Author Archives: AlzScience

Ketogenic Drug Shows Promise in Early Clinical Trials for Alzheimer’s Disease

There’s a lot of hype surrounding the ketogenic diet, but unlike many other fads, this one may actually have the potential for real benefits. In a study published this week in Experimental Gerontology, researchers tested a recently-developed drug called caprylidene that can simulate the effects of the ketogenic diet.

A small cohort of sixteen Alzheimer’s disease patients was recruited for the study. Fourteen of them were randomly assigned to take caprylidene for 45 days, while the other two took a placebo. The researchers administered brains scans before and after the 45-day period to monitor any changes in the patients’ cerebral blood flow.

They found that most of the subjects who took the caprylidene had higher blood flow in several regions of the brain. This suggests that the drug enhanced the patients’ abilities to metabolize energy in these specific regions. However, the drug seemed to have no effect on patients who possessed the APOE4 allele, a genetic variant that is associated with a greater risk of Alzheimer’s disease.

This small study provides some evidence in favor of the ketogenic diet as a possible treatment for neurodegeneration. As I’ve discussed in one of my previous articles (see Alzheimer’s and Coconut Oil: What does the science say?), the ketogenic diet is based on shifting your body’s primary energy source from carbohydrates to fats. When you deprive your body of glucose, this induces a state of “ketosis,” in which your liver begins breaking down fat stores to form another type of energy-storing molecule called ketones.

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An overview of the ketogenic diet. Image Source

Recently, evidence began to emerge that suggested the ketogenic diet could be useful for people with Alzheimer’s disease. Studies show that the brains of Alzheimer’s patients have a harder time metabolizing glucose, which causes their neurons to be starved for energy. This has led some to suggest that by providing neurons with ketones, the ketogenic diet might allow the brain to access an alternative energy source and perhaps restore some function.

Those of you who have cared for a loved one with Alzheimer’s disease may recognize that implementing a strict dietary plan like the ketogenic diet is next to impossible. This makes drugs like caprylidene, which induces ketosis artificially, a useful alternative.  While the small number of subjects used in this study is cause for caution, it suggests possible merit to this hypothesis and a need to replicate these intriguing findings with a larger sample size.

 

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Herpes Virus Infection May Contribute to Alzheimer’s Disease

A virus with a nearly 100% infection rate could increase the risk of developing Alzheimer’s disease.

The idea that Alzheimer’s disease may be caused in part by microbial infections has been around for decades and recently started to gain increased support with the scientific community. Hundreds of studies have observed an increased incidence of many types of infections in Alzheimer’s disease patients. However, most of these studies could not establish a direct causative link, and they provided little insight into the mechanisms of this interaction.

Recently, a study published in the journal Neuron provided some of the strongest evidence yet for the infectious theory of Alzheimer’s. Researches from the Icahn School of Medicine at Mount Sinai collected portmortem brain samples from people with preclinical Alzheimer’s disease, as well as healthy controls, and used an advanced laser-capture technology to analyze the gene expression in their neurons. They then constructed computational models to predict which patterns of gene expression were associated with Alzheimer’s disease. They noticed that many of these genes that had different expression in the Alzheimer’s brains played a role in immune system’s response to viral infection.

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This figure from the paper illustrates how researchers employed computational models to connect viral infection rates with the signatures of Alzheimer’s disease.

To further investigate this viral connection, the researchers analyzed the levels of viral RNA in each of the brain samples. They found that the Alzheimer’s brains had significantly more RNA from two types of human herpes viruses (HHV): type 6A and type 7. (Note that HHV is not to be confused with human simplex virus [HSV], which is a sexually transmitted infection.) This suggests that people with Alzheimer’s disease have higher rates of HHV infection in their brains.

Furthermore, they found that the viral infections could perturb many genes that are linked to the development of Alzheimer’s disease, including BACE1, which helps create the sticky plaques that are characteristic of the Alzheimer’s brain. HHV-6A also decreases expression of a microRNA gene called miR-155. When they created mice that lacked expression of miR-155, these mice developed Alzheimer’s plaques in their brains, suggesting that this gene could be an important link between herpes infection and Alzheimer’s.

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This figure from the paper shows the complex network of genes that may link herpes virus infection with the development of Alzheimer’s disease.

