Tag Archives: amyloid beta

How Sleep “Cleans” Your Brain and Fends Off Alzheimer’s Disease

Sleep: we spend nearly a third of our lives doing it, yet only recently have we begun to understand its true purpose. You’ve probably read countless articles about how getting enough sleep is important for preventing a variety of diseases, including diabetes, depression, and even Alzheimer’s. However, while strong correlations have existed for decades, until recently there was still little evidence to show why we sleep or how it fends off disease.

As some of you may know, I’m currently living in Switzerland, where I’m conducting research at EPFL over the summer. My research is on the connection between sleep deprivation and Alzheimer’s disease, so for me it’s especially important to help others understand why sleep is so important for your brain’s overall health. A few recent breakthroughs in sleep science research have revolutionized the field and brought about an exciting new era of neuroscience, particularly for Alzheimer’s disease research.

The Brain: A Dumping Ground for Neuronal Waste

While you’re awake, the 100 billion neurons in your brain are hard at work. Through an incredibly complex network of connections and signals, your neurons keep your heart pumping, your muscles moving, and your attention focused on the task at hand. Every time a neuron fires a signal, it undergoes a series of chemical reactions to produce neurotransmitters, which it uses to communicate with other cells. These reactions also produce waste byproducts that need to be disposed of. The neuron packages the waste into vesicles and excretes them into the fluid that surrounds cells in the brain. How these waste products were cleared from the fluid remained a mystery for a long time. More on that in a bit.

These waste products used to not be seen as particularly important to study. But in 2005, a group of scientists came up with a crazy idea that would end up shaking the foundations of Alzheimer’s research: what if amyloid-beta is one of these byproducts of neuronal activity? As a bit of background, amyloid-beta is a protein that forms sticky plaques in the brains of people with Alzheimer’s disease. At large enough sizes, these plaques become toxic to neurons, resulting in neurodegeneration. This is believed to be one of the main driving forces behind the development of Alzheimer’s disease. At the time, we  knew that amyloid-beta came from neurons, but were unsure what caused the neurons to produce it or how to stop them.

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This is what an amyloid-beta plaque looks like inside a real brain. Image Source

The researchers tested their hypothesis using mice genetically engineered to produce human amyloid-beta. They surgically implanted an electrode in the mice’s brains, which was used to measure the neurons’ activity levels. They also implanted a microdialysis probe, which sampled the mice’s brain fluid periodically to monitor levels of amyloid-beta. When the researchers electrically stimulated the mice’s brains, causing neurons to become highly active, they saw an abrupt increase in amyloid-beta levels in the area of stimulation. Conversely, when they used drugs to decrease neuronal activity, amyloid-beta levels dropped.

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This is one of the figures from that study. Panel A shoes the mice’s EEG activity (a measure of neuronal firing) before and after the electrical stimulation. Panel B shoes the immediate increase in amyloid-beta levels after stimulation, while Panel C shoes the decrease after drug treatment to reduce neuronal activity.

The results of this landmark study were published in the journal Neuron and have since been cited hundreds of times by other papers. Many other studies have confirmed the initial results and expanded into other model organisms. The revelation that amyloid-beta is excreted during neuronal activity was huge, because until then we’d assumed that only “diseased” neurons were releasing the toxic protein. This new research showed that not only were healthy neurons releasing amyloid-beta, but they did so every time they were activated.

Sleep: The Good Kind of “Brainwashing”

This brings us back to the question I brought up earlier: how does the brain get rid of all these waste products? If amyloid-beta and other toxic byproducts of neuronal activity were allowed to accumulate unchecked, we’d probably all develop Alzheimer’s disease in infancy. The brain must have some way of cleaning itself. We knew that the waste products eventually ended up being flushed into the cerebrospinal fluid, but no one was sure how exactly it got there from within the brain.

The answer finally came in 2012 with the discovery of the glymphatic system. Researchers found that cerebrospinal fluid was able to enter the brain through a cavity called the subarachnoid space, and flush out toxins via drainage vessels running parallel to the veins. They demonstrated that this pathway was capable of clearing away amyloid-beta from the brain in mice.

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The recently-discovered glymphatic system pumps cerebrospinal fluid through the subarachnoid space into the brain, where it flushes out toxins (including amyloid-beta) through vessels surrounding the veins. Image Source

Only a year later, another breakthrough came. A paper published in Science revealed that the glymphatic system was intricately linked with sleep. During sleep, the channels that carry fluid through your brain expand by 60%, resulting in enhanced glymphatic drainage. The researchers showed that in sleeping mice, the expanded glymphatic vessels cleared away amyloid-beta from the brain twice as quickly as they did when the mice were awake. This paper received a lot of attention because it shed light on a likely function of sleep: to allow the brain to clean itself. New studies quickly came forward with additional evidence, showing that amyloid-beta levels in your brain increase throughout the day and then decrease again when you sleep.

