One-Month Hiatus from AlzScience

Hi everyone! Thanks for your amazing support for AlzScience thus far. I wanted to let my subscribers know that I will be taking a brief hiatus from AlzScience during the month of May. I’m taking a backpacking trip across Europe and won’t have the time or the internet access to post articles regularly. (To follow me on my journey, check out my travel blog, Brains and Backpacks.) At the end of May I’ll begin a summer internship in Switzerland, where I’ll be able to resume writing articles. Until then, stay curious!

Homocysteine and Dementia: Impact of Nutrition on Neurodegeneration

This week’s article is a guest post by Dr. Nafisa Jadavji, a research associate and lecturer at Carleton University and the University of Ottawa. To submit your own guest post to AlzScience, please contact us.

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High levels of homocysteine have been implicated in neurodegenerative diseases, such as dementia, mild cognitive impairment, and Alzheimer’s disease. Homocysteine can be measured in blood easily, which has led to several studies in humans reporting that elevated levels of homocysteine lead to increased risk of developing neurodegenerative diseases or affect progression. Interestingly, homocysteine levels in our bodies increase as we age.

Vascular cognitive impairment (VCI) is the second leading cause of dementia after Alzheimer’s disease.  VCI is the result of reduced blood flow to the brain, however, the pathology is not well understood. Reduced blood flow ben be a result of age and health (e.g. high cholesterol). The clinical presentation of VCI varies, most the patients have some degree of cognitive decline. There are currently no treatments for VCI since the actual pathology remains unknown.

Nutrition is a risk factor for VCI, specifically high levels of homocysteine. High levels of homocysteine can be reduced by B-vitamins, like folates or folic acid. Folates are the natural occurring form of the vitamin, these are often found in food such as green leafy vegetables or liver. Whereas folic acid is the chemically synthesized form that is often taken in supplemental form.

My research program focuses on how nutrition affects the brain, specifically how folates affect neurodegeneration.

Using a mouse model of VCI we have reported that deficiencies in folates, either dietary or genetic, affect the onset and progression of VCI. Using the Morris water maze task, we report that mice with VCI and folate deficiency performed significantly worse compared to controls. We assessed changes in the brain using MRI and interestingly found that folate deficiency changed the vasculature in the brain of mice with VCI. Because of either a genetic or dietary folate deficiency, all the mice had increased levels of homocysteine. However, we did not observe any significant association between elevated levels of homocysteine and behavioral impairment or changes in the brain tissue of VCI affected mice.

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In the Morris water maze, a mouse is placed in a pool and must swim to find a hidden platform. The mouse’s memory is measured based on how long it takes to find the platform after it’s placed in the pool a second time. Image source

Our results suggest that it is not elevated levels of homocysteine making the brain more vulnerable to damage, but the deficiency in folates, either dietary or genetic that changes the brain. In the cell, folates are involved in DNA synthesis and repair as well as methylation. These are vital functions for normal cell function. Therefore, reduced levels of folate may be changing the cells in the brain and making them more vulnerable to any types of damage. I would like to suggest that high levels of homocysteine may just be out put measurement of some sort of deficiency (e.g. reduced dietary intake of folates). Several studies using brain cells that are grown in petri dishes have reported that extremely high levels of homocysteine need to be added to cells to cause damage. These levels are usually not observed in humans.

In terms of future directions, more research is required to understand how deficiencies in folates, homocysteine and other nutrients that reduce levels of homocysteine like choline change cells in the brain throughout life and how these changes are related to neurodegeneration.

For more information about my research please visit my personal website.

 

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Probiotics May Improve Cognitive Function in Alzheimer’s Disease

The gut microbiome has recently become the focus of a lot of biomedical research, as we begin to understand how important the microbes living in our gastrointestinal tracts are for our overall health. While it’s still unclear what exactly makes your gut microbes healthy or unhealthy, previous research has shown that probiotics shift the balance in the right direction. Probiotics are live bacterial or yeast cultures often found in fermented foods like yogurt, sauerkraut, and pickles. These cultures seem to increase the proportion of “good” microbes in your gut. While the gut microbiome is clearly important for gastrointestinal health, recent studies suggest that it can also influence the brain. Scientists have coined the term “microbe-gut-brain axis” to describe this close relationship.

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The brain and the gut microbiome are closely related and can influence each other’s function. Image Source

In a study published in Frontiers in Aging Neuroscience, researchers from Iran attempted to determine whether probiotics could be beneficial for dementia patients. They randomly divided sixty patients diagnosed with Alzheimer’s disease into two groups. One group received milk containing a mixture of probiotics, while the other group received regular milk as a control. The study had a double-blind design, meaning neither the researchers or the subjects knew who received each type of milk until after the data analysis was completed. This design helps to ensure that unconscious biases do not influence the results. Additionally, none of the subjects were allowed to consume probiotic-rich foods like yogurt during the study, ensuring that any gut microbiome differences would be due to the experiment and not any dietary interference.

