Tag Archives: brain

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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Alzheimer’s Linked to a Reduction in Unsaturated Fats in the Brain

Fats are classified into two main types: saturated and unsaturated. These distinctions have to do with the molecules’ chemical structure. Fats are basically long strings of carbon atoms. Saturated fats contain only single bonds, which allows the carbon chains to pack tightly together. This is the reason why saturated fats are usually solid at room temperature, like butter or coconut oil. Unsaturated fats contain at least one double bond, which creates a kink in the carbon chain so that they can’t pack together as tightly. This causes them to be liquid at room temperature, like olive oil or fish oil. The “omega” fats, such as omega-6 and omega-3, are types of unsaturated fats.

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Unsaturated fats contain a double bond, which makes them liquid at room temperature. Image Source

Unsaturated fats have been receiving a lot of attention lately for their importance in the brain. In a study published last week in PLOS Medicine, researchers analyzed 43 postmortem brains from individuals aged 57 to 95 years old. The brains were classified into three groups. The first group had healthy brains. The second group had clumps of amyloid-beta and tau in their brains (two toxic proteins typically found in Alzheimer’s disease), but no signs of memory or cognitive impairment. The third group had amyloid-beta and tau, along with symptoms of Alzheimer’s disease.

The researchers analyzed the brains for their levels of nearly 5,000 different molecules. They focused on three different brain regions, shown in the image below.

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The researchers analyzed three brain regions. The cerebellum (CB) is resistant to Alzheimer’s pathology, while the inferior temporal gyrus (ITG) and middle frontal gyrus (MFG) are more vulnerable.

They found relatively small differences between the control group and asymptomatic group. However, the Alzheimer’s brains had significantly reduced levels of six different unsaturated fats, including several omega-6 and omega-3 fatty acids. Lower levels of these fats were correlated with higher amyloid-beta and tau levels in the brain, as well as greater cognitive impairment. The greatest changes were observed in the two vulnerable brain regions (ITG and MFG), but there were also differences in the cerebellum as well, indicating that this brain region may not be as invulnerable as previously thought. These results suggest that disruptions in unsaturated fat metabolism could be linked to the progression of Alzheimer’s disease.

The small sample size makes this study difficult to generalize beyond the study group. Additionally, we can’t conclude which factor is causative of the other. The reduced fat levels may be causing the disease, or vice versa. However, this is not the first study to link reductions in unsaturated fats with Alzheimer’s disease. For example, others have found that feeding Alzheimer’s disease rats a diet rich in omega-3 fats can improve memory.

While the link between unsaturated fats and dementia remains fuzzy, prioritizing these “healthy fats” in your diet is a simple way to improve overall health and possibly protect your brain as well. Start by replacing your cooking oils that are high in saturated fat (butter, lard, coconut oil) with unsaturated fat alternatives (olive oil, nut oils, vegetable oil). Other good sources of unsaturated fat are fatty fish, nuts, seeds, avocados, and olives.

 

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An Often-Ignored Type of Brain Cell May Be the Key to Aging

As we age, a multitude of changes occur in our bodies at the genetic level. A gene is essentially just an instruction manual for building a particular protein. When the gene is activated, it’s like the book is wide open, allowing the cellular machinery to access the instructions and build the encoded protein. This is called “gene expression.” Genes can also be inactivated, like sealing a book shut so that the instructions can’t be accessed. When this happens, the protein that’s encoded by the gene cannot be synthesized.

This system of modifiable gene expression is necessary for complex multicellular organisms like ourselves to function. It’s what makes a heart cell different from a lung cell: even though their DNA sequence is the same, different genes are turned on and off in each type of cell. While the sequence of our DNA (i.e., the words written in all the instruction manuals) generally stays the same throughout our lifetime, a variety of factors can alter the pattern gene expression in individual cells. One of these factors is aging.

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An overview of gene expression. DNA is transcribed into an intermediate molecule called RNA, which then is translated into the final protein. Source

In a study published this week in Cell Reports, researchers from the UK examined all the changes in gene expression that occur in our brains during aging. They used a total of 480 post-mortem human brains from individuals aged 16 to 106 and performed a comprehensive analysis of gene expression based on specific regions of the brain. To their surprise, they found that neurons (the primary brain cells that are responsible for our actual “thinking”) had relatively small changes in regional gene expression over time.

