Category Archives: Alzheimer’s In the News

Alzheimer’s Patients May Experience “Silent Seizures”

If you’ve read our recent article on sleep science, you know that neurons release amyloid-beta (a toxic protein implicated in Alzheimer’s disease) during periods of activity. The protein is excreted as a waste product whenever neurons fire an electrical signal. This is probably why patients with epilepsy often have large amyloid-beta plaques in their brains, as the fast pulses of activity created by seizures cause neurons to excrete large amounts of the protein. Based on this observation, some have theorized that the buildup of amyloid-beta in Alzheimer’s disease could be caused by hyperactive neurons.

In a paper published recently in Nature Medicine, researchers used electrodes to monitor neuronal activity in the medial temporal lobe (MTL) of two patients with early Alzheimer’s disease. The MTL is highly vulnerable to amyloid plaque buildup in Alzheimer’s disease and contains structures important for memory, including the hippocampus and entorhinal cortex. Typically a scalp EEG is used for measuring seizure activity, but because the MTL is buried deep within the brain, it’s difficult to observe in this way. The researchers got around this problem by inserting electrodes directly into the patients’ MTL.

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This figure shows the placement of the electrodes in one of the patients.

Patient 1 showed high neuronal activity in the MTL, ranging from 400 spikes per hour when awake to 850 spikes per hour during sleep. The electrodes recorded three small seizures during the 12-hour monitoring period, all of which occurred during sleep. One caused the patient to awaken, while the others had no noticeable effect. When the patient was treated with levetiracetam, an antiepileptic drug, the spiking activity in the MTL was reduced by 65% and she experienced no further seizures for the next 48 hours before the electrodes were removed.

The second patient had comparatively lower neuronal activity: about 16 spikes per hour when awake and 190 spikes per hour during sleep. Mood disturbances prevented her from being administered the levetiracetam.

In both patients, 95% of the spikes and all of the seizures in their MTL were not detectable by EEG, which was recording at the same time as the electrodes. Thus these clinically silent seizures have remained unknown until now, invisible to both patients and doctors. This new electrode recording method shows that patients in the early stages of Alzheimer’s disease may have hyperactive neurons in the MTL, a possible explanation for why this region is often affected by high amyloid-beta levels. If this is the case, some patients may benefit from antiepileptic drugs to prevent Alzheimer’s disease from progressing further.

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While EEG (pictured here) is an easy and noninvasive method of measuring neuronal activity, this study showed that is cannot reliably detect seizures in subcortical structures like the hippocampus.

With only two patients, it’s hard to say whether this study generalizes to the rest of the population. These patients could be exceptions to the rule and display unusually high MTL activity. However, the study is certainly intriguing and merits further investigation with a larger number of test subjects.

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Sleep Apnea May Contribute to Alzheimer’s Disease

*Thank you all for your patience during my one-month hiatus. To read about my adventures backpacking across Europe or my current internship researching Alzheimer’s disease in Switzerland, check out my travel blog, Brains and Backpacks.*

 

Around 3-7% of adults suffer from obstructive sleep apnea, a condition in which the upper airway tract periodically collapses during sleep. This can lead to loud snoring and poor sleep quality. If left untreated, it can contribute to a multitude of health conditions and decreased overall quality of life. Among these possible complications is Alzheimer’s disease. People with Alzheimer’s are five times more likely to have obstructive sleep apnea than the general population.

Recent evidence has provided more direct proof for the link between sleep apnea and Alzheimer’s. In an editorial published in the journal Oncotarget, researchers from Tokyo’s National Institute of Neuroscience described their recent work investigating a new mouse model of Alzheimer’s disease. To do so, they subjected the mice to intermittent hypoxia by decreasing oxygen levels in their cages for one minute, followed by two minutes of normal oxygen levels. This cycle repeated for eight hours per day while the mice slept for periods ranging from 5 to 28 days. This type of model has been used before to simulate the effects of sleep apnea.

When the researcher’s examined the mice’s hippocampi, the part of the brain responsible for long-term memory formation, they observed that many of the processes associated with aging were also triggered by the intermittent hypoxia. This suggests that sleep apnea could lead to an increased rate of aging in the brain. The mice also had high levels of hyperphosphorylated tau, a toxic protein that forms tangles in the brains of Alzheimer’s patients. These results are in line with other recent studies, which have shown that intermittent hypoxia causes neurons to become hyperexcited and produce greater amounts of amyloid-beta, another protein involved in Alzheimer’s disease.