After twelve weeks consuming the milk on a daily basis, the subjects took a mini-mental state exam, which is used to assess memory and cognition. The probiotic group scored an average of 28% better on the exam compared to their score before starting the treatment. In contrast, the control group’s score decreased by an average of 5%. This difference was statistically significant, indicating that the probiotics substantially improved memory in these subjects.

The researchers also tested the subjects’ blood for many different biochemicals. The probiotic group had improved markers of insulin metabolism, suggesting that the treatment might be helpful in reducing the risk of insulin resistance, a condition associated with type 2 diabetes. They also had lower levels of triglycerides, a type of body fat.

Despite the sample size of this study being fairly small, the dramatic improvement in cognitive status after only three months of probiotic treatment suggests that the gut microbiome could be intimately involved in dementia. Probiotics have no known health detriments, and are proven to assist in gastrointestinal health. While we wait for larger studies to provide a conclusive answer on probiotics’ utility in Alzheimer’s disease, it can’t hurt to try increasing them in our diets, or in the diet of a loved one with dementia.

 

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Alzheimer’s Linked to a Reduction in Unsaturated Fats in the Brain

Fats are classified into two main types: saturated and unsaturated. These distinctions have to do with the molecules’ chemical structure. Fats are basically long strings of carbon atoms. Saturated fats contain only single bonds, which allows the carbon chains to pack tightly together. This is the reason why saturated fats are usually solid at room temperature, like butter or coconut oil. Unsaturated fats contain at least one double bond, which creates a kink in the carbon chain so that they can’t pack together as tightly. This causes them to be liquid at room temperature, like olive oil or fish oil. The “omega” fats, such as omega-6 and omega-3, are types of unsaturated fats.

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Unsaturated fats contain a double bond, which makes them liquid at room temperature. Image Source

Unsaturated fats have been receiving a lot of attention lately for their importance in the brain. In a study published last week in PLOS Medicine, researchers analyzed 43 postmortem brains from individuals aged 57 to 95 years old. The brains were classified into three groups. The first group had healthy brains. The second group had clumps of amyloid-beta and tau in their brains (two toxic proteins typically found in Alzheimer’s disease), but no signs of memory or cognitive impairment. The third group had amyloid-beta and tau, along with symptoms of Alzheimer’s disease.

The researchers analyzed the brains for their levels of nearly 5,000 different molecules. They focused on three different brain regions, shown in the image below.

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The researchers analyzed three brain regions. The cerebellum (CB) is resistant to Alzheimer’s pathology, while the inferior temporal gyrus (ITG) and middle frontal gyrus (MFG) are more vulnerable.

They found relatively small differences between the control group and asymptomatic group. However, the Alzheimer’s brains had significantly reduced levels of six different unsaturated fats, including several omega-6 and omega-3 fatty acids. Lower levels of these fats were correlated with higher amyloid-beta and tau levels in the brain, as well as greater cognitive impairment. The greatest changes were observed in the two vulnerable brain regions (ITG and MFG), but there were also differences in the cerebellum as well, indicating that this brain region may not be as invulnerable as previously thought. These results suggest that disruptions in unsaturated fat metabolism could be linked to the progression of Alzheimer’s disease.

The small sample size makes this study difficult to generalize beyond the study group. Additionally, we can’t conclude which factor is causative of the other. The reduced fat levels may be causing the disease, or vice versa. However, this is not the first study to link reductions in unsaturated fats with Alzheimer’s disease. For example, others have found that feeding Alzheimer’s disease rats a diet rich in omega-3 fats can improve memory.

While the link between unsaturated fats and dementia remains fuzzy, prioritizing these “healthy fats” in your diet is a simple way to improve overall health and possibly protect your brain as well. Start by replacing your cooking oils that are high in saturated fat (butter, lard, coconut oil) with unsaturated fat alternatives (olive oil, nut oils, vegetable oil). Other good sources of unsaturated fat are fatty fish, nuts, seeds, avocados, and olives.

 

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Study Identifies a Promising Therapeutic Target for Alzheimer’s Disease

As our regular readers know by now, Alzheimer’s disease is characterized by the buildup of a toxic protein called amyloid-beta in the brain. While amyloid-beta was considered for many years to be the primary driver of the disease, we now know that the full picture is much more nuanced, with many different genes likely involved (see The Genetics of Alzheimer’s Disease). One of the genes that is often inhibited in people with Alzheimer’s disease is Nrf2. Nrf2 is a transcription factor, meaning it can control which other genes are turned on or off in a cell. In particular, Nrf2 is important for controlling cellular defense genes, including genes responsible for antioxidant activity and DNA repair. It’s been shown in mice that increasing the levels of Nrf2 in the brain can improve the symptoms and pathology of Alzheimer’s disease.

Several drugs have been designed to activate Nrf2 in the hopes that this could help treat Alzheimer’s and other neurodegenerative conditions. While these drugs were effective in mouse models of the disease, they were often toxic in humans. To address this problem, a group of researchers in England decided to try a different approach by targeting two proteins called GSK-3 and Keap1. These proteins are produced in normal human cells and act as inhibitors of Nrf2. Thus, the researchers hoped that by blocking GSK-3 or Keap1, they might be able to indirectly activate Nrf2.