How Sleep Deprivation Can Poison Your Brain

In less than 10 years, our understanding of sleep and Alzheimer’s disease has been turned upside down. We now know that during the day, when neurons are highly active, they release amyloid-beta into the brain fluid. Then when you sleep, your brain’s glymphatic vessels expand and flush away the amyloid-beta and other waste products before they can accumulate to toxic levels. This newly-discovered relationship brings up an ominous possibility: could sleep deprivation reduce amyloid-beta clearance and thus lead to Alzheimer’s disease?

Correlational studies suggest the answer may be yes. Elderly people with insomnia and other sleep disorders are at an increased risk of dementia and have higher levels of amyloid-beta in their brains. A recent study suggested an even more troubling possibility. The paper showed that chronic sleep deprivation may cause neurons to become hyperactive, so that they excrete greater amounts of amyloid-beta into the brain. In turn, this amyloid-beta can interact with other neurons to make it harder to sleep, creating a vicious cycle that could spiral out of control and perhaps lead to Alzheimer’s disease.

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The authors suggested that sleep deprivation could start a vicious cycle, with amyloid-beta deposition increasing exponentially.

The possibility that sleep deprivation could contribute to Alzheimer’s disease is deeply concerning. The CDC reports that 1 in 3 adults routinely do not get at least 7 hours of sleep per night. The problem may be even more severe for elderly people, of whom nearly half report sleep disturbances. By not getting enough sleep, we could be accumulating toxic levels of amyloid-beta in our brains and setting ourselves up for Alzheimer’s disease as we age.

Despite being rather frightening, these recent findings also come with an aspect of hope. While seemingly a major risk factor for Alzheimer’s disease, sleep deprivation is also preventable. By prioritizing sleep as a vital facet of overall health, as well as seeking medical assistance for sleep disorders like insomnia and sleep apnea, we may all be able to reduce our risk for Alzheimer’s and perhaps even other brain diseases. So put down that phone, turn off the lights and head to bed at a reasonable hour tonight. You’ll wake up with a squeaky clean brain in the morning!

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New Alzheimer’s Drug Shows Promise in Clinical Trials

One of the main hallmarks of Alzheimer’s disease is the accumulation of toxic protein clumps called amyloid-beta plaques inside the brain (for more detail see Alzheimer’s Disease: A General Overview). For the past several decades, the predominant theory among neuroscientists has been that these plaques are the main cause of the disease, and that removing them is the key to a cure. This is known as the amyloid cascade hypothesis.

A recent study published in Nature, one of the world’s premier scientific journals, reported promising results from a phase 1b clinical trial of a new drug called aducanumab. This drug works by selectively targeting amyloid-beta aggregates and marking them for destruction by the body’s immune system, an approach known as immunotherapy. The researchers demonstrated using mice that the drug is able to penetrate the blood-brain barrier and reduce levels of amyloid-beta plaques.

Various doses of the drug were injected into patients with mild Alzheimer’s disease once per month for one year. PET scans showed that the 125 subjects who completed the trial had reduced amyloid-beta levels in their brains compared to controls who were given a placebo. This reduction was enhanced the longer the drug was administered and the higher the dose. The subjects given the drug also had higher scores on tests of cognitive function. Notably, the drug slowed but did not prevent or reverse cognitive decline in these subjects, and the effects varied substantially based on the dosage.

Dozens of previous immunotherapeutic drug candidates for Alzheimer’s disease have failed early in clinical trials, and so these positive results are very exciting. However, this drug is far from being declared a cure, and there are several important caveats to keep in mind.

Problematic side effects have plagued Alzheimer’s drug trials for decades, and unfortunately this one was no exception. Nearly 25% of the subjects withdrew from the trial due to side effects, which included headache, urinary tract infection, upper respiratory infection, and an interesting phenomenon known as amyloid-related imaging abnormalities (ARIA). ARIA are small abnormalities that appear on MRI scans and are believed to be the result of cerebral microhemorrhages (“mini-strokes”). ARIA is a common side affect of amyloid-beta immunotherapy and is considered to be a serious condition. 41% of subjects given the highest dose of aducanumab experienced ARIA, compared to zero controls. Several subjects were also diagnosed with another type of serious hemorrhaging called superficial siderosis of the central nervous system. No deaths due to side effects were reported.

Additionally, it’s important to note that all of the subjects in the study were only in the earliest stages of Alzheimer’s disease, so it’s not clear how well this drug will work with patients in later stages. The trial was also relatively short-term and only in phase 1b. It’s not uncommon for drugs to succeed in early clinical trials but fail when they reach the final phase 3 trials, which is was happened with a promising Alzheimer’s drug candidate earlier this year.