In contrast, large changes were observed in non-neuronal brain cells called glia. Glia were once seen as just passive connective tissue, but we now know that they play a variety of important roles in the brain including maintaining the proper environment for neurons, aiding in the speed of neuronal transmissions, and protecting the brain from infection or injury. The glia’s gene expression changes were highly dependent on their region of the brain, with the most prominent shifts being observed in the hippocampus and the substantia nigra, structures associated with Alzheimer’s and Parkinson’s diseases, respectively.

The researchers also found that genes specific to microglia, a type of glial cell that serves as the brain’s primary immune system, had higher gene expression overall in older brains compared to younger brains. In contrast, genes specific to neurons or oligodendrocytes (another type of glia) had lower overall expression in older brains. These changes were accompanied by greater numbers of microglial cells and fewer neurons and oligodendrocytes in specific areas of the brain.

Overall, the changes in glial gene expression were a better predictor of age than changes in neuronal gene expression. This suggests that glia may be the primary driving force behind the process of brain aging, highlighting the importance of future research on these once-ignored cells.

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This illustration shows neurons in yellow and various type of glia in teal or red. Glia play many important roles in the brain and are closely linked to aging. Source

A notable limitation of this study is that their calculations were based on levels of RNA rather than protein. RNA is an intermediate molecule between DNA and proteins, but the amount of protein produced from a particular RNA molecular is highly variable. Thus, it’s hard to determine from this study how much the proteins encoded by these genes were actually altered during aging.

Regardless, these results provide strong evidence that glia play a much greater role in aging than previously thought. This reflects a change that has gradually started occurring in the neuroscience community in which some of the focus is shifted from neurons to glia. Perhaps these poorly-understood cells will turn out to be the key to brain aging.

 

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How to Reduce Your Dementia Risk in 2017

2017 is almost upon us, and that means it’s time for New Year’s resolutions. Many of us resolve to lose weight, quit smoking, or spend less money. However, I’d like to suggest a new resolution for you to try out this year: improving the health of your brain. Though Alzheimer’s disease and other dementias are not completely preventable, there are a variety of steps you can take to substantially reduce your risk. The younger an age you start implementing these simple lifestyle changes, the more benefits you will reap, but it’s never too late to start protecting your brain.

Tip #1: Improve Your Oral Hygiene

Nearly half of all adults in America have periodontitis, a severe form of gum disease that gradually destroys the bone sockets holding your teeth in place, resulting in tooth loss. Recent evidence suggests that the bacteria  that cause periodontitis may be able to enter the brain, and their presence has been correlated with reduced cognitive function. Protect your mouth and your brain by brushing twice per day, flossing once per day, and visiting the dentist twice per year. To read more see How Oral Hygiene Protects Your Brain From Dementia

Tip #2: Get Your Daily Dose of Vitamin D

A recent meta-analysis concluded that vitamin D deficiency is a strong risk factor for dementia. Vitamin D is not easily obtained through food, but our bodies can synthesize it when our bare skin (without sunscreen) is exposed to sunlight. The time required to meet your daily dose of vitamin D depends on your skin tone, the amount of sunlight available, and how much skin you have exposed. On a sunny summer day, 10-15 minutes is often enough. You may want to consider taking vitamin D supplements during the winter, if you live in an often-cloudy area, or if you do not go outside every day.

Tip #3: Reduce Your Risk of Diabetes

Nearly 30 million Americans (around 10% of the total population) have diabetes, and another 86 million are prediabetic. People with diabetes have an approximately 54% higher risk of Alzheimer’s disease. According to the NIH’s Diabetes Prevention Program, even people at high risk of diabetes can prevent the disease through a combination of weight loss (5-7% of your total body weight), a healthy diet, and regular exercise. The National Diabetes Education Program offers lots of great tips for transitioning to a healthier lifestyle. To read more see Alzheimer’s Disease: Diabetes of the Brain?

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The impact of dietary choices on the risk of type 2 diabetes. Source

Tip #4: Get Your Brain Health Checkup

Healthy Brains is a website created by the Cleveland Clinic Lou Ruvo Center for Brain Health. The website is centered around the six pillars of brain health: physical exercise, food/nutrition, medical health, sleep/relaxation, mental fitness, and social interaction. One of my favorite parts about the site is the Brain Health Checkup, a free quiz that takes around 20 minutes to complete. After taking the quiz, you can read personalized tips on how to improve your brain health. Click here to check it out.

