Tag Archives: amyloid

Why People with Down Syndrome are at High Risk for Alzheimer’s Disease

Down syndrome is a neurodevelopmental disorder caused by inheriting an extra copy of chromosome 21. The most common symptoms include intellectual disability, unusual facial features, and heart defects. About 1 in 700 babies is born with this condition.

The average lifespan for a person with Down syndrome is 60 years. Sadly, the last few years of their lives are often lost to Alzheimer’s disease. Nearly two-thirds of Down syndrome patients are diagnosed with Alzheimer’s before the age of 60. This is far higher than the general population, of whom less than 1% develop Alzheimer’s this early in life.

The reason for this greatly elevated risk of Alzheimer’s disease comes down to genetics. While chromosome 21 contains hundreds of different genes, a single gene is believed to cause Alzheimer’s disease in Down syndrome patients: APP. This gene encodes a protein called amyloid-beta. Amyloid-beta is a toxic, sticky protein that can clump together and accumulate inside the brain, which is believed to be a major contributing factor to Alzheimer’s disease.

Because of their extra copy of chromosome 21, people with Down syndrome produce more amyloid-beta than normal. Nearly 100% of Down syndrome patients start to develop amyloid-beta aggregates in their brains during their 40s. This puts them at a very high risk of developing Alzheimer’s at an early age.

After the practice of institutionalizing people with Down syndrome became less common, their life expectancy improved dramatically, up from only 25 in 1983 to 60 today. However, this means that more Down syndrome patients are living long enough to develop Alzheimer’s disease, which is a frightening prospect to these individuals and their families.

Despite the troubling statistics, there is hope for people with Down syndrome. Many neuroscientists believe that early intervention is key for preventing Alzheimer’s disease. However, ethical standards make it difficult to administer treatments to people before we know for sure that they’ll develop a disease, particularly if those treatments come with certain risks. This makes it challenging to test out new preventative therapies for Alzheimer’s disease.

Because of the very high rate of Alzheimer’s disease among Down syndrome patients, they may be an exception to this rule. New drug candidates can be tested on these individuals beginning early in life, which may prove to be a more effective strategy for preventing Alzheimer’s. While only time can tell whether these treatments will prove beneficial, many remain hopeful for the future of research.

 

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The New Definition of Alzheimer’s Disease Raises Ethical Dilemmas

A redefinition of Alzheimer’s disease could be a boon for clinical trials, but some warn that it could put patients at risk.

The current guidelines for diagnosing Alzheimer’s disease were established in 2011 by the National Institute on Aging and the Alzheimer’s Association. The guidelines, originally published in the journal Alzheimer’s and Dementia, focus on observable symptoms such as memory impairments, language problems, and personality changes.

However, the same group recently proposed a new set of guidelines based on biomarkers rather than symptoms. Biomarkers are physiological changes that can be easily measured and may be associated with a disease. For Alzheimer’s disease, the most widely-recognized biomarkers are amyloid-beta and tau, two toxic proteins that accumulate in the brains of people with this disease. The new guidelines propose that Alzheimer’s disease should be defined based on the presence of amyloid-beta and tau in the brain, without regard to cognitive symptoms.

This new way of defining Alzheimer’s disease brings with it both advantages and potential risks. In a recent Perspectives article published in Neural Regeneration Research, my colleagues and I discussed what the new guidelines could mean for the future of Alzheimer’s disease research and brought up some of the ethical dilemmas that it could pose.

Positive Aspects of the New Definition

The new way of defining Alzheimer’s disease offers several advantages, particularly for pharmaceutical companies. Most drug candidates for Alzheimer’s disease work by trying to get rid of amyloid-beta from the brain. Unfortunately, Alzheimer’s clinical trials have been a resounding failure for the past 30 years (see Where’s our cure to Alzheimer’s disease?). As a result, several pharma companies including Pfizer have shut down their Alzheimer’s research programs entirely.

Many pharma researchers believe that the reason these drugs failed is because they were administered too late in the disease’s progression. By the time Alzheimer’s disease is diagnosed, the patient’s brain is already full of large amyloid-beta deposits. But perhaps if we could administer the drugs to people in their 30s or 40s, when amyloid-beta has started to accumulate but cognitive symptoms are not yet apparent, they might be more effective.