The final point I want to make is that the success of aducanumab hinges on the amyloid cascade hypothesis being correct. The theory was considered dogmatic for years, but lately it has been experiencing scrutiny, due in large part to the discovery that nearly 1 in 3 elderly people have high levels of amyloid-beta in their brains despite being cognitively normal (for a deeper look at this controversy, see Where’s our cure to Alzheimer’s disease?). Though the majority of mainstream neuroscientists still support the amyloid cascade hypothesis, it’s important to keep its criticisms in mind. The scientific community will wait with bated breath for the drug’s phase 3 trial results.

 

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The Genetics of Alzheimer’s Disease

If you’d asked me at age sixteen what my life’s dream was, I’d say it was to discover the Alzheimer’s gene. Statements like that one would make any geneticist cringe, or chuckle, or both. It’s a common misconception that one “bad” gene causes Alzheimer’s disease, and that discovering this gene would lead to a cure. The fact of the matter is that Alzheimer’s disease, and most other diseases, are so much more complicated than a single gene. There are a multitude of genes involved, as well as an entire spectrum of non-genetic influences. To try and make sense of this confusing topic, I’ve written this article as a brief overview of the genetics of Alzheimer’s disease.

Note: If you’re not familiar with the science of Alzheimer’s, you may want to look at Alzheimer’s Disease: A general overview to provide a bit of background.

The Amyloid-Beta Protein

Genes encode proteins, and so to understand the role of genetics in Alzheimer’s, we need to first look at the proteins involved. Senile plaques are considered one of the main hallmarks of Alzheimer’s disease. These toxic protein clumps accumulate in the brain over many years and eventually lead to the death of neurons, causing the brain to physically shrink. They form when a protein called amyloid-beta becomes “sticky” and begins to adhere to itself, forming large star-shaped clumps.

Amyloid-beta begins as a longer protein called amyloid precursor protein (APP). APP is usually cut by enzymes called secretases to form a non-sticky version of amyloid-beta that is 40 amino acids long. However, if APP is cut by a different set of secretases, a longer version of amyloid-beta with 42 amino acids is formed. This longer form is what sticks together to form senile plaques in Alzheimer’s disease [1].

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Formation of the longer amyloid-beta protein by beta-secretase and gamma-secretase. Source: https://www.rndsystems.com

Familial Alzheimer’s Disease

Alzheimer’s disease is divided into two forms. Approximately 5% of cases are of the familial, early-onset form. This type of Alzheimer’s typically affects individuals in their mid-forties and fifties. There are three genes known to be involved with familial Alzheimer’s disease: APP, PSEN1, and PSEN2. APP, as I described above, is the precursor to amyloid-beta, and so certain mutations can make it prone to the cleavage pathway that results in the sticky 42-length protein. Similarly, PSEN1 and PSEN2 are believed to affect the gamma-secretase complex that cleaves APP into amyloid-beta.

Mutations in these three genes are autosomal dominant. This means that only one copy of the mutation is needed to cause the disease, and that carriers have a fifty-percent chance of passing on the gene to each of their children. The mutations also tend to have high penetrance, meaning that their effects cannot be readily altered by environmental factors–i.e., having the mutation nearly always leads to the disease [2], [3].

Sporadic Alzheimer’s Disease

In contrast to the relatively simple genetics of familial Alzheimer’s, late-onset sporadic Alzheimer’s disease (which makes up 95% of cases) is far more complex. The only gene that has been conclusively identified as a risk factor is apolipoprotein E, abbreviated as apoE. We still aren’t sure exactly how apoE affects the brain, but the main hypothesis is that it’s involved with clearing away amyloid-beta before it can accumulate to toxic levels. There are three major versions of this gene: apoE2, apoE3, and apoE4. Having one copy of the apoE4 allele increases the risk of Alzheimer’s by 3 times, while having two copies increases the risk by nearly 15 times. Conversely, having at least one copy of the apoE2 allele reduces the risk of Alzheimer’s [2][4].

It is important to note that unlike the genes involved with familial Alzheimer’s, the apoE alleles are not highly penetrant. Approximately 1 in 5 people have at least one copy of apoE4, yet the majority of them never develop Alzheimer’s. Additionally, there are many people who develop Alzheimer’s without possessing apoE4. The allele increases the risk of developing the disease but is far from a guarantee [2][4]. Overall, it’s estimated that apoE accounts for less than 20% of the genetic risk for sporadic Alzheimer’s [5], [6].