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Nrf2 is a type of enzyme called a transcription factor. Inhibitor molecules, such as GSK-3 and Keap1, can bind to Nrf2 and prevent it from functioning. Thus, blocking these inhibitors could increase the activity of Nrf2. Image Source

Their results were published last week in PLoS Genetics. The study utilized fruit flies as a model of Alzheimer’s disease. When the flies were treated with lithium, which can act as a GSK-3 inhibitor, the defects in Nrf2 activity were not resolved. However, the results for the Keap1 inhibitor were much more promising. Not only was Nrf2 activity returned to normal levels, but the flies also experienced reduced toxicity of the amyloid-beta protein. The researchers even observed increased degradation of amyloid-beta, helping to reduce the levels of this protein in the brain. Similar protective effects were observed when neurons cultured from mouse brains were treated with a drug to block the interaction between Keap1 and Nrf2.

This study provides strong evidence for Keap1 as a possible therapeutic target in Alzheimer’s disease. By blocking Keap1, it may be possible to increase the activity of Nrf2 and in turn the activation of cellular defense genes, protecting our brains from neurodegenerative diseases like Alzheimer’s. The authors also suggested that a combined treatment for both Keap1 and GSK-3 may have added benefits. While the neuroprotective effects GSK-3 inhibition seem to involve a mechanism independent of Nrf2, the mice treated with both Keap1 and GSK-3 inhibitors fared better than those treated with either drug alone.

Targeting cell defense pathways like Nrf2 may provide a more effective treatment method than those previously attempted. The majority of past studies have tried to directly remove amyloid-beta from the brain, yet these drugs have been a resounding failure in humans (see Where’s our cure to Alzheimer’s disease?) The Keap1 and GFK-3 inhibitors are different, in that their main action is not to remove amyloid-beta but simply to reduce its toxicity. Future research will investigate the safety and efficacy of these drugs in humans.

 

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Autoimmune Diseases May Be Linked to Dementia

Our immune system is pretty great. It helps us recover from injury and fight off deadly pathogens. However, sometimes the immune system does its job a little too well. In certain autoimmune diseases, immune cells can mistakenly recognize a part of our own body as a foreign invader and start attacking it. Depending on what type of tissue is being targeted, autoimmunity can lead to a variety of conditions including rheumatoid arthritis, celiac disease, and multiple sclerosis. Approximately 50 million Americans (20% of the population) have an autoimmune disease.

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Some of the most common autoimmune diseases. Image Source

A study published this week in the Journal of Epidemiology and and Community Health looked at the relationship between autoimmune diseases and dementia. The researchers used health records of more than 1.8 million people in England who were hospitalized for an autoimmune condition between 1998 and 2012. They found that these patients were 20% more likely to be later hospitalized for dementia compared to controls. They identified 18 autoimmune diseases that were significantly associated with dementia. When they examined the type of dementia, the autoimmune patients were at the greatest risk for vascular dementia, with a 28% higher risk than normal. The increased risk for Alzheimer’s disease was relatively small at 6%.

This study is in line with several previous papers that hinted at a possible link between autoimmunity and dementia. It’s been shown that people with two common autoimmune diseases, type 1 diabetes and thyroid autoimmune disease, are at an increased risk of dementia. The mechanism for this connection remains unknown, but it raises the interesting question of whether dementia may be related to the immune system.

Additionally, the study supports the possible use of NSAIDs as a way to reduce the risk of dementia. NSAIDs (which include aspirin, ibuprofen, and naproxen) are some of the most commonly-used painkillers and can also be used to combat inflammation in autoimmune conditions. People who take NSAIDs tend to have a reduced risk of Alzheimer’s disease, suggesting that using these drugs to treat an overactive immune system could have cognitive benefits as well.

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Advil, Aleve, and Motrin are some of the most common NSAIDs available over-the-counter. Image Source

Many doctors have begun prescribing baby aspirins to their patients in the hopes of decreasing their risk of dementia as well as cardiovascular disease. However, caution is necessary when considering an NSAID regimen. It’s possible that for some people, NSAIDs could be doing more harm than good, as one study suggested that these drugs may reduce the risk of Alzheimer’s but increase the risk of vascular dementia. More research is needed before we can say conclusively whether NSAIDs may be beneficial for cognitive health.

 

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How Alzheimer’s and Depression are Linked to Hearing Loss (Reblog)

Our article this week is a reblog from the New Generation Hearing Blog. It’s a fairly short article, but I like that sheds light on the little-known connection between brain health and hearing loss. Click the link below to give it a read!

 

There are at least 38 million people who suffer from hearing loss throughout America. Many senior citizens expect to lose their hearing over time but few know that it could increase the chances for depression and even increase the risk of Alzheimer’s disease. In fact, hearing loss can influence every aspect of an individual’s life […]

via How Alzheimer’s and Depression are Linked to Hearing Loss — New Generation Hearing Blog

 

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