This study is different from previous ones in several ways. It includes a large sample size from throughout the United States, which provides higher statistical rigor to the conclusions. It also suggests a possible mechanisms by which viral infections could contribute to the development of Alzheimer’s disease via disruption of neuronal gene expression. The results support the intriguing possibility that the toxic amyloid-beta protein, which has long been thought to be the primary cause of Alzheimer’s disease, could actually be a beneficial response to viral infection, a theory that I described in a previous article. While this study is not yet conclusive proof that herpes infection can directly lead to Alzheimer’s disease, it opens that door for many interesting new avenues for research that should be investigated further.

A connection between herpes and Alzheimer’s disease is both troubling and encouraging. HHV types 6 and 7 are extremely common, with nearly 100% of individuals infected by age 3. Most of us are likely infected as infants through the saliva of our parents or other relatives. After the initial infection, the virus becomes latent and remains circulating in the bloodstream for life. For most of us, HHV-6 and HHV-7 infections are completely asymptomatic. However, as we grow older, our immune systems weaken, allowing these viruses to travel from the bloodstream to the brain. Some reports suggest that the resulting neuroinflammation could contribute to common age-related neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases.

Yet these results also offer hope. If microbial infections such as HHV are the initial cause of Alzheimer’s disease, this suggests that we could treat the disease using immunosuppressant or antiviral drugs. Should future studies confirm this to be true, this could be a huge boon for the development of effective Alzheimer’s therapies.

 

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The Villain of Alzheimer’s Disease Could Actually Be a Hero

The toxic amyloid-beta protein has long been considered the cause of Alzheimer’s disease–but what if it’s actually been a hero all along?

If you were to look inside the brain of someone with Alzheimer’s disease, you’d immediately see that something has gone terribly wrong. The first thing you’d notice is that it’s much smaller than a healthy brain, appearing shriveled up like a raisin. Upon closer examination, you’d see that the brain is filled with large, dark clumps of protein. That protein, called amyloid-beta, can stick to itself and form toxic aggregates that poison the brain from within. Your first instinct would probably be the same as most scientists: in order to cure Alzheimer’s disease, we need to get rid of these amyloid-beta clumps.

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Artistic rendition of amyloid-beta plaques surrounding neurons in the brain. Image Source

It’s a reasonable assumption. These clumps of amyloid-beta, formally known as senile plaques, are among the most recognizable hallmarks of Alzheimer’s disease, and they’re toxic to brain cells in high doses. So it makes sense to think that getting rid of them will be the key for curing Alzheimer’s.

For three decades now, that’s exactly what scientists have been trying to do. They created drugs that targeted and destroyed amyloid-beta, or prevented it from being formed in the first place. They invented vaccines to help our own immune systems recognize amyloid-beta, and inhibitors that stopped amyloid-beta from sticking together to form toxic clumps. Yet, despite hundreds of scientists and billions of dollars devoted to the research, these efforts failed. Of the more than 200 drug candidates for Alzheimer’s disease that have reached clinical trials in the past 30 years, not a single one successfully cured the disease or slowed its progression. The drugs currently on the market for Alzheimer’s disease offer some patients a small improvement in their cognitive symptoms, but since they do not treat the underlying pathology, their effects are temporary and they cannot prevent the patient’s deterioration.

Even worse than the poor efficacy of these drugs were the severe side effects they often created. Many patients involved in these trials developed a condition called Amyloid-Related Imaging Abnormalities (ARIA), which results from leaky blood vessels bleeding into the brain. Other patients experienced dangerous infections or skin cancer, and a few even saw their cognition decline faster than patients who weren’t taking the drug at all.

The disastrous results of these clinical trials have shaken the field of neuroscience to its core. A few companies, including the pharma giant Pfizer, have even given up their Alzheimer’s research programs entirely. Yet I would argue that there is still hope for a cure to Alzheimer’s disease, and it lies by viewing the toxic amyloid-beta protein in a new light. In fact, I think that amyloid-beta might actually turn out to be a powerful ally in the fight against Alzheimer’s.

The Evolutionary Riddle of Amyloid-Beta

I’m a geneticist by training, and that means I think a lot about evolution. And so the first question that came to my mind when I first learned about amyloid-beta was, why do we have it in the first place? After all, the core premise of natural selection is that harmful traits tend to disappear from a population over evolutionary time. If amyloid-beta is nothing more than a toxic substance that makes us sick, then we’d expect it to become rarer as our species evolved, and eventually disappear completely.

