Category Archives: Alzheimer’s In the News

Study Shows How Alzheimer’s Affects Men’s and Women’s Brains Differently

Women are around twice as likely to develop Alzheimer’s disease during their lifetimes compared to men. This effect is also seen in mouse models of the disease. When mice are genetically engineered to developed Alzheimer’s, the female mice tend to have an earlier diseae onset and more severe pathology compared to hte male mice. The reasons for this discrepancy are unknown. However, a recent study published in Neurobiology of Aging attempted to shed some light on the mystery.

The researchers were interested in studying adult neurogenesis, which is our brains’ ability to create new neurons throughout our lives. Neurogenesis primarily occurs in two areas of the brain: the olfactory bulb, which is involved with the sense of smell, and the hippocampus, which is important for memory. In this study, the scientists wanted to figure out whether neurogenesis in the hippocampus was different for male and female mice with Alzheimer’s disease.

First, they subjected the mice to a test designed to test spatial memory, which is particularly important for the hippocampus. They placed the mice in a container with two objects and allowed them to explore for a few minutes. The next day, they placed the mice back in the container, but now one of the objects had been moved to a new location. We would expect the mice to spend more time sniffing and investigating the object that had been moved, and less time sniffing the object that was in the same place as before.

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When one of the cups is moved to a new location, the mouse should spend more time sniffing it compared to the cup that wasn’t moved. This test is used to analyze the mouse’s spatial memory. Image Source

The result was interesting. While the male mice had no trouble rembering which cup had been moved, the female mice did significantly worse, spending the same amount of time sniffing both of the cups. This suggested that the female mice might have some impairment in their spatial memory.

Next, the researches looked at the mice’s brains. They used a technique that caused all newly-born neurons to be labeled bright green, and counted how many neurons were born in the hippocampus during a two-week period. The male mice produced more than four times as many neurons as the female mice. Conversely, the female mice had nearly twice as many astrocytes in their hippocampi compared to the males. Astrocytes are another type of brain cell that is often associated with inflammation. These results suggested that the female mice’s brains were producing many astrocytes but few neurons, perhaps contributing to their impaired spatial memory.

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This image from the paper shows astrocytes labeled in red. In the top right panel, you can see that the female Alzheimer’s (APP/PS1) mice have far more red area than the males, indicating a greater number of astrocytes.

The results of this study suggest that the brains of female mice with Alzheimer’s may be devoting so many resources to creating new astrocytes that there’s not enough left to create neurons. However, it opens up many new questions. What is causing this overproliferation of astrocytes in the female mice? The authors of the paper suggest estrogen as a possible cause, since this hormone has been shown to influence memory. Additional studies are needed to determine the true cause.

 

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New Alzheimer’s Study Sheds Light on the Mysterious Tau Protein

If you’re a regular reader of AlzScience, you know that Alzheimer’s disease is believe to be caused by two toxic proteins that accumulate in the brain: amyloid-beta and tau. (For more background, see Alzheimer’s Disease: A General Overview.) Recently, it’s been shown that tau is actually a better predictor of Alzheimer’s disease progression than amyloid-beta, suggesting that this mysterious protein might have a larger role in the disease than we once thought.

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Amyloid-beta plaques and tau tangles form toxic clumps in the brains of Alzheimer’s patients. Source

A study published last week in Nature provided deeper insight into tau. The scientists were interested in studying the ApoE gene, which is considered the strongest genetic risk factor for Alzheimer’s (see The Genetics of Alzheimer’s Disease.) Specifically, having two copies of the ApoE4 allele increases your risk of Alzheimer’s by nearly 15 times, and it’s been shown that people with this allele have greater buildup of amyloid-beta in their brains. However, the researchers in this study wanted to see whether ApoE could also affect tau accumulation.

To test this, they used genetically engineered mice that overexpress the tau gene, causing them to develop many of the symptoms of Alzheimer’s. They then tampered with these mice’s genes so that they would also overexpress ApoE4. (Note: Overexpressing the tau and ApoE4 genes means those genes were more active than they normally would be in the mice. Think of it like a light switch stuck in the “on” position.) They found that these mice had more tau in their brains, and also more severe brain shrinkage due to neuronal death.

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This figure from the paper shows brain slices from different mice. The far left panel shows a healthy mouse brain. The next two (representing the ApoE2 and ApoE3 alleles) have slightly more brain atrophy, while the harmful ApoE4 allele causes very severe atrophy. In contrast, the far right brain, which does not express ApoE at all, has relatively little atrophy.