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Clumps of amyloid-beta (shown in this illustration) can appear in the brain decades before the appearance of Alzheimer’s disease symptoms. Image Source

Under the current guidelines, these younger people who have amyloid-beta in their brains but no memory problems would not be considered to have Alzheimer’s disease. As a result, pharma companies would have to overcome steep legal issues in order to administer an experimental drug to people without a diagnosed disease. However, the new guidelines would allow these people to be diagnosed with Alzheimer’s, and thus they could be included in clinical trials.

This change would be great news for pharma companies, and possibly for the rest of us too. If they discover new drugs that can stop Alzheimer’s disease when administered at an earlier stage, it would be a huge breakthrough in preventing people from getting the disease. However, despite these advantages, there are some risks that we need to consider as well.

Ethical Issues with the New Guidelines

One of the biggest problems with this new definition is that many people who have amyloid-beta in their brains do not go on to develop the symptoms of Alzheimer’s disease. In fact, some studies suggest that as many as 1 in 3 seniors have enough amyloid-beta in their brains to meet the diagnostic criteria, yet they show no cognitive issues.

This discrepancy means that if we start diagnosing Alzheimer’s disease based on amyloid-beta alone, some people who receive the diagnosis in their 30s or 40s will never go on to experience any symptoms. Being diagnosed with a disease (particularly one that is currently incurable) can cause a substantial degree of anxiety and depression. There are ethical issues to be considered when we start diagnosing people with a disease they may never actually experience, causing undue stress for the patients and their families.

Another problem is that these asymptomatic individuals could be subjected to unnecessary treatments. In addition to the financial costs of such treatments, many Alzheimer’s clinical trials report adverse side effects, including increased rates of re-emergent infections and certain kinds of cancer. Treatments targeting amyloid-beta also increase the risk of ARIA (amyloid-related imaging abnormalities) by five-fold. ARIA is caused by tiny micro-bleeds in the brain’s blood vessels, which can result in confusion, headaches, and difficulty walking.

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Cerebral micro-bleeds from ARIA appear as abnormal white regions on this brain scan. Image Source

In redefining Alzheimer’s disease based on amyloid-beta, rather than the symptoms that actually affect patients’ lives, we will be subjecting many patients to unnecessary emotional hardship and potentially-harmful treatments. Whether the benefits to clinical trails are worth this sacrifice is a question worth careful consideration.

Does Amyloid-Beta Actually Cause Alzheimer’s?

In addition to the ethical problems that I’ve discussed, there’s a darker possibility that this new definition could severely derail Alzheimer’s disease research. For decades, the “amyloid cascade hypothesis” was widely accepted among neuroscientists. This hypothesis states that amyloid-beta is the initial cause of Alzheimer’s disease, and therefore we must get rid of it in order to cure the disease.

However, a growing body of evidence suggests that the amyloid cascade hypothesis could be wrong. For one thing, many people with amyloid-beta never develop this symptoms of Alzheimer’s disease, as I mentioned earlier. In addition, several studies suggest that amyloid-beta actually serves important roles in the brain and body (see The Villain of Alzheimer’s Disease Could Actually Be a Hero). For example, it may help the immune system to fight off infections by clumping around microbes and preventing them from spreading.

It’s possible that getting rid of amyloid-beta is the wrong strategy for fighting Alzheimer’s. And if that’s the case, then redefining Alzheimer’s in terms of amyloid-beta will only distract future research efforts away from the real path to a cure.

Concluding Thoughts

The advantages of the new definition for aiding future clinical trials are important, and they could help us discover treatments that are effective before the development of symptoms. However, we need to weigh this against the ethical risks of diagnosing asymptomatic people with Alzheimer’s, as well as the questionable validity of the hypothesis the guidelines are based on.

This debate should not be only left up to researchers and clinicians; I believe it is important that patients and their families also discuss this important issue and make their voices heard by the scientific community.

 

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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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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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What Naked Mole Rats Can Teach Us About Alzheimer’s Disease

Yes, you read that title correctly. I’m talking about naked mole rats, the burrowing hairless rodents with a face only a mother could love. You might just know them for their strange appearance, but naked mole rats have fascinated scientists for decades due to their extreme longevity. They are by far the longest-lived rodent species, with a maximum lifespan of more than 30 years, compared to only 2 years for your typical mouse. They also are practically immune to cancer, for reasons we don’t entirely understand.