Yet when you actually look at the data, the opposite seems to be true. In fact, every vertebrate species (including mammals, birds, and reptiles) produces a version of amyloid-beta that’s almost identical to our own. It’s even been found in sea anemones and hydra, meaning that amyloid-beta has been around for at least 600 million years.

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The hydra, a tiny invertebrate often found in ponds, has its own version of amyloid-beta. This suggests that the protein has been remarkably conserved across evolutionary time. Image Source

From an evolutionary perspective, this makes no sense. Why would a toxic, harmful protein have been conserved for so many years across such diverse species? The most likely explanation is that there’s more to amyloid-beta than meets the eye. Specifically, it must be serving some kind of beneficial purpose that’s caused it to be maintained for so long.

The idea that amyloid-beta could actually serve some kind of biological function was originally met with controversy, but as more evidence has emerged, the scientific community has begun to accept this shift in view. In fact, the more we look at amyloid-beta, the more functions we seem to uncover.

The Hero We Never Knew We Had

The beneficial roles of amyloid-beta have become something of a fascination for me. One of its coolest functions is within the immune system. Amazingly, the properties that allow amyloid-beta to aggregate into toxic clumps in the brains of Alzheimer’s patients can also be used to trap harmful microbes, preventing them from spreading. Once the microbes are stuck, amyloid-beta can kill them by tearing holes in their cell membranes. In fact, amyloid-beta’s chemical properties suggest that it’s part of a family of immune proteins called antimicrobial peptides, which all utilize a similar manner of clumping and ripping microbes to protect the body from infection.

In addition to its role in the immune system, amyloid-beta has many other functions. Some research suggests that it may suppress the growth of cancer cells, which could explain why people with Alzheimer’s disease tend to have a lower risk of developing cancer. Others propose that amyloid-beta could help prevent leaks in the brain’s blood vessels by clumping into a kind of “scab” that restricts bleeding. It also seems to be helpful in recovery from neuronal injuries, as mice that are unable to produce amyloid-beta have worse outcomes from traumatic brain injuries, spinal cord injuries, strokes, and even multiple sclerosis. Finally, recent evidence has suggested that amyloid-beta helps to regulate the signaling activity of neurons, which is extremely important for learning and memory.

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This figure, adapted from our recent publication in Frontiers in Aging Neuroscience, summarizes some of amyloid-beta’s possible roles in human biology.

In light of amyloid-beta’s newly-discovered functions, the side effects that occurred in Alzheimer’s clinical trials begin to make more sense. By removing amyloid-beta from the patients’ brains and bodies, these drugs may have inadvertently led to ARIA, infections, and other harmful outcomes.

A New Dawn for Alzheimer’s Research

So what do the beneficial roles of amyloid-beta mean for the future? Well, if the last 30 years of clinical trials tell us anything, it’s that our current approaches aren’t working, and the functions of amyloid-beta may explain why.

Of course, the fact remains that amyloid-beta is toxic to neurons, and it tends to accumulate within the brains of Alzheimer’s patients. But I would argue that getting rid of amyloid-beta outright is not the answer. Instead, we need to consider what might have caused it to start accumulating in the first place.

For example, maybe the amyloid-beta clumps are actually a protective barrier surrounding infectious microbes that have infiltrated the brain, or a scab that prevents blood from leaking into the brain. As we get older, brain infections and leaky blood vessels become more common, which might explain why amyloid-beta levels tend to increase over time. Perhaps after a certain threshold, the amyloid-beta that’s responding to these issues becomes more harmful than helpful to the brain. It’s doing its job too well–there are too many microbes or leaky blood vessels for amyloid-beta to clump around without its toxic properties damaging the brain in the process.

We can’t just get rid of amyloid-beta at this stage, because then the microbes or vascular leaks that it was protecting us from in the first place will be left unchecked. Instead, we need to first treat the underlying cause of the problem. Only once that has been resolved can we then go back with anti-amyloid-beta drugs and remove the toxic clumps from patients’ brains.

I want to be entirely clear here: at this point, everything I’ve said in this last section is pure speculation. We don’t know if all amyloid-beta plaques are caused by some other factor, or whether resolving that factor will make our drugs more effective. However, a few early studies have provided tantalizing hints that this hypothesis may be correct. For example, one study found that among Alzheimer’s patients who were infected with H. pylori, a common type of bacteria that causes stomach ulcers, treating this infection with antibiotics resulted in a 65% lower risk of Alzheimer’s progression after one year.