 Tip #5: Get Enough Sleep

You’ve probably heard a million times about the health consequences of sleep deprivation, but did you know that it may also increase the risk of Alzheimer’s? The Baltimore Longitudinal Study on Aging found that people over the age of 70 who report little sleep or low-quality sleep have higher levels of amyloid beta (a toxic protein linked to Alzheimer’s disease) in their brains. Additionally, a 2013 study found that amyloid beta and other toxic substances can actually be flushed out of the brain during sleep.

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Age-based recommendations from the National Sleep Foundation. Source

Tip #6: Adopt the Mediterranean Diet

The Mediterranean diet is often praised for its cardiovascular benefits, but recent studies show that it’s also great for your brain. This diet, commonly consumed in places like Italy and Greece, has been linked to a reduced risk of Alzheimer’s and improved cognitive function in older adults, as well as a longer average lifespan. The Mediterranean diet is characterized by high consumption of plant-based foods including fruits, vegetables (especially leafy greens), whole grains, legumes, and nuts. Red meat and dairy are consumed no more than a few times per month, replaced instead by poultry or fish.

Tip #7: Be Socially Active

Engaging in social interactions is a great way to stimulate your brain, and having a large social network is correlated with a reduced risk of dementia. While a causal relationship is difficult to determine, social engagement has also been shown to improve overall quality of life, especially for older adults. For introverts, there are many ways to be socially active besides going out with friends. These could include adopting a pet, conversing on social media websites, volunteering, or joining a community group.

Tip #8: Get More Exercise

This one might already on your list of resolutions, but here’s one more reason to get off the couch. Studies have consistently shown that people who get regular physical exercise have a substantially lower risk of Alzheimer’s disease and other dementias. Aerobic exercise, such as walking, jogging, biking, or dancing, seem to have the biggest protective effect on brain health. The CDC recommends that adults get 2.5 hours of moderate aerobic activity or 1.25 hours of vigorous aerobic activity each week, plus at least two sessions of muscle strength training.

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The many benefits of exercise for your brain. Source

Tip #9: Protect Your Brain From Injuries

Traumatic brain injuries (TBI’s), which may be the result of contact sports, falls, or car accidents, affect nearly 1.7 million Americans each year. TBI’s, including mild injuries that do not necessarily cause a concussion, have been repeatedly linked to an increased risk of Alzheimer’s disease. TBI’s are especially damaging in children, whose brains are still in the process of developing. Minimize your risk of a TBI by wearing a helmet when playing contact sports, installing house fixtures to protect from falls, and always wearing a seatbelt while driving.

Tip #10: Never Stop Learning

Lifelong education, whether formal or informal, is vital for keeping your brain active and maintaining proper cognitive function. Formal education could include taking classes at a nearby community college or online, teaching yourself a new language, or learning to play an instrument. More informal types of mental stimulation could include reading, doing crossword puzzles, social interaction, or attending musical or theatrical performances.

 

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Sniffing Out Dementia: What Your Nose Can Tell You About Your Brain

Detecting Alzheimer’s disease can be tricky, especially in its earliest stages.  Alzheimer’s is frequently misdiagnosed, due in part to the expensiveness and complexity of the current diagnostic tools. According to a 2012 examination of the National Institute on Aging’s Alzheimer’s Disease Centers, physicians may fail to detect more than 1 in 10 Alzheimer’s cases.

Alarmingly, some centers also had a false positive rate of more than 50%, meaning that half of the patients who were diagnosed with Alzheimer’s actually did not have the disease. The symptoms of these individuals may have been due to other conditions such as vascular dementia or thyroid dysfunction. An incorrect diagnosis could have resulted in the true cause of these patients’ memory loss going untreated (see Is It Really Alzheimer’s? 10 common misdiagnoses you should know about).

However, there might be a simpler and more cost-effective way to help diagnose Alzheimer’s disease: your sense of smell. As strange as it sounds, your nose can provide some key insight into the health of your brain.

Sniffing Out Dementia

Just like vision and hearing, our sense of smell tends to gradually deteriorate as we get older. Anosmia, the complete inability to smell, affects more than 50% of people over the age of 65 and 75% of people over 80. This likely contributes to the loss of appetite that many elderly people experience, as our sense of smell is closely tied to our ability to taste and enjoy food. Changes in the nose’s smell receptors and in the parts of the brain responsible for olfactory processing are likely to blame for age-related anosmia.

While anosmia is common among all elderly individuals, it seems to be especially prevalent in certain neurological conditions, including dementia. The frequency of anosmia among dementia patients has been known since the 1970s, but only recently has this observation begun to attract the attention of researchers.