To figure out how ApoE4 might be causing more tau accumulation, the researchers looked at the mice’s microglia, the immune cells of the brain. The microglia overexpressing ApoE4 tended to overreact to infections, releasing high amounts of pro-inflammatory molecules called cytokines. Neurons and other brains cells are very sensitive to cytokines, and high levels might cause them to produce more tau.

Finally, the researchers turned to human research. They used postmortem brain tissues taken from people who had tauopathies, which are diseases caused by accumulation of tau (but not amyloid-beta) in the brain.  The people possessing the ApoE4 allele had more severe neurodegeneration and greater tau buildup in certain areas of the brain.

Overall, this study demonstrates that ApoE4 does not only act on amyloid-beta, but tau as well. It gives strong support to the notion that tau may be as important as amyloid-beta in understanding the pathology of Alzheimer’s disease. In an interview with Science News, Harvard neurologist Dennis Selkoe described this deadly combination of amyloid-beta and tau as a “double whammy.” Yet this study provides hope that future therapies against ApoE4 could be capable of halting both of these toxic proteins at once.

 

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Artificial Intelligence Could Help Us Predict Alzheimer’s Disease

Many experts agree that preventing the progression of Alzheimer’s disease is much more effective than trying to reverse it once the damage is done. This makes early diagnosis critical. Unfortunately, most Alzheimer’s patients are not diagnosed until relatively late in disease progression, when toxic amyloid plaques have already accumulated in their brains to potentially irreversable levels. However, this might soon be changing with the recent surge in artificial intelligence technology.

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This diagram shows the stages of Alzheimer’s disease, which can begin up to 20 years before diagnosis. Most patients are not diagnosed until the mild or moderate stage, since this is when cognitive impairments become more noticeable. Image Source

This research was described in a paper published in Neurobiology of Aging by scientists from McGill University in Canada. Their goal was to create an algorithm to predict whether people with mild cognitive impairment would progress to dementia. They utilized a noninvasive technology called positron emission tomography (PET). PET involves the patient lying inside a donut-shaped machine, similar to a CAT scanner. The machine can measure which areas of the brain have higher or lower activity levels based on how much glucose each brain region is consuming.

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A patient lying inside of a PET machine. Image Source

The researchers used PET scans from 273 patients with mild cognitive impairment. 43 of these patients were diagnosed with probable Alzheimer’s disease at a follow-up appointment two years later. Then the scientists trained an artificial intelligence algorithm to predict which patients would develop Alzheimer’s based on their PET scans.

They used the data to generate the map of the brain that’s shown below. The red-colored areas indicate a higher odds ratio (OR). This means that unusual activity levels in those brain areas are associated with an increased risk of Alzheimer’s disease. For example, an odds ratio of 3 means that a person with unusual activity levels in that brain area is 3 times as likely to develop Alzheimer’s compared to someone with normal activity levels.

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Figure 2 of the paper shows which brain regions are the most important for predicting the risk of Alzheimer’s disease.

The algorithm was able to predict which patients would progress to Alzheimer’s disease with an accuracy of 84%. This is better than any previously-developed PET algorithms, and comparable to more invasive diagnostic techniques such as spinal taps. This is exciting news because it suggests that a painless, noninvasive technology can be used to predict Alzheimer’s disease with a fairly high degree of accuracy.

As always, we have to point out a few problems with this study. For one thing, it’s impossible to know for sure whether the patients’ Alzheimer’s disease diagnoses performed by doctors at the follow-up appointment were actually correct. This is because many forms of dementia have similar cognitive symptoms, and can be easily confused during diagnosis. Parkinson’s disease, vascular dementia, or even a urinary tract infection can be misdiagnosed as Alzheimer’s disease. (For more info see Is it really Alzheimer’s? 10 common misdiagnoses you should know about). Only a postmortem brain analysis can reveal for sure whether the patients truly had Alzheimer’s. This muddles our ability to judge how accurate the algorithm really was.

Another problem is that PET scans can be quite expensive, costing upwards of $7,000. If a patient is incorrectly diagnosed with Alzheimer’s, this could lead to futher costs for medication to treat a disease they don’t actually have. Finally, while the mild cognitive impairment stage is earlier than most Alzheimer’s patients are diagnosed, it can still be up to ten years after the true beginning of the disease. We still have no reliable way to make diagnoses that early. Nonetheless, this study is at least a step in the right direction. With future advances in artificial intelligence, we might be able to improve our diagnostic accuracy at earlier stages of the disease.

 

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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.