Tag Archives: neuroscience

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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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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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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AlzScience Interview on Straight from a Scientist Podcast

Straight from a Scientist is a podcast series where scientists talk about their research for a general audience. I recently had the amazing opportunity to be interviewed on the show, and I’ve pasted the link below where you can listen to it. It was a great discussion about Alzheimer’s disease, axon guidance, and life as an undergraduate researcher. Be sure to stay tuned for the show’s Alzheimer’s Disease Roundtable episode, which should be coming out within the next week.

 

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Vascular Damage May Affect Progression to Alzheimer’s Dementia

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Guest author: Rachana Tank has a master’s degree in Neuropsychology from Maastricht University in the Netherlands. Her goal is to pursue a PhD in psychology exploring cognitive ageing, where her research interests lie.

As we grow older, we tend to become a little forgetful which is thought to be a normal part of ageing, but when does forgetfulness turn into abnormal ageing? Sometimes even slight but noticeable changes in thinking skills can be symptoms of an underlying issue. Alzheimer’s dementia is a continuous process, a progression taking place over many years, during which individuals experience considerable deficits before reaching clinical dementia. Stages leading up to Alzheimer’s dementia are referred to as predementia stages and are considered to be on the spectrum of Alzheimer’s dementia. In such stages, cognitive deficits are typically experienced as deterioration of memory, attention, and language skills.

Predementia stages can include individuals who self-report a decline in cognitive abilities (subjective cognitive impairments), or experience cognitive impairments that can be diagnosed by standardised testing (mild cognitive impairments). Both of these can, but not always, indicate an initial phase of neurodegeneration that may suggest they are in an early stage of Alzheimer’s dementia.

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The difference between normal brain ageing (purple line) and stages of cognitive decline experienced as part of abnormal brain ageing in dementia. Image source

Individuals with subjective or mild cognitive impairments tend to have a higher incidence of future cognitive decline than the general population and more often show Alzheimer related pathology. However, it is still difficult to predict which individuals in these stages will progress to Alzheimer’s dementia.

Differentiating between those who will progress and who will not is a difficult task. However, biomarkers can be utilised to indicate the presence of Alzheimer’s pathology to detect and diagnose predementia stages. Namely, amyloid protein plaques and neurofibrillary tau tangles are the hallmarks of Alzheimer’s disease, with amyloid pathology being the earliest identifiable change in the brain. Although amyloid and tau have both been fundamental to understanding and estimating the pathological cascade, there is a lot of emerging evidence to suggest that it is not just tau and amyloid in isolation that contribute to progression of Alzheimer’s pathology and subsequent cognitive symptoms.

As evidence indicates there is more to consider than amyloid and tau, recent research, including my master’s research, investigates mixed Alzheimer’s pathology in early stages. Mixed pathology refers to hallmark Alzheimer pathology, such as amyloid and tau, that coexist with additional abnormalities such as vascular disease. Vascular disease is of particular interest in predementia stages as it is the most common disease to coexist with typical Alzheimer pathology early in the disease process.

Vascular disease can be defined as any condition that affects the arteries, veins, and capillaries responsible for carrying blood to and from the heart. Vascular damage can compromise brain health by reducing blood flow to vital areas, leading to loss of neurons. Such damage to the brain affects how well certain areas function, sometimes leading to decreased cognitive abilities such as language difficulties, attention problems or memory issues. There is evidence that vascular disease shortens time to progression when coexisting with traditional Alzheimer pathology. However, the mechanisms by which they may interact is not known.

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Arterial plaques are one example of vascular disease. Image source

My research investigated mixed pathology in 269 memory clinic patients aged 39 or older with subjective or objective cognitive impairments. Levels of amyloid burden and vascular damage were recorded at baseline and at follow-up between 1 and 5 years later. Those who progressed to Alzheimer’s dementia were then compared to those who did not. Vascular damage was assessed using MRI scans, and level of amyloid pathology was determined via cerebrospinal fluid samples.

The results of my research found that Alzheimer’s disease patients with vascular damage had less amyloid in their brains than Alzheimer’s patients who did not have vascular damage. This suggests that vascular damage may worsen the effects of amyloid plaques on cognitive decline and Alzheimer’s. These findings are compatible with other studies that investigated vascular damage in relation to amyloid burden.

Different amounts of amyloid in patients did not show any direct relationship with vascular damage, suggesting that the presence or absence of vascular disease does not influence the presence of Abeta. However, both vascular damage and amyloid pathology increased the risk of progressing to Alzheimer’s dementia significantly, and 93% of individuals who progressed to Alzheimer’s dementia showed abnormal levels of both amyloid and vascular pathology, indicating that both contribute to the development of Alzheimer’s dementia. These research insights help us to better understand early stages and the influencing factors involved. This allows us to develop interventions, for example, promoting cardiovascular health in those at risk by encouraging memory clinic patients to participate in exercise programs.

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Macular Degeneration: Alzheimer’s Disease of the Eye?

Macular degeneration affects more than 10 million Americans, making it the leading cause of vision loss. It occurs when, for reasons that aren’t entirely understood, the central region of the retina (known as the “macula”) begins to deteriorate. The disease is considered incurable and usually occurs in people over the age of 55. Smokers and individuals of Caucasian decent are at an increased risk, as well as anyone with a family history of the disease.

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This animation from the American Macular Degeneration Foundation shows the loss of central vision that occurs with this disease.

Surprisingly, there are many parallels between macular degeneration and Alzheimer’s disease. Though the two conditions may seem unrelated, both are believed to be caused by the buildup of a toxic protein called amyloid-beta. In Alzheimer’s disease, amyloid-beta plaques accumulate in the brain, while in macular degeneration, amyloid-beta forms fatty deposits behind the retina called “drusen.” Plaques and drusen appear to have similar composition of proteins and fats, and utilize the same mechanisms to damage surrounding tissue.

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Diagram of a normal eye and an eye with macular degeneration. Image Source

The similarities between these two diseases don’t end there. Older people with macular degeneration are three times as likely to have cognitive impairment, suggesting that the same processes leading to amyloid-beta accumulation in the retina could also be occurring in the brain. This makes sense, since the retina and the brain are both part of the central nervous system. Additionally, several mouse models of Alzheimer’s disease exhibit amyloid-beta buildup in both the brain and the retina, further cementing the link between the two conditions.

The emerging connection between Alzheimer’s and macular degeneration has several important consequences. If amyloid-beta buildup in the retina could be a sign of a similar process happening in the brain, it raises the possibility that eye exams could serve as a non-invasive method to screen people for Alzheimer’s disease. Clinical trials for this idea are still ongoing, but the early results seem encouraging. These eye exams could potentially allow for earlier Alzheimer’s diagnosis or a lower risk of misdiagnosis.

This relationship also suggests that people with Alzheimer’s disease could be at a greater risk of macular degeneration, or vice versa. If you or a loved one is experiencing dementia, it’s recommended to minimize the risk of macular degeneration by receiving regular eye exams, protecting the eyes from sunlight, and maintaining a healthy diet.

 

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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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