The authors suggested that this protocol could be useful in developing new animal models of Alzheimer’s disease, since it triggers many of the disease’s pathological signatures using only an environmental stimulus. The models could be applied for studying how aging and sleep disruptions contribute to development of Alzheimer’s over time.

At present, there is not yet enough concrete evidence to conclude a direct link between sleep apnea and Alzheimer’s disease. However, if you or a loved one experiences sleep apnea or other sleep disorders, there would certainly be no harm in seeking medical help. Correcting sleep problems can lead to greater quality of life and reduced risk of many medical conditions. Perhaps Alzheimer’s is among them.

Probiotics May Improve Cognitive Function in Alzheimer’s Disease

The gut microbiome has recently become the focus of a lot of biomedical research, as we begin to understand how important the microbes living in our gastrointestinal tracts are for our overall health. While it’s still unclear what exactly makes your gut microbes healthy or unhealthy, previous research has shown that probiotics shift the balance in the right direction. Probiotics are live bacterial or yeast cultures often found in fermented foods like yogurt, sauerkraut, and pickles. These cultures seem to increase the proportion of “good” microbes in your gut. While the gut microbiome is clearly important for gastrointestinal health, recent studies suggest that it can also influence the brain. Scientists have coined the term “microbe-gut-brain axis” to describe this close relationship.

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The brain and the gut microbiome are closely related and can influence each other’s function. Image Source

In a study published in Frontiers in Aging Neuroscience, researchers from Iran attempted to determine whether probiotics could be beneficial for dementia patients. They randomly divided sixty patients diagnosed with Alzheimer’s disease into two groups. One group received milk containing a mixture of probiotics, while the other group received regular milk as a control. The study had a double-blind design, meaning neither the researchers or the subjects knew who received each type of milk until after the data analysis was completed. This design helps to ensure that unconscious biases do not influence the results. Additionally, none of the subjects were allowed to consume probiotic-rich foods like yogurt during the study, ensuring that any gut microbiome differences would be due to the experiment and not any dietary interference.

After twelve weeks consuming the milk on a daily basis, the subjects took a mini-mental state exam, which is used to assess memory and cognition. The probiotic group scored an average of 28% better on the exam compared to their score before starting the treatment. In contrast, the control group’s score decreased by an average of 5%. This difference was statistically significant, indicating that the probiotics substantially improved memory in these subjects.

The researchers also tested the subjects’ blood for many different biochemicals. The probiotic group had improved markers of insulin metabolism, suggesting that the treatment might be helpful in reducing the risk of insulin resistance, a condition associated with type 2 diabetes. They also had lower levels of triglycerides, a type of body fat.

Despite the sample size of this study being fairly small, the dramatic improvement in cognitive status after only three months of probiotic treatment suggests that the gut microbiome could be intimately involved in dementia. Probiotics have no known health detriments, and are proven to assist in gastrointestinal health. While we wait for larger studies to provide a conclusive answer on probiotics’ utility in Alzheimer’s disease, it can’t hurt to try increasing them in our diets, or in the diet of a loved one with dementia.

 

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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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Study Identifies a Promising Therapeutic Target for Alzheimer’s Disease

As our regular readers know by now, Alzheimer’s disease is characterized by the buildup of a toxic protein called amyloid-beta in the brain. While amyloid-beta was considered for many years to be the primary driver of the disease, we now know that the full picture is much more nuanced, with many different genes likely involved (see The Genetics of Alzheimer’s Disease). One of the genes that is often inhibited in people with Alzheimer’s disease is Nrf2. Nrf2 is a transcription factor, meaning it can control which other genes are turned on or off in a cell. In particular, Nrf2 is important for controlling cellular defense genes, including genes responsible for antioxidant activity and DNA repair. It’s been shown in mice that increasing the levels of Nrf2 in the brain can improve the symptoms and pathology of Alzheimer’s disease.

Several drugs have been designed to activate Nrf2 in the hopes that this could help treat Alzheimer’s and other neurodegenerative conditions. While these drugs were effective in mouse models of the disease, they were often toxic in humans. To address this problem, a group of researchers in England decided to try a different approach by targeting two proteins called GSK-3 and Keap1. These proteins are produced in normal human cells and act as inhibitors of Nrf2. Thus, the researchers hoped that by blocking GSK-3 or Keap1, they might be able to indirectly activate Nrf2.