The ability to identify different odors is frequently impaired in early-stage Alzheimer’s patients, with complete anosmia appearing in the later stages of the disease. A small study involving 90 patients with mild cognitive impairment found that individuals with greater olfactory impairment were more likely to progress to Alzheimer’s disease during the two-year study period. Many of these patients were unaware of their own inability to smell.

#AlzFact: Peanut butter might help identify early-stage Alzheimer’s. A small study from the University of Floria found that Alzheimer’s patients have difficulty smelling peanut butter, especially with the left nostril.

An olfactory assessment called the Pocket Smell Test has shown promise as a diagnostic tool for Alzheimer’s disease. In a small 60-patient study, this simple three-item test was able to distinguish Alzheimer’s from vascular dementia and major depressive disorder with 95% accuracy, a dramatic improvement from the 50% false-positive rate by NIA physicians that I described earlier. All of the Alzheimer’s patients in the study had two or three incorrect responses to the smell test, while nearly all of the vascular dementia and depression patients had zero or one incorrect response.

Another small study suggested that smell tests could also be used to distinguish Alzheimer’s from semantic dementia, frontotemporal dementia, and corticobasal dementia. Notably, smell tests would probably be less useful for distinguishing Alzheimer’s from Parkinson’s disease, since anosmia seems to be equally common in these two conditions. However, simple smell-detection tests could serve as an inexpensive method to improve the accuracy of Alzheimer’s diagnoses when combined with more traditional diagnostic tools.

Could Infections Be To Blame?

The reasons for the prevalence of anosmia in patients with Alzheimer’s or other dementias remain poorly understood. One interesting hypothesis, first proposed back in 1986, posits that the olfactory nerve (which transmits smell information from the nose to the brain) could serve as a potential entry point for environmental toxins or microbial agents to reach the brain. This has since been dubbed the olfactory vector hypothesis.

The brain is protected from external agents by the blood-brain barrier, which prevents most microbes and chemical substances from crossing between the nervous system and the blood. Olfactory neurons are unusual in that they are directly exposed to the external environment, making them vulnerable to infiltration. Unlike any other sensory cells, olfactory neurons connect directly to the brain without any intermediate synapses. Microbes can taken advantage of this direct connection as an ideal route to bypass the blood-brain barrier.

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Olfactory neurons (shown in yellow) serve as a direct connection between the nasal cavity and the brain. Image source

Animal studies show that the viruses that cause polio, influenza, rabies, hepatitis, and herpes are all capable of infecting the brain via the olfactory nerve. In addition, many environmental toxins including metals, chemicals, and nanoparticles can be taken up by olfactory neurons and transported to the brain. This may help explain why prolonged exposure to air pollution or certain industrial chemicals can greatly increase the risk of Alzheimer’s (see Air Pollution, Aluminum, and Vitamin D Deficiency Linked to Dementia Risk).

The olfactory vector hypothesis remains a speculative model, and more evidence is needed to prove whether infiltration of the brain by external agents via the olfactory nerve can lead to Alzheimer’s. It is an intriguing idea that certainly warrants further study.

 

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Breakthrough in Alzheimer’s Research: What We Thought About Tau Tangles May Be All Wrong

The main hallmark of Alzheimer’s disease is the accumulation of toxic protein species in the brain. These toxic deposits include senile plaques (made of the amyloid-beta protein) and neurofibrillary tangles (made of the tau protein). In general, recent drug development research for Alzheimer’s has focused on targeting amyloid-beta. This is because previous research suggested that amyloid-beta is responsible for initiating a set of chemical reactions that lead to the phosphorylation of tau. This p-tau (phosphorylated tau) is then more prone to sticking to itself and forming tangles. Thus, the thinking was that if we could get rid of amyloid-beta, tau would no longer form tangles, allowing us to eliminate both toxic proteins at once.

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Plaques and tangles in a normal and Alzheimer’s disease brain.

However, a study published this week in the journal Science may completely change how we think about amyloid-beta and tau. Researchers from Australia looked at enzymes of the p35 family, which are believed to mediate amyloid-beta’s ability to initiate p-tau formation. They focused on a member of this protein family called p35-delta (p35D), after determining that it was the only p35 protein that localized to synapses (the communication junctions between neurons.)

The exciting part of this study came when the researchers generated Alzheimer’s mice that lacked the gene for p35D. These mice experienced exacerbated symptoms of Alzheimer’s disease, including worsened excitotoxicity, memory loss, and premature death. The researchers determined experimentally that these worsened symptoms were dependent on p35D’s ability to create p-tau. In other words, it seems that the presence of p35D (and in turn, the presence of p-tau) was actually protecting the mice from more severe symptoms of Alzheimer’s disease.

