Computer Algorithm Diagnoses Alzheimer’s Disease from Brain Scans

Alzheimer’s disease is notoriously difficult to diagnose. Its symptoms are very similar to other conditions like Parkinson’s disease and vascular dementia (and may even occur simultaneously in some patients), making the task of diagnosing a patient’s condition challenging for physicians. An even more difficult task is predicting whether an individual with mild cognitive impairment will later progress to Alzheimer’s disease. Even advanced techniques have poor predictive power. Positron emission tomography (PET), a type of brain scan that measures the energy consumption of different brain regions, has only a 57.2% rate of accuracy.

To address this dilemma, a team of Canadian and South Korean scientists tested five different computer algorithms for their accuracy in diagnosing or predicting Alzheimer’s disease. Their results were published this week in Scientific Reports.

The researchers used a database of PET scans from the Alzheimer’s Disease Neuroimaging Initiative to train the computer models. Their study included 94 patients with Alzheimer’s disease and 111 age-matched healthy patients. They found that one model, called the Support Vector Machine with Iterative Single Data Algorithm (SVM-ISDA), could distinguish the Alzheimer’s patients from healthy controls with 80% accuracy.

The researchers then tested the performance of the computer models on three different PET scan databases. This time, rather than distinguishing Alzheimer’s disease from healthy patients, they wanted to see whether the models could predict whether individuals with mild cognitive impairment would develop Alzheimer’s disease within the next 3 years. Here the SVM-ISDA once again came out on top, though its predictive power was lower than for the previous task. The model predicted which patients would develop Alzheimer’s disease with an overall accuracy of around 51-59%. The other algorithms all had less than 50% accuracy.

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PET scanners like this one measure how much energy is consumed by different brain regions.

They next wanted to see whether the computer models could distinguish Alzheimer’s disease from two other types of dementia: Lewy body disease and Parkinson’s disease. These conditions are both frequency misdiagnosed as Alzheimer’s disease. They found that in patients who had Parkinson’s disease but had not yet developed dementia, the computer models could distinguish between Alzheimer’s and Parkinson’s. However, for patients with Lewy body disease or Parkinson’s disease dementia, the models could not distinguish them from Alzheimer’s disease.

The conclusion for this study was that the SVM-ISDA is the most accurate computer model for diagnosing and predicting dementia based on PET scans. However, while the model performed fairly well in diagnosis, its ability to predict Alzheimer’s disease in patients with mild cognitive impairment was barely more than 50%, and it couldn’t distinguish Alzheimer’s from other forms of dementia.

This highlights how much research is still needed to be able to predict patients’ prognosis. Earlier diagnosis could mean earlier administration of treatments, which might make them more effective in slowing or preventing the onset of Alzheimer’s disease. It would also allow patients and their families more time to plan for the future.

 

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What “Childhood Alzheimer’s Disease” Can Teach Us About the Brain

Niemann-Pick disease type C (NPC) is a condition you’ve probably never heard of. It’s an extremely rare disease, occurring in approximately 1 in 100,000 live births. But despite its rarity, the strange connections between NPC and a much more common condition, Alzheimer’s disease, are now leading researchers to consider how the connected mechanisms of these two diseases may help us in our search for a cure.

What Is Niemann-Pick Disease?

Children with NPC, including Addison and Cassidy Hempel shown in this article’s top image, typically appear normal until reaching middle to late childhood. Around that age, they begin experiencing subtle symptoms such as clumsiness, poor handwriting, and impaired speech. Some children lose the ability to move their eyes up and down or side to side. These problems gradually worsen over time, with affected children eventually losing the ability to speak or swallow. They may also develop seizures, involuntary muscle contractions, or other movement disorders.

Perhaps even more tragic than the physical symptoms are the effects of NPC on the brain. Children with this condition experience a progressive loss of memory and cognition, which has led to the disease’s unofficial name of “childhood Alzheimer’s disease.” Eventually, after a decline that can last many years, these children succumb due to respiratory failure or severe seizures. There is currently no effective cure or treatment.