The study of amyloid-beta’s biological functions is still in its infancy, and we have a lot to learn about the true role that it plays in Alzheimer’s disease. But if additional research can confirm that amyloid-beta is a side effect of the disease instead of its root cause, it could usher in a new age of Alzheimer’s research and bring us one step closer to finding a cure.

 

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Genetic Evidence Suggests Iron is Linked to Alzheimer’s Disease

According to a recent study, people with a rare variant in the HFE gene are three times less likely to develop dementia than the general population.

You’ve probably heard that consuming enough iron is important for overall health. However, too much iron can also be a bad thing. In particular, people with Alzheimer’s disease often have abnormally high levels of iron in their brains. (See The Role of Metals in Alzheimer’s Disease). The question of whether iron is a cause or consequence in Alzheimer’s still remains unanswered.

In a paper published this week in PLoS One, a group of Italian researchers investigated whether the genes that control levels of iron in the body could be related to the risk of dementia. They recruited 765 subjects who had Alzheimer’s disease, vascular dementia, or mild cognitive impairment, as well as 1,086 healthy controls of a similar age. Then they took DNA samples from the subjects and looked at four different genes that are involved in iron metabolism.

They found that one gene called High Ferrum (HFE), which is responsible for controlling absorption of iron from the blood, was protective against dementia. Specifically, subjects who had a particular variant of the HFE gene were one-third as likely to develop Alzheimer’s disease or vascular dementia compared to subjects who didn’t have the protective variant. The effect was even stronger for mild cognitive impairment, which the HFE variant reduced the risk to only one-fifth.

The researchers then looked at another gene called APOE, which has previously been shown to be involved in Alzheimer’s disease. People with the APOE4 variant of this gene were more than four times as likely to have Alzheimer’s. However, in subjects who also possessed the protective HFE variant, the impact of APOE4 was completely attenuated, and their risk of Alzheimer’s was normal.

How could the HFE gene protect people from dementia? One possibility, known as the metal hypothesis of Alzheimer’s disease, suggests that iron makes amyloid-beta plaques more toxic. Amyloid-beta, a protein that accumulates in Alzheimer’s patients’ brains, can interact with various metal ions to become extra toxic. Normally metals are blocked from entering the brain by the blood-brain barrier, but this barrier tends to become leaky in older people. Thus the hypothesis suggests that influx of iron and other metals into the brain may cause amyloid-beta to aggregate and become more toxic, thus contributing to the development of Alzheimer’s.

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The metal hypothesis suggests that the toxicity of beta-amyloid could be increased when it binds to metal ions. Image Source

However, the metal hypothesis can’t entirely explain these recent findings. For one thing, the variants in iron-controlling genes were also protective against vascular dementia, which does not involve amyloid-beta. In addition, the researchers did not observe any differences in blood iron levels based on these genetic variants, so it’s unclear exactly how these genes may be affecting iron metabolism. Future studies are needed to clarify if and how iron could be involved in Alzheimer’s and other types of dementia.

 

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What is the difference between dementia and Alzheimer’s disease?

This is probably the most common question I’m asked by my readers, so I decided to devote an entire article to clearing up the confusion. Doctors and scientists often throw around words like “dementia,” “Alzheimer’s,” and “mild cognitive impairment” without making it clear what the difference is between them. Understanding what each of these terms mean is important for being able to interpret articles and recognize how scientific findings may apply to you.

Let’s start with dementia. Dementia itself is actually not a disease, but a set of symptoms. The most well-known dementia symptom is memory loss, but it also includes other things such as difficulty communicating, impaired attention, poor judgement, and a decline in visual perception.

Dementia symptoms can be caused by many different diseases. The most common cause of dementia is Alzheimer’s disease, which makes up around 60% of all dementias. However, many other diseases can cause dementia, including Parkinson’s disease, vascular dementia, frontotemporal dementia, and Lewy body disease. Dementia is often referred to as an “umbrella term” for a range of symptoms than can be caused by multiple diseases.

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Dementia is an “umbrella term” for a set of symptoms that can be caused by several different diseases. Image Source

I like to use an analogy to make this distinction a bit clearer. Think of Alzheimer’s disease like the flu. These are both diseases with a particular cause. Now think of some of the symptoms of having the flu: congestion, chills, nausea, and so on. There are many different diseases that can cause these symptoms, like a cold or sinus infection. In the same way, there are multiple diseases that can cause dementia symptoms.