This study is big news in the field of neuroscience because it suggests that the formation of tangles by the p-tau protein may be helpful rather than harmful. Whereas in the past scientists have viewed tangles as a harmful side effect of amyloid-beta plaques, these new results indicate that p-tau may actually be a beneficial reaction to the plaques which keeps their toxicity in check. This is consistent with additional data from the study showing that humans with Alzheimer’s disease have reduced expression of p35D. The authors of the paper suggested that a decline in p35D expression, and in turn a decline in p-tau levels, may be a major contributor to the development of Alzheimer’s disease.

Alzheimer’s researchers around the world are very excited about this paper and the ramifications it could have for future studies. Where previously we had been trying to deplete toxic p-tau, this strategy may actually worsen the disease. Rather, perhaps we should be trying to increase levels of p35D and/or p-tau in early Alzheimer’s patients in order to prevent disease progression. It’s possible that this study may also help explain why approximately 1 in 5 elderly adults contain the signature pathology of Alzheimer’s in their brains and yet do not experience any cognitive deficits. Perhaps these individuals benefit from higher expression of p35D which helps fight of the toxicity of amyloid-beta. Future studies will investigate whether this is indeed the case.

As always, we must interpret these results with caution. Since this study was based in mice, a lot of additional research will be needed to determine whether similar neurochemical pathways occur in humans and, if so, whether these can be utilized to design a preventative treatment for Alzheimer’s. Only time can tell how far-reaching the impacts of this study will be.

 

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Alzheimer’s Disease: Diabetes of the Brain?

When I first heard an argument for Alzheimer’s disease to be considered a form of diabetes, I was pretty skeptical. The two diseases seem at first glance to be completely unrelated. But the more I delved into the science behind the hypothesis, the more parallels arose. Understanding the complex relationship between Alzheimer’s and diabetes is incredibly important for people who have or are at risk of either disease. Whether they are considered distinct diseases or parts of a single spectrum, the interplay between Alzheimer’s and diabetes has far-reaching consequences for how we view our health and lifestyle.

A Quick Intro to Diabetes

Just as the term “cancer” refers to a wide spectrum of conditions, diabetes mellitus (or just diabetes for short) is not one but several diseases that all lead to chronic high blood sugar, or hyperglycemia. Normally, when blood sugar levels get too high, cells in the pancreas release a hormone called insulin, which tells other cells in the body to absorb the sugar and use it for energy. However, in people with diabetes, there is a disruption of proper insulin signaling, causing blood sugar levels to rise unchecked. Nearly 30 million Americans (around 10% of the total population) have diabetes, and another 86 million are prediabetic.

Around 90% of diabetes cases are type 2. People with type 2 diabetes can usually produce insulin just fine, but their muscle, fat, and liver cells are desensitized to insulin signaling. Despite the pancreas releasing insulin to tell to the rest of the body that blood sugar levels are too high, the cells aren’t absorbing enough sugar in response to that insulin. This condition is referred to as insulin resistance. Susceptibility to type 2 diabetes can be influenced by genetics, but the biggest risk factors are obesity and physical inactivity.

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Insulin resistance in type 2 diabetes. Source

Could Diabetes Cause Alzheimer’s?

Due to mechanistic similarities between the Alzheimer’s and diabetes, many scientists have proposed that the two diseases may interact. A recent meta-analysis concluded that people with diabetes are at an increased risk of Alzheimer’s disease, even after correcting for the effects of obesity. Diabetes also increases the risk of non-dementia cognitive impairment, and it has been associated with poorer performance in multiple cognitive domains including verbal memory, working memory, processing speed, and attention.

Several mechanisms have been proposed to explain how type 2 diabetes might lead to the development of Alzheimer’s. The predominant view is that diabetes alone is not sufficient to cause Alzheimer’s directly. This is supported by multiple studies showing that the cellular pathologies associated with Alzheimer’s disease (i.e., the buildup of certain toxic proteins in the brain) are not increased in diabetic people if other variables are accounted for. However, when other risk factors such as obesity, aging, and high blood pressure are combined with diabetes, evidence suggests that they can work together to contribute to the development of Alzheimer’s disease.