So what does this have to do with Alzheimer’s? Well, another one of the naked mole rat’s strange quirks is that it possesses extremely high levels of amyloid-beta, the toxic protein that is believed to cause Alzheimer’s disease. In humans, amyloid-beta aggregates into sticky plaques in the brain, which can cause a whole host of problems. Amazingly, naked mole rats have even higher amyloid-beta levels than 3xTg-AD mice, which are an Alzheimer’s mouse model genetically engineered to over-produce amyloid-beta. However, the amyloid-beta found in naked mole rats is less sticky and does not tend to form plaques, despite being just as toxic to neurons. Additionally, while amyloid-beta in humans increases as we age, its levels remain constant in naked mole rats. This suggests that amyloid-beta could be harmless (or possibly even beneficial) when it’s present in its non-sticky form. A 2015 report also found that the brains of old naked mole rats look more like what you’d expect to see in a baby animal’s brain, with high numbers of new neurons constantly being formed.

The fact that naked mole rats possess exceedingly high levels of amyloid-beta throughout their lifespan, yet do not develop Alzheimer’s disease, makes them an extremely useful research subject. If scientists can unravel what makes these rodents so resistant to amyloid-beta, we might be able to apply this finding to humans in the form of a treatment for Alzheimer’s disease. So even though they may not be the cutest creatures, you might someday have the naked mole rat to thank for keeping your brain healthy!

Here are some more fun facts about naked mole rats!

  • They have no sense of pain and are nearly blind.
  • They are almost entirely cold-blooded, relying on their environment to regulate body temperature.
  • In order to live underground, naked mole rats have evolved very low rates of breathing and metabolism, and can survive for up to 5 hours in low-oxygen conditions.
  • They live in eusocial colonies similar to ants or bees, with a single queen that produces all the colony’s offspring.

 

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New Alzheimer’s Study Sheds Light on the Mysterious Tau Protein

If you’re a regular reader of AlzScience, you know that Alzheimer’s disease is believe to be caused by two toxic proteins that accumulate in the brain: amyloid-beta and tau. (For more background, see Alzheimer’s Disease: A General Overview.) Recently, it’s been shown that tau is actually a better predictor of Alzheimer’s disease progression than amyloid-beta, suggesting that this mysterious protein might have a larger role in the disease than we once thought.

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Amyloid-beta plaques and tau tangles form toxic clumps in the brains of Alzheimer’s patients. Source

A study published last week in Nature provided deeper insight into tau. The scientists were interested in studying the ApoE gene, which is considered the strongest genetic risk factor for Alzheimer’s (see The Genetics of Alzheimer’s Disease.) Specifically, having two copies of the ApoE4 allele increases your risk of Alzheimer’s by nearly 15 times, and it’s been shown that people with this allele have greater buildup of amyloid-beta in their brains. However, the researchers in this study wanted to see whether ApoE could also affect tau accumulation.

To test this, they used genetically engineered mice that overexpress the tau gene, causing them to develop many of the symptoms of Alzheimer’s. They then tampered with these mice’s genes so that they would also overexpress ApoE4. (Note: Overexpressing the tau and ApoE4 genes means those genes were more active than they normally would be in the mice. Think of it like a light switch stuck in the “on” position.) They found that these mice had more tau in their brains, and also more severe brain shrinkage due to neuronal death.

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This figure from the paper shows brain slices from different mice. The far left panel shows a healthy mouse brain. The next two (representing the ApoE2 and ApoE3 alleles) have slightly more brain atrophy, while the harmful ApoE4 allele causes very severe atrophy. In contrast, the far right brain, which does not express ApoE at all, has relatively little atrophy.

To figure out how ApoE4 might be causing more tau accumulation, the researchers looked at the mice’s microglia, the immune cells of the brain. The microglia overexpressing ApoE4 tended to overreact to infections, releasing high amounts of pro-inflammatory molecules called cytokines. Neurons and other brains cells are very sensitive to cytokines, and high levels might cause them to produce more tau.

Finally, the researchers turned to human research. They used postmortem brain tissues taken from people who had tauopathies, which are diseases caused by accumulation of tau (but not amyloid-beta) in the brain.  The people possessing the ApoE4 allele had more severe neurodegeneration and greater tau buildup in certain areas of the brain.

Overall, this study demonstrates that ApoE4 does not only act on amyloid-beta, but tau as well. It gives strong support to the notion that tau may be as important as amyloid-beta in understanding the pathology of Alzheimer’s disease. In an interview with Science News, Harvard neurologist Dennis Selkoe described this deadly combination of amyloid-beta and tau as a “double whammy.” Yet this study provides hope that future therapies against ApoE4 could be capable of halting both of these toxic proteins at once.

 

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