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These images from the National Niemann-Pick Disease Foundation show the tragic progression of this disease in a child.

The Cholesterol Connection

NPC is caused by a mutation in one of two genes, known as NPC1 and NPC2. These genes are necessary for cells to be able to process and transport cholesterol. While cholesterol is often seen as something to avoid in our diets, we actually require a small amount of it to survive. Our cells need cholesterol to create new membranes or synthesize steroid hormones. When we consume cholesterol, it gets engulfed in cellular compartments called lysosomes, where it is processed and later released into the cell membrane. In people with NPC, cholesterol can’t be properly processed, so it gradually accumulates inside their lysosomes, especially within neurons. With all their cholesterol trapped, the neurons eventually begin to degenerate and die.

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This image shows the spleen of a patient with NPC. The white blobs are large accumulations of cholesterol. Image Source

NPC is an extreme example of what can happen when cholesterol metabolism goes awry. However, it’s not the only neurological disease that cholesterol plays a role in. People with Alzheimer’s disease, the most common form of dementia, tend to have higher levels of cholesterol in their brains than healthy controls. This may result in increased production of amyloid-beta, a toxic protein that’s considered one of the main causes of Alzheimer’s disease. Interestingly, patients with NPC also show increased levels of amyloid-beta in their cerebrospinal fluid, as well as the accumulation of tau (another toxic protein related to Alzheimer’s disease) inside their brains.

The connections between NPC and Alzheimer’s disease don’t stop there. Studies have found that mutations in NPC1 and other genes involved with cholesterol metabolism lead to an increased risk of Alzheimer’s disease. This suggests that cholesterol could be a key contributor to the neurodegeneration that occurs in both Alzheimer’s disease and NPC.

Where We Go From Here

Rare diseases like NPC are largely ignored by pharmaceutical companies, simply because they aren’t common enough for the research and development of a drug to turn a profit. While each of these diseases by itself is extremely uncommon, because there are thousands of different conditions out there, it’s estimated that 25 million Americans suffer from a rare disease. Most of these have no effective treatment.

Studying rare diseases may not be profitable, but they’re still incredibly important. As previously discussed in a fantastic SciShow video, rare diseases can often provide insight into the causes of more common conditions that share the same underlying mechanism. NPC and Alzheimer’s disease provide just one example of how researching cures for a disease that affects only a few thousand people worldwide could help us to learn about another condition that kills millions every year.

 

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How Music Impacts Alzheimer’s Patients

This article is a guest post by Carolyn Ridland, the founder of CaregiverConnection. You can read more about Carolyn at the bottom of this page.

It is challenging to watch a loved one go through problems with memory and thinking and exhibit behavioral changes that are characteristic of Alzheimer’s disease. Even more challenging is the fact that the condition develops very gradually until a point reaches where the patient cannot coordinate the normal day to day activities. While it might be impossible to treat the condition, there is a spectrum of therapies that have been suggested and deemed very useful in reversing the progression of the disease. One of these therapies is the use of music. Many people who have a loved one with the condition are glad to try anything that might work, but the important question is, how does music affect the function of the brain, and what impact will it have on a patient with Alzheimer’s?

How does Alzheimer’s affect the brain?

Most people think that Alzheimer’s and dementia, in general, are a regular component of the aging process. However, it is not a normal part of aging, despite that its greatest risk factor is age. There are people who start exhibiting symptoms of Alzheimer’s disease before they reach 65, which is known as early-onset. It is known that the brain typically shrinks with age, but it does not typically lose its neurons; this is not the case with Alzheimer’s patients. In fact, as they age, the neurons get destroyed, and this widespread damage makes most neurons lose their connections with each other, impairing metabolism, communication and repair (Jacobsen et al., 2015). The disease eats away at the brain function until the person can hardly function. While there is no known cure for Alzheimer’s, early detection and the use of the right therapies can help in slowing down the effects of the disease.