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Schematic showing how T2DM (type 2 diabetes mellitus) might lead to Alzheimer’s through interactions with other risk factors. Source

Type 3 Diabetes

In the brain, insulin functions differently than in the rest of the body. Rather than primarily regulating sugar metabolism, insulin signaling in the brain mediates multiple complex processes that are necessary for neuronal survival and function. If the brain were to become insulin-resistant, these vital processes could be perturbed.

In 2005, a team of researchers led by Dr. Susan de la Monte discovered that the brains of people with Alzheimer’s have greatly reduced genetic expression of insulin and a related molecule called insulin-like growth factor (IGF), as well as the cellular receptors for insulin and IGF. This condition resembled the insulin resistance that’s found in muscle, fat, and liver cells in type 2 diabetes. In addition, the insulin-mediated pathways that regulate neuronal survival, energy metabolism, mitochondrial function, and gene expression were disrupted in the patients’ brains.

de la Monte proposed that neuronal insulin resistance contributes to the development of Alzheimer’s disease. She and her team coined the term “type 3 diabetes” to describe this condition of brain insulin resistance/deficiency, describing it as similar to but distinct from diabetes mellitus. Essentially, rather than suggesting that type 2 diabetes could lead to Alzheimer’s (as some other scientists had previously proposed), these researchers instead argued that Alzheimer’s itself is a form of diabetes.

Growing Support for the Hypothesis

Since the 2005 study was published, new evidence has emerged to offer support for the type 3 diabetes hypothesis. de la Monte’s team later demonstrated that deficits in insulin and IGF signaling begin in the earliest stages of Alzheimer’s and gradually deteriorate with the clinical progression of the disease.

Another study investigated causal evidence for the link between brain insulin resistance and Alzheimer’s using a drug called streptozotocin. When streptozotocin is injected into rats’ abdominal cavity, the drug travels to the pancreas and kills the insulin-producing cells, leading to diabetes. de la Monte and her team wondered what would happen if streptozotocin was instead injected directly into the rats’ brains. They found that the rats did not develop the symptoms of diabetes mellitus, since the drug was localized to the brain and could not reach the pancreas. However, since streptozotocin blocked all insulin and IGF signaling in the brain, the rats developed many symptoms resembling Alzheimer’s disease, including reduced brain volume, increased neuronal and glial cell death, and accumulation of toxic protein species (tau and amyloid-beta). This study demonstrated that brain insulin/IGF depletion and oxidative stress are together sufficient to cause an Alzheimer’s-like condition in rats.

What Does This Mean For You?

If Alzheimer’s is indeed a form of diabetes, this suggests that antidiabetic drugs could be useful in treating Alzheimer’s. The studies of this concept are limited, but early results are promising. de la Monte’s team found that when their rats were treated with a type of antidiabetic drug called a peroxisome proliforator-activated receptor (PPAR) agonist, the rats’ brain insulin resistance was resolved and they did not develop the Alzheimer’s-like neurodegeneration that had been observed previously. Additional studies are currently in the works to further test this idea.

Additionally, the relationship between type 2 diabetes and Alzheimer’s risk is widely accepted in the scientific community, as strong evidence demonstrates that being diabetic can substantially increase the risk of cognitive impairment in conjunction with other risk factors. This is a vital concept for the general public to be aware of, as type 2 diabetes is considered a preventable condition. According to the NIH’s Diabetes Prevention Program, even people at high risk of diabetes can prevent the disease through a combination of weight loss (5-7% of your total body weight), a healthy diet, and regular exercise. The National Diabetes Education Program offers lots of great tips for transitioning to a healthier lifestyle.

type_2_diabetes_infographic

The impact of dietary choices on the risk of type 2 diabetes. Source

 

Final Thoughts

Reducing your risk of diabetes, or properly managing the diabetes you already have, will help you live longer by reducing your risk of Alzheimer’s and protecting you from other diabetes-related complications including cardiovascular disease, blindness, kidney failure, and amputations. In addition, this new research suggests that preventing brain insulin resistance can also reduce your risk of Alzheimer’s and cognitive impairment, ensuring that your mind is intact through your later years to watch your children and grandchildren grow up and to experience life to the fullest. Even small steps can make a big difference for protecting the health of your brain and body.

 

Additional Reading

“Alzheimer’s Disease is Type 3 Diabetes–Evidence Reviewed” by Susan de la Monte
“Is Alzheimer’s Type 3 Diabetes?” by Mark Bittman
“Alzheimer’s Disease and Type 2 Diabetes: A growing connection” by the Alzheimer’s Association

 

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