To put it another way: everyone with Alzheimer’s disease has dementia, but not everyone with dementia has Alzheimer’s disease.

Now, there’s a third term you may have also heard thrown around: mild cognitive impairment, or MCI. It’s characterized by memory problems that are noticeable but not severe enough to interfere with daily life, such as forgetting appointments, losing your train of thought, and having trouble with planning or organization. Some people with MCI later progress to Alzheimer’s disease or other dementias, while others do not. Around 20% of adults over age 65 have MCI.

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Mild cognitive impairment sometimes progresses to Alzheimer’s disease or other dementia-causing diseases. Image Source

So there you have it! To summarize:

  • Dementia is a set of symptoms that include memory loss, impaired attention, and and poor judgement.
  • Alzheimer’s is one of several diseases that can lead to dementia symptoms.
  • Mild cognitive impairment is a less serious memory problem than can, but does not always, progress to dementia.

Hopefully that helps to clear up some of the confusion surrounding these three terms! As always, feel free to comment or send me a message if there are any other topics you’d like me to explain.

 

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Dementia Patients’ Awareness of their Own Illness May Predict Cognitive Decline

According to new research, anosognosia (“lack of self awareness”) may be used to predict whether patients with mild cognitive impairment will progress to Alzheimer’s disease.

Anosognosia describes the inability to recognize that one is experiencing a mental illness. It is most well-known in schizophrenia, where patients frequently cannot acknowledge that their delusions are the result of a mental condition and not based in reality. However, anosognosia can also occur with dementias, such as Alzheimer’s disease. In later stages of the disease, people with Alzheimer’s may lose their ability to recognize their own cognitive deficits.

In a paper published this week in Neurology, researchers from McGill University wanted to assess whether anosognosia could be used to predict whether patients with mild cognitive impairment would later progress to Alzheimer’s disease. Mild cognitive impairment (MCI) is a condition that affects nearly 20% of adults over 65. It is characterized by memory problems that are noticeable but not severe enough to interfere with daily life. Some people with MCI later progress to Alzheimer’s disease, while others do not, and we currently do not have a reliable method to predict whether a person with MCI will develop Alzheimer’s.

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Mild cognitive impairment sometimes progresses to Alzheimer’s disease or other types of dementia. Image Source

The study included a total of 468 MCI patients recruited through the Alzheimer’s Disease Neuroimaging Initiative, a large consortium of researchers searching for reliable ways to predict and diagnose Alzheimer’s. The researchers looked at the subjects’ cognitive self-assessment and compared it to their spouse or caregiver’s assessment of the patient’s cognition. Individuals who rated their own cognition substantially higher than what their caregiver rated them were categorized as anosognosic.

The researchers then administered spinal taps on each subject. They found that the anosognosic patients had higher levels of the toxic tau protein in their cerebrospinal fluid. These patients also had higher levels of amyloid-beta in their brains. Additionally, PET scans revealed that the patients lacking self-awareness had reduced levels of activity in a part of their brains called the default mode network. The default mode network is a group of brain structures that become less active when you’re focusing on a particular task, and more active when you’re daydreaming. Studies have found that the default mode network is among the first parts of the brain to degenerate in Alzheimer’s disease, but its specific role in the disease still remains unclear.

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This fMRI image shows the brain structures that make up the default mode network. Image Source

The final phase of the study involved a follow-up examination two years after the initial assessment. The researchers found that 28% the subjects with anosognosia progressed to Alzheimer’s disease, compared to only 12% of those with intact self-awareness. This shows that assessing MCI patients’ awareness to their own cognition could be a useful tool for predicting whether they will later develop Alzheimer’s disease. The study also suggests that the default mode network might be important for our ability to recognize our own mental status.

 

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Amyloid-Beta: Villain or Hero in Alzheimer’s Disease? (Podcast)

Last week I was interviewed on Straight from a Scientist, a podcast series where scientists talk about their research for a general audience. In Part 1, which you can listen to here, we had an informal conversation about my research and background. You can now listen to Part 2, a roundtable segment where the host, Connor Wander, and I discuss current topics in Alzheimer’s disease research, including a new look at the physiological roles of amyloid-beta. Enjoy!

 

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