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Nrf2 is a type of enzyme called a transcription factor. Inhibitor molecules, such as GSK-3 and Keap1, can bind to Nrf2 and prevent it from functioning. Thus, blocking these inhibitors could increase the activity of Nrf2. Image Source

Their results were published last week in PLoS Genetics. The study utilized fruit flies as a model of Alzheimer’s disease. When the flies were treated with lithium, which can act as a GSK-3 inhibitor, the defects in Nrf2 activity were not resolved. However, the results for the Keap1 inhibitor were much more promising. Not only was Nrf2 activity returned to normal levels, but the flies also experienced reduced toxicity of the amyloid-beta protein. The researchers even observed increased degradation of amyloid-beta, helping to reduce the levels of this protein in the brain. Similar protective effects were observed when neurons cultured from mouse brains were treated with a drug to block the interaction between Keap1 and Nrf2.

This study provides strong evidence for Keap1 as a possible therapeutic target in Alzheimer’s disease. By blocking Keap1, it may be possible to increase the activity of Nrf2 and in turn the activation of cellular defense genes, protecting our brains from neurodegenerative diseases like Alzheimer’s. The authors also suggested that a combined treatment for both Keap1 and GSK-3 may have added benefits. While the neuroprotective effects GSK-3 inhibition seem to involve a mechanism independent of Nrf2, the mice treated with both Keap1 and GSK-3 inhibitors fared better than those treated with either drug alone.

Targeting cell defense pathways like Nrf2 may provide a more effective treatment method than those previously attempted. The majority of past studies have tried to directly remove amyloid-beta from the brain, yet these drugs have been a resounding failure in humans (see Where’s our cure to Alzheimer’s disease?) The Keap1 and GFK-3 inhibitors are different, in that their main action is not to remove amyloid-beta but simply to reduce its toxicity. Future research will investigate the safety and efficacy of these drugs in humans.

 

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Autoimmune Diseases May Be Linked to Dementia

Our immune system is pretty great. It helps us recover from injury and fight off deadly pathogens. However, sometimes the immune system does its job a little too well. In certain autoimmune diseases, immune cells can mistakenly recognize a part of our own body as a foreign invader and start attacking it. Depending on what type of tissue is being targeted, autoimmunity can lead to a variety of conditions including rheumatoid arthritis, celiac disease, and multiple sclerosis. Approximately 50 million Americans (20% of the population) have an autoimmune disease.

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Some of the most common autoimmune diseases. Image Source

A study published this week in the Journal of Epidemiology and and Community Health looked at the relationship between autoimmune diseases and dementia. The researchers used health records of more than 1.8 million people in England who were hospitalized for an autoimmune condition between 1998 and 2012. They found that these patients were 20% more likely to be later hospitalized for dementia compared to controls. They identified 18 autoimmune diseases that were significantly associated with dementia. When they examined the type of dementia, the autoimmune patients were at the greatest risk for vascular dementia, with a 28% higher risk than normal. The increased risk for Alzheimer’s disease was relatively small at 6%.

This study is in line with several previous papers that hinted at a possible link between autoimmunity and dementia. It’s been shown that people with two common autoimmune diseases, type 1 diabetes and thyroid autoimmune disease, are at an increased risk of dementia. The mechanism for this connection remains unknown, but it raises the interesting question of whether dementia may be related to the immune system.

Additionally, the study supports the possible use of NSAIDs as a way to reduce the risk of dementia. NSAIDs (which include aspirin, ibuprofen, and naproxen) are some of the most commonly-used painkillers and can also be used to combat inflammation in autoimmune conditions. People who take NSAIDs tend to have a reduced risk of Alzheimer’s disease, suggesting that using these drugs to treat an overactive immune system could have cognitive benefits as well.

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Advil, Aleve, and Motrin are some of the most common NSAIDs available over-the-counter. Image Source

Many doctors have begun prescribing baby aspirins to their patients in the hopes of decreasing their risk of dementia as well as cardiovascular disease. However, caution is necessary when considering an NSAID regimen. It’s possible that for some people, NSAIDs could be doing more harm than good, as one study suggested that these drugs may reduce the risk of Alzheimer’s but increase the risk of vascular dementia. More research is needed before we can say conclusively whether NSAIDs may be beneficial for cognitive health.

 

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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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