So where does the other 80% come from? The answer gets even more complicated here. There are dozens of genes that are weakly correlated with overall risk, age of onset, rate of progression, or other disease variables. Individually, each of these genetic variants has only a tiny effect, but when combined, each person’s unique combination of variants creates a genetic profile that influences his or her risk of developing the disease (see A New Approach to Predicting Risk of Alzheimer’s Disease). The majority of these weakly-associated genetic variants have yet to be identified [3].

Non-Genetic Factors

In familial Alzheimer’s, there is little that a person can do to prevent the disease if he or she has inherited the gene. However, only 24-33% of a person’s risk for sporadic Alzheimer’s disease is attributable to genetics alone [5], [6].  The remaining risk is modulated by non-genetic factors, including medical conditions, diet, and lifestyle choices. A recent meta-analysis identified 13 non-genetic factors that significantly increase the risk for Alzheimer’s disease, including smoking, being overweight in midlife, cardiovascular disease, low education, and depression. In addition, they identified 23 factors that reduce the risk of Alzheimer’s, including a healthy diet, physical activity, mental stimulation, and certain medical conditions [7].

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Non-genetic protective and risk factors for Alzheimer’s disease. Source: Xu et al., 2015.

Conclusion

It was once thought that we couldn’t change our brains after birth, but the discovery of neuroplasticity revolutionized the field by showing us that our daily actions can have enormous impacts on the structure and function of our brains. Similarly, the growing study of epigenetics (meaning “above genetics”) proves that we are not at the mercy of our genes. Though we are born with a set DNA sequence, the choices we make throughout our lives determine which genes are turned on or off, a process that can significantly influence our risk of disease. We may not be able to change the genetic risk coded into our DNA, but we can all help protect our brains from Alzheimer’s disease through simple lifestyle choices.

 

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Where’s our cure to Alzheimer’s disease?

(This article was originally written for the Junior Committee of the Central Ohio Alzheimer’s Association’s blog. Click here to view the original on their website.)

Biomedical research has made great strides in the past several decades. Our death rates for most major diseases have decreased significantly, including heart disease, cancer, stroke, and HIV. However, one conspicuous exception to this trend is Alzheimer’s disease, for which total deaths increased by 71% between 2000 and 2013. Why does research on Alzheimer’s disease seem to be bearing meagre fruits, and when can we expect the next breakthrough?

To answer these questions, we need to have a bit of background on the science of the disease (for more detailed background, see Alzheimer’s Disease: A General Overview). Alzheimer’s disease is differentiated from other types of dementia by the presence of abnormal protein deposits in the brain known as amyloid beta (AB) plaques. Several studies have demonstrated that genetic mutations that increase production of the AB protein increase the risk of developing Alzheimer’s, while a rare mutation that decreases AB production is protective against Alzheimer’s (see The Genetics of Alzheimer’s Disease). This led most researchers to adopt the amyloid cascade hypothesis, which proposes that the gradual accumulation of AB in the brain is the main cause of Alzheimer’s disease. This hypothesis suggested that a cure to Alzheimer’s lay in discovering a drug that could prevent or reverse the buildup of AB plaques.

Between 2002 and 2012, more than 400 drug candidates were discovered that could dissolve AB plaques in mice. However, despite these promising results, the drugs consistently failed in human clinical trials. The patients’ symptoms improved only marginally, if at all. Even worse, many drugs came with a host of severe side effects, including skin cancer (see The Strange Link Between Alzheimer’s and Cancer), gastrointestinal problems, and micro-hemorrhaging, which forced the trials to be canceled prematurely. Hundreds of millions of dollars were spent searching for new ways to destroy the plaques, yet each new drug met the same fate.

Following this torrent of failed clinical trials, some researchers began to wonder if there was a serious problem to the way we were studying Alzheimer’s disease. The long-dogmatic amyloid cascade hypothesis was brought into question when new studies showed that nearly 1 in 3 cognitively normal people have high levels of AB in their brains, suggesting that the plaques could not be the only factor contributing to dementia symptoms.

The scientific community was initially slow to react to criticisms of the amyloid cascade hypothesis. However, in recent years, new areas of research have begun to open up that consider new mechanisms for Alzheimer’s disease development. Many exciting theories have been suggested, including the tau protein, neuroinflammation, microbial infection, mitochondrial dysfunction, and oxidative DNA damage, among others. It’s likely that all of these factors, in conjunction with Ab accumulation, contribute together to this complex disease.

With this new generation of neuroscientists approaching the problem with a fresh perspective, it’s likely that our understanding of Alzheimer’s will be radically transformed in the coming years. Though it’s impossible to predict exactly when the next breakthrough will come, the scientific community’s shift away from the amyloid cascade hypothesis toward more nuanced theories will bring our search for a cure that much closer.

 

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