’s sleep, we should be able to reduce their risk of developing Alzheimer’s disease—or at least delay its onset. Tentative support has emerged from clinical studies in which middle- and older-age adults have had their sleep disorders successfully treated. As a consequence, their rate of cognitive decline slowed significantly, and further delayed the onset of Alzheimer’s disease by five to ten years.fn9
My own research group is now trying to develop a number of viable methods for artificially increasing deep NREM sleep that could restore some degree of the memory consolidation function that is absent in older individuals with high amounts of amyloid in the brain. If we can find a method that is cost effective and can be scaled up to the population level for repeat use, my goal is prevention. Can we begin supplementing the declining deep sleep of vulnerable members of society during midlife, many decades before the tipping point of Alzheimer’s disease is reached, aiming to avert dementia risk later in life? It is an admittedly lofty ambition, and some would argue a moon shot research goal. But it is worth recalling that we already use this conceptual approach in medicine in the form of prescribing statins to higher-risk individuals in their forties and fifties to help prevent cardiovascular disease, rather than having to treat it decades later.
Insufficient sleep is only one among several risk factors associated with Alzheimer’s disease. Sleep alone will not be the magic bullet that eradicates dementia. Nevertheless, prioritizing sleep across the life span is clearly becoming a significant factor for lowering Alzheimer’s disease risk.
Chapter 8
Cancer, Heart Attacks, and a Shorter Life
Sleep Deprivation and the Body
I was once fond of saying, “Sleep is the third pillar of good health, alongside diet and exercise.” I have changed my tune. Sleep is more than a pillar; it is the foundation on which the other two health bastions sit. Take away the bedrock of sleep, or weaken it just a little, and careful eating or physical exercise become less than effective, as we shall see.
Yet the insidious impact of sleep loss on health runs much deeper. Every major system, tissue, and organ of your body suffers when sleep becomes short. No aspect of your health can retreat at the sign of sleep loss and escape unharmed. Like water from a burst pipe in your home, the effects of sleep deprivation will seep into every nook and cranny of biology, down into your cells, even altering your most fundamental self—your DNA.
Widening the lens of focus, there are more than twenty large-scale epidemiological studies that have tracked millions of people over many decades, all of which report the same clear relationship: the shorter your sleep, the shorter your life. The leading causes of disease and death in developed nations—diseases that are crippling health-care systems, such as heart disease, obesity, dementia, d
iabetes, and cancer—all have recognized causal links to a lack of sleep.
This chapter describes, uncomfortably, the many and varied ways in which insufficient sleep proves ruinous to all the major physiological systems of the human body: cardiovascular, metabolic, immune, reproductive.
SLEEP LOSS AND THE CARDIOVASCULAR SYSTEM
Unhealthy sleep, unhealthy heart. Simple and true. Take the results of a 2011 study that tracked more than half a million men and women of varied ages, races, and ethnicities across eight different countries. Progressively shorter sleep was associated with a 45 percent increased risk of developing and/or dying from coronary heart disease within seven to twenty-five years from the start of the study. A similar relationship was observed in a Japanese study of over 4,000 male workers. Over a fourteen-year period, those sleeping six hours or less were 400 to 500 percent more likely to suffer one or more cardiac arrests than those sleeping more than six hours. I should note that in many of these studies, the relationship between short sleep and heart failure remains strong even after controlling for other known cardiac risk factors, such as smoking, physical activity, and body mass. A lack of sleep more than accomplishes its own, independent attack on the heart.
As we approach midlife, and our body begins to deteriorate and health resilience starts its decline, the impact of insufficient sleep on the cardiovascular system escalates. Adults forty-five years or older who sleep fewer than six hours a night are 200 percent more likely to have a heart attack or stroke during their lifetime, as compared with those sleeping seven to eight hours a night. This finding impresses how important it is to prioritize sleep in midlife—which is unfortunately the time when family and professional circumstances encourage us to do the exact opposite.
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