Category Archives: Alzheimer’s In the News

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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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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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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Brain “Gatekeeper” Cells Could Cause Half of All Dementia Cases

Pericytes are a type of brain cell you’ve probably never heard of. But according to new research, these hard-working cells may be your brain’s most important defense against dementia.

Your brain, as you may know, is composed of grey matter and white matter. Grey matter mostly consists of the central regions, or “cell bodies”, of neurons, forming the outer layer of the brain. White matter is made of axons, which are long extensions that neurons use to send electrochemical signals to each other, kind of like telephone wires. Leaks or blockages of the brain’s arteries, known as cerebral small vessel disease (CSVD), can damage the surrounding white matter. Research has shown that CSVD contributes to 50% of all dementia cases, including Alzheimer’s disease.

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Neuronal cell bodies form the grey matter on the outside of the brain, while the inner white matter layers are made of long extensions called axons. Image Source

That brings us to the key player in this story: pericytes. These humble cells aren’t a part of our common vocabulary, but that doesn’t make them unimportant. Pericytes surround the blood vessels in your brain, maintaining the arterial wall and controlling the rate of blood flow. They also serve as “gatekeepers” by helping to regulate what can cross the blood-brain barrier. And now, thanks to research published this week in Nature Medicine, we now know of a new function for these little-known pericytes: protecting brain’s white matter from damage.

 

The researchers in this study first looked at postmortem brain tissues from 31 different people. They saw that the people with Alzheimer’s disease had 50% fewer pericyes than the healthy controls. As a result, the Alzheimer’s brains contained three times as much fibrinogen as the healthy brains. Fibrinogen is a protein found in the blood plasma, and its presence in the brain indicates the existence of capillary leaks. In other words, it seemed that the Alzheimer’s patients had leaky blood vessels in their brains, possibly as a result of having fewer pericytes. These leaks caused the Alzheimer’s brains to have substantially more white matter damage than the healthy brains.

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Pericytes, shown here in green, surround blood vessels in the brain and help to guard against damage. Image Source

To understand the mechanisms by which this might occur, the researchers then turned to experiments on laboratory animals. They utilized mice that had a mutation causing them to develop fewer pericytes than normal. Sure enough, these mice soon developed leaky capillaries, as evidenced by high levels of fibrinogen in their brains. The levels of fibrinogen progressively worsened with age. The mutant mice also had 30-40% fewer fibers within the white matter than non-mutant counterparts by the time they were 36-48 weeks old (which is middle-aged for a mouse). These results showed that the loss of pericytes was sufficient to cause leaks in the blood-brain barrier and white matter damage.

Next, the researchers analyzed whether this white matter damage had any functional effects on the mice’s behavior. They found that the mutant mice that were deficient for pericytes performed well at a young age, but began to show impairments on memory tests as they grew older. The older mice also had significant cell death in the hippocampus, the part of the brain responsible for long-term memory formation.

The final experiment was to determine whether treating the mice with capillary-strengthening drugs could reverse the defects caused by a lack of pericytes. Their drug of choice was ancrod, a substance derived from the venom of the Malayan pit viper. Ancrod by itself is not poisonous, and it has the interesting property of being able to prevent leaks in the brain’s capillaries. When the mutant mice were treated with ancrod, their blood-brain barriers were substantially less leaky and they also had less white matter damage.

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Ancrod, derived from the venom of the Malayan pit viper, could one day be used to fortify leaky brain capillaries and prevent the development of dementia. Image Source

The results of this study are exiting, because they suggest that dysfunctional pericytes could be one of the earliest factors leading to the development of Alzheimer’s disease. Furthermore, the white matter damage that contributes to 50% of all dementias could possibly be preventing by strengthening the integrity of our brain capillaries. In 2009, clinical trials using ancrod to repair brain capillary damage in ischemic stroke patients were terminated due to ineffectiveness of the drug. However, this study shows that it might be beneficial for dementia as well, and will need to be investigated in future trials.

 

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Anxiety and Depression May Be Early Signs of Alzheimer’s Disease

Though most people with Alzheimer’s disease aren’t diagnosed until after age 65, the disease can begin in their brains years or even decades before that. For this reason, scientists have been trying to identifying biomarkers that will allow us to diagnose Alzheimer’s at an earlier stage, prior to the onset of cognitive symptoms.

In a study published last week in The American Journal of Psychiatry, researchers from Harvard University examined 270 subjects aged 62 to 90, all of whom lived in a retirement community and initially showed no signs of cognitive impairment or mental illness. The subjects were given a test for geriatric depression and a PET scan of their brains annually for five years.

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Researchers used a PET scanner like this one to examine amyloid-beta levels in the subjects’ brains.

At the beginning of the study, participants who had depression had higher levels of amyloid-beta, a toxic protein linked to Alzheimer’s disease, in their brains. Furthermore, participants with higher amyloid-beta levels at baseline had steeper increases in their geriatric depression scores after five years. These results suggest that a sudden development or worsening of depressive symptoms could be a sign of early Alzheimer’s disease.

Next, the researchers looked at the participants’ subscores for different sections of the depression test. They found that only the anxiety subscore was correlated with amyloid-beta levels. The other two subscores, which relate to apathy and unhappiness, had no relationship to amyloid-beta. This suggests that anxious-depressive symptoms are the strongest predictor of early Alzheimer’s disease.

It’s difficult to determine from this study whether anxiety or depression could lead to Alzheimer’s disease, or if instead preclinical Alzheimer’s causes anxiety/depression. It’s likely that there are many other factors at play, such as social interaction, diet, and exercise levels. Additionally, the small sample size prevents us from drawing broad conclusions. However, the authors of the study are currently working on a follow-up analysis of these subjects, which should illuminate whether the people with higher amyloid-beta levels went on to be diagnosed with Alzheimer’s disease.

In the meantime, if you or a loved one notices a sudden increase in anxious-depressive symptoms, this should be taken seriously and brought up with a doctor. An earlier Alzheimer’s disease diagnosis, prior to the development of dementia, may allow our drugs to act more effectively and slow the rate of cognitive decline.

 

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Could Young Blood Cure Alzheimer’s Disease?

You may have heard the buzz lately about research surrounding the use of young people’s blood to treat Alzheimer’s disease. The latest findings were presented at the recent Clinical Trials on Alzheimer’s Disease conference, as reported by TIME Magazine. After previous studies showed that injecting an old mouse with the blood of a younger mouse (a process called parabiosis) caused improved memory and cognition, neuroscientists have been curious to see whether the same effect could be true in humans.

A group of researchers from Stanford conducted a small clinical trial to test this idea. They recruited 18 elderly volunteers and injected them weekly with young people’s blood plasma (taken from a local blood bank) or a placebo over the course of four weeks. They found that those receiving the young plasma treatments showed significantly enhanced measures of independence, including ability to shop for themselves or balance their own checkbook. No harmful side effects were noted.

The researchers did not study the subjects’ memory or cognitive ability as part of the trial, but these measures are being planned for future studies with a larger sample size. While still very preliminary, this small trial does suggest that there could be some factors in young people’s blood that could improve cognition in older people. While it’s far too early to start storming the blood banks demanding a transfusion, the link between our brains and our blood suggests that we need to be paying particular attention to our cardiovascular health as we age.

 

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