Category Archives: Alzheimer’s In the News

A Third of Dementia Cases Could Be Preventable

Dementia is caused by a variety of genetic, environmental, and lifestyle factors. A new study published in The Lancet offers hope that many of us could avoid dementia by making healthier choices for our brains. The study was conducted by the International Commission on Dementia Prevention, Intervention, and Care, a panel of 24 experts assembled to conduct a review and meta-analysis of existing dementia research. The scientists concluded that with a cure to Alzheimer’s disease likely to still be years away, the best approach is to focus on prevention.

Among the contents of the report was a series of recommendations for reducing the risk of dementia. They identified nine modifiable risk factors that are responsible for 35% of dementia cases. These factors seem to act primarily at a particular stage of life:

  • Childhood: Low educational attainment
  • Mid life: Hypertension, obesity, hearing loss
  • Late life: Depression, diabetes, physical inactivity, smoking, social isolation

The researchers argue that by addressing these modifiable risk factors, a third of dementia cases could be prevented. They showed that by reducing the prevalence of these risk factors by only 10%, more than 1 million dementia cases could be avoided worldwide. The report also included several recommendations for dementia management and care. These included pharmacological treatment of dementia patients at all disease stages, individualized care tailored to each patient, managing neuropsychiatric symptoms with social or environmental interventions, and providing support for caregivers, who are at an increased risk of depression and other health problems.

A press release of the data presented at the Alzheimer’s Association International Conference noted that there are many other likely risk factors associated with dementia, including diet, air pollution, and sleep. These were not mentioned in the report due to a lack of conclusive research, but it is likely that even more dementia cases could be preventable with these other factors considered. For more information on brain health and dementia prevention, see How to Reduce Your Dementia Risk in 2017.

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Image Source: Keck Medicine of USC

 

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“Silent Modulator” Drug Reverses Alzheimer’s Disease in Mice

Glutamate is a neurotransmitter, a chemical used to transmit signals between neurons. Its dynamics in the brain are highly complex and it is sensed by a variety of receptors, including metabotropic glutamate receptor 5 (mGluR5). mGluR5 is of particular interest due to its recently-uncovered role in Alzheimer’s disease. The receptor can interact with short strings (“oligomers”) of amyloid-beta, a toxic protein implicated in the pathology of Alzheimer’s. Multiple studies show that loss or inhibition of mGluR5 can alleviate Alzheimer’s symptoms in animal models.

An important question remaining to be answered is exactly how mGluR5 contributes to Alzheimer’s. One hypothesis is that the receptor’s interactions with amyloid-beta oligomers trigger a pathogenic signaling cascade. Another possibility is that amyloid-beta is not involved, and instead the dysregulated glutamate signaling is to blame.

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Glutamate is regulated by many different neuronal receptors, including mGluRs. It is an important molecular for neuronal signaling. Image Source

A recent study published in Cell Reports attempted to solve this dilemma. Researchers from Yale University used a silent allosteric modulation (SAM) drug to target mGluR5. In humans, complete inhibition of mGluR5 would be deadly, since the receptor is necessary to maintain proper glutamate signaling in the central nervous system. To avoid this problem, the SAM drug was carefully designed so that it blocked the ability of mGluR5 to interact with amyloid-beta oligomers, but still allowed it to function normally in glutamate signaling.

The researchers then administered the drug to mice that have a mutation causing them to develop Alzheimer’s disease. After four weeks of treatment, the mice underwent a battery of tests designed to test memory and cognition. Normally, the mice with Alzheimer’s disease perform very poorly on these tests. However, after treatment with the drug, the Alzheimer’s mice performed as well as the non-Alzheimer’s mice. This result is striking, because most drug candidates for Alzheimer’s disease are only able to stop the cognitive decline from getting any worse. It is rare for a treatment to actually reverse the memory deficits.

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One type of memory test is called novel object recognition. When a healthy mouse sees a novel object, it will sniff it more than it would a familiar object. Mice with Alzheimer’s disease normally can’t distinguish novel from familiar objects, but the SAM drug in this study was able to return the mice’s test scores to healthy values.

The scientists took it a step further by examining what was going on inside the mice’s brains at the cellular level. They found that levels of amyloid-beta plaques and damage to glial cells were unchanged by the drug. This is surprising, because these two factors are often considered to be among the main driving forces of Alzheimer’s disease. In contrast, they observed a dramatic change in the mice’s synapses, the junctions where neurons send signals to each other. Mice with Alzheimer’s disease typically have fewer synapses than normal mice. However, those receiving the treatment showed recovery of synapses, suggesting that modulation of synapses could be how the drug reverses memory decline.

An important limitation of the mice used in these experiments is that they only develop the amyloid-beta pathology of Alzheimer’s disease. In humans, there are many other toxic proteins involved, including a particularly important one called tau. To address this problem, the researchers also administered the drug to a different mouse strain, which expressed both amyloid-beta and tau. They saw that levels of tau were alleviated in the mice receiving the treatment.

This study helps to solve an important dilemma, demonstrating that mGluR5’s contributions to Alzheimer’s disease are solely due to its interactions with amyloid-beta, and not due to abnormalities in glutamate signaling. Thus by developing human versions of the SAM drug used in this study, it might be possible to stop or even reverse memory decline in Alzheimer’s patients. However, it’s important not to get too excited just yet. We’ve seen time and time again that the vast majority of drug candidates that have encouraging results in mice end up failing to treat the disease in humans. Only time will tell whether these results could have clinical applications.

 

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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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