Tag Archives: neuroscience

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.


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.


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.


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.


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.


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.


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.


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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Could We Ever Bring Back Alzheimer’s Patients’ Memories?

We spend our whole lives collecting memories. To many of us, these are far more precious than any of our material possessions. Perhaps this is why diseases like Alzheimer’s that rob us of our memories feel especially tragic and frightening.

There’s a lot of brilliant research being done on ways to prevent Alzheimer’s disease or to halt its progress, and each day the field is making great strides toward this goal. Yet many scientists are reluctant to address the elephant in the room: what about the memories that are already gone? Will we ever be able to bring back a lifetime of precious memories to a patient who’s forgotten them all? It’s a difficult question, one that no one can predict with absolute certainty, but here I’ll attempt to describe where our current research stands and the obstacles we must overcome if we’re ever to achieve this goal.

The Hunt for the Engram

Here’s a deceptively simple question for you: what is a memory? You might think you know the answer. Of course, memories are our way of looking pack on our past, the images you recall from your wedding day, the mouthwatering smell of your grandma’s brownies, the lyrics to your favorite song. But what are they really? Do memories exist in physical space, governed by simple chemical reactions like the rest of our bodies? Or are they more ethereal, an untouchable something that’s a part of us yet separate from our physical form? These questions have been a source of philosophical debate for centuries, going back to the time of Plato and Aristotle.

In the early 1900s, neuroscientist Richard Semon hypothesized that our brains undergo an enduring physical or chemical change whenever we form a new memory. He coined a new term, “engram,” to describe this physical manifestation of memory. The nature of the engram was a topic of considerable debate. Some, like William James, believed that each memory is stored within a single neuron. “Every brain-cell has its own individual consciousness, which no other cell knows anything about,” James famously wrote. According to this theory, there’s a cell for all your memories of your grandmother, a cell for memories of macaroni and cheese, a cell for memories of the color blue, and so on. Others took a more holistic approach to memory theory. They believed that memories were stored as a pattern of activity within a particular group of neurons, rather than in a single neuron.


According to William James, everyone has a “grandmother cell” which contains all the memories you have of your grandmother. Image Source

For nearly a century, neuroscience lacked the proper tools to resolve this debate. Finally, in 2007, a revolutionary paper was published in the journal ScienceThe researchers in the study genetically engineered mice so that any neurons that became activated while learning a new behavior were permanently “tagged.” The researchers observed a particular group of neurons that were activated after learning the new behavior, but not in control mice that received no training. When the mice were exposed once again to the training, causing them to recall their previous memory, the same group of neurons became active. This was seen as the first proof that engrams existed within the brain and could be reactivated when recalling memories.

Subsequent research provided more concrete evidence that these neurons were indeed an engram. In one study, researchers placed rats in a cage where they received a foot shock. Normally, if the rats were placed in that cage again, they would remember the foot shock and display signs of fear such as “freezing.” However, when the researchers selectively destroyed the cells within that engram, the rats seemed to forget the memory and did not freeze when placed back in the cage.

The next breakthrough came in 2011 with the invention of optogenetics, which allows us manipulate the activity of individual neurons without destroying them. Using this technique, it was shown that activating the fear engram caused the rats to freeze, even if they weren’t in the cage where the shock happened. Conversely, inactivating the engram blocked the memory, so that the rats would not freeze when placed back in the cage where they had been shocked.


Optogenetics allows researchers to directly manipulate neuronal activity using pulses of light. (Don’t worry, this is painless for the mouse!) Image Source

These studies show that engrams are probably formed by the activity of multiple neurons, casting doubt on James’s theory of one memory per cell. However, the mystery of the engram is not yet completely resolved. Today we are still trying to figure out what kinds of changes are occurring at the cellular and molecular level within these neurons when a memory is formed.

Alzheimer’s Disease: Memory Destroyer or Memory Blocker?

Now that we have a better understanding of what exactly a memory is, I can return to my original question: can the memories lost by Alzheimer’s patients ever be rescued? The answer to this question depends on what is actually happening to the memories in this disease. If the engrams encoding these memories are destroyed, it seems unlikely that we could ever rebuild them. However, there is a more hopeful possibility. What if the memories are still present in the brain, but Alzheimer’s simply prevents us from accessing them?

This is essentially a question of what aspect of memory is lost in Alzheimer’s disease. Memory formation is divided into three stages:

  1. Encoding. Your brain translates the raw data obtained through your senses into a pattern of neuronal activity, which forms a short-term memory.
  2. Storage. If the memory is deemed by your brain to be important, it is transferred into long-term storage.
  3. Retrieval. Whenever you recall that memory, your brain accesses its stored engram and allows you to remember.

It is still not entirely clear which stage of memory is disrupted in Alzheimer’s disease. Are the patients simply unable to encode new memories? Can they form memories but not transfer them to long-term storage? Or maybe the memories are there but simply can’t be retrieved?


A computer is a useful metaphor for understanding the stages of memory (even if it is a bit of an over-simplification). You encode information using the keyboard, which is stored on the hard drive or disk. When you want to retrieve that information, it is displayed on the monitor. Image Source

A study published last year in Nature took a step toward addressing this dilemma. Researchers used a mouse model of Alzheimer’s disease and selected mice that were 7 months old. This age group is a representation of early Alzheimer’s disease, when short-term memory is normal while long-term memory experiences deficits. Using the same foot-shock protocol I described before, they saw that the mice showed freezing behavior 1 hour after the training but had forgotten 24 hours later.

Next, the researchers used optogenetics to activate the engram associated with the fear memory 24 hours after the training period. This time, the mice showed freezing behavior, indicating that the memory had been recalled using the light stimulation. This result is encouraging because it suggests that, at least in the early stages of Alzheimer’s disease, memories can be consolidated into long-term storage, and the problem is simply an inability to retrieve them.

Will We Ever Rescue Lost Memories?

Our understanding of Alzheimer’s disease, and of the nature of memory itself, remain incomplete. The study I’ve just described does not address whether activating an engram can retrieve a memory formed months or even years ago. It also does not explore whether mice in later stages of the disease can have their memories revived in this way. Furthermore, at present we do not have a noninvasive method for activating particular engrams in humans.

However, it does provide at least of glimmer of hope. If it is the case that the memories of Alzheimer’s patients are still present in their brains, then the possibility of restoring the memories becomes much more feasible than if they were completely destroyed. It also suggests that emerging therapies like deep brain stimulation could one day be used to help restore memory.


Deep brain stimulation uses an electrode to provide stimulation directly into the brain. These devices have had encouraging results for Parkinson’s disease and are now starting to be tested for Alzheimer’s. Image Source

Sometimes, people with Alzheimer’s disease will seem to momentarily remember something they had previously forgotten. They are plenty of videos of this online, such as this one, where a man suffers from severe dementia and yet can inexplicably recall the lyrics to his favorite songs; or this one, where a woman with Alzheimer’s recognizes her daughter after having forgotten her. Perhaps those other memories are not gone but just inaccessible. Perhaps the memories are still buried deep inside their brains, just waiting for the right stimulus to bring them back to the surface.


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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.


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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