Music therapy for Alzheimer’s patients

Studies have shown that when patients who suffer from Alzheimer’s are led through songs that they recognize, their cognitive abilities are boosted, and they are able to recall memories and emotions tied to the songs. When participants with Alzheimer’s took a test on cognitive ability and life satisfaction, those that listened or sang during the test scored better in the test. Here are ways in which music could be beneficial to your loved one with Alzheimer’s.

Music evokes emotions that are attached to memories

Everyone has music pieces which are attached to very specific memories. These tied connections stay in the brain for decades, and the moment that the song is played, the attached emotions come flowing back, bringing with them the attached memories. Since a patient with Alzheimer’s is already having a hard time dealing with their memories, there is no better ways to trigger them than to play their favourite songs.

Musical aptitude and appreciation is the brain ability that stays the longest

As mentioned, people who suffer from Alzheimer go through a gradual loss of their cognitive abilities until their brain function completely deteriorates. However, the great news is that as the other abilities fade away, the ability to remember and appreciate music and the attached memories remains much longer than many others. This means that you can use music as a way of connecting with your loved one when they can no longer discuss their childhood or the memories which you made together. In addition, by playing music, you will make the person feel that they are still good at something, which makes them feel good.

Singing becomes a hobby

There is nothing that is more frustrating to a person with Alzheimer’s than the knowledge that they knew how to do something such as playing chess, but for some reason, they no longer can do it. Well, if your loved one’s condition has gotten to the point where they no longer remember these activities which they once used to enjoy, think about introducing music because it brings along fun games such as karaoke, sing along, and dancing games. Research shows that a simple act of watching music stimulates certain areas of the brain, which helps the patients exercise and polish their mind-power.

Music as a mood booster

People who have dementia tend to have a constant feeling of the blues and lots of episodes of stress induced agitation. Music has the ability to calm the listener’s nerves, elevate their mood and stimulate positive interactions with others. The good thing about music and especially the instrumental part of it is that it does not need a lot of cognitive processing, which means that it will not need a person with dementia to use their cognitive function to enjoy.

How to select the right music

The mental health and cognitive benefits that patients with Alzheimer’s get from listening to music are endless. It is therefore important to make sure that you include it in their daily routine. When choosing music for a loved one, always consider the following factors:

  • Consider the preferences that your loved one used to have. Using music as a mood booster will only work when the music is something the person can relate with.
  • To set the mood using music, play slow and mellow tunes when you want them to wind down and sleep. On the other hand, when you want them to get active, play faster beats.
  • Encourage movement when playing the music by inviting the person to dance with you or asking them to sing along.
  • When you are playing the music, try your best to cancel out all other sources of noise as you do not want to overstimulate their brain and agitate them.
  • Pay attention to the response which they give to each type of music. The response is what will guide you towards ticking the songs they like and eliminating those that they do not.

Those are a few important things to know about the use of music to help Alzheimer’s patients cope better with their condition and enjoy life. Keep looking for creative ways to incorporate music into their day to day life, and this may even help them hold on to their memories for an even longer time.

 

Middle Aged Woman Smiling With Hands On CheeksThis article is a guest post by Carolyn Ridland, the founder of CaregiverConnection. About 10 years ago, her parents began reaching the point where they could not be self-sufficient anymore. She was just married with two toddlers, so she felt like she couldn’t take them in, yet she wanted to make sure they were taken care of. Carolyn wanted to share her story, and to let others know that they are not alone if they are in a similar position. Children are expected to take care of their elderly parents when the time comes, but it’s not always that easy. Caregiver Connection emerged from a place of real love and compassion. They understand the struggle that exists when you care deeply about your loved ones, but you’re faced with decisions you never wanted to make. Their main message is that nobody should have to face these times alone.

 

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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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