Neurons Changing their DNA Could Lead to Alzheimer’s Disease

A recent study finds that neurons can spontaneously change the sequence of a gene called APP, which is involved with Alzheimer’s disease.

In most cases, the DNA that you’re born with stays the same throughout your entire life. However, according to a paper recently published in Nature, neurons can randomly change their own DNA sequence, which may contribute to the development of Alzheimer’s disease.

The study was led by Dr. Jerold Chun’s research group at the University of California San Diego and the Sanford Burnham Prebys Medical Research Institute. Dr. Chun’s lab and others have previously shown that adult neurons can alter their own DNA sequence. As a result, different neurons inside your brain can have their own unique genomes, a phenomenon known as genomic mosaicism. This is distinct from epigenetic modifications, which can turn genes on or off but do not change the actual genetic sequence.

Genomic mosaicism, which occurs by a seemingly random process, can range in size from a single nucleotide to entire chromosomes. These changes tend to accumulate as we age, which led many scientists to wonder if they could be related to neurodegenerative diseases.

Our Mosaic Brains and Alzheimer’s Disease

In their recent Nature paper, Dr. Chun’s group investigated a single gene called Amyloid Precursor Protein, or APP for short. APP is the precursor to amyloid-beta, a toxic sticky protein that builds up in the brains of people with Alzheimer’s disease. The researchers were curious whether different forms of the APP gene could exist throughout the brain.

Using postmortem brain samples from five people with sporadic Alzheimer’s disease, as well as five age-matched controls, they extracted DNA from individual neurons and sequenced the APP gene. They found that more than 6,000 variants of APP existed across different neurons.

Interestingly, the Alzheimer’s brains had far greater diversity of genetic variants than the healthy brains. This suggests that these unusual APP variants could be related to the development of Alzheimer’s. When they took three of these variants and expressed them in a cell culture, two of them resulted in cell death. In addition, the Alzheimer’s brains had several APP variants that have been linked to familial Alzheimer’s disease (a rare, genetic form of early-onset Alzheimer’s), while none of the healthy brains contained these variants.

Next, the researchers wanted to understand how all these different APP variants might arise in neurons. They used a hamster cell culture that was made to express the human APP gene. When they used chemicals to induce DNA double-stranded breaks, the cells began producing unique APP variants, just like human neurons. The researchers also showed that this process relies on reverse transcription, which converts an RNA sequence to DNA.

Impacts for Alzheimer’s, AIDS, and Memory

This discovery is a major shift for Alzheimer’s researchers. Previous anti-APP drug candidates have generally only targeted one form of the gene, and this work shows that a huge array of genetic variants can exist in our brains. We will certainly need to reconsider our strategy for Alzheimer’s therapies moving forward.

In addition, the link between genomic mosaicism and reverse transcription has some intriguing implications for HIV. Previously studies have shown that people with HIV who are over age 65 have a lower rate of Alzheimer’s disease than the general population. One explanation could be the anti-retroviral drugs that they take. These drugs prevent the HIV multiplying by inhibiting reverse transcription, a process that the virus requires for replication. An unintended consequence of this could be that these people do not develop the APP variants that are linked to Alzheimer’s. If this turns out to be the case, anti-retroviral drugs could possibly be used as a preventative measure for Alzheimer’s.

So far, none of this has addressed the reason why neurons are so prone to developing different APP variants. In the Nature study, another Alzheimer’s-related gene called PSEN1 did not have such a wide variety, suggesting that the mechanism is specific to APP. In addition, non-neuronal cells did not develop all these APP variants. A possible explanation could be that this process is important for memory formation. The authors suggest that storing so many unique version of APP could be a mechanism for memory storage and recall at the molecular level. This idea remains speculative, but it does have a kind of poetic irony to it: the gene responsible for forming memories could also destroy those memories as we age.

 

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Interview with a Dementia Researcher: Rory Boyle, Cognitive Neuroscience Researcher

What areas of research are you currently pursuing?

My PhD research is focused on using machine learning to identify markers of cognitive ageing. Currently, I am working on a project which uses machine learning and MRI scans to create a model of normal or healthy brain ageing. This model can be used to estimate how well, or poorly, a person’s brain is ageing and this estimation is termed the brain-predicted age difference, or brainPAD.

It has already been shown that people who have high brainPAD scores (which means their brains are ‘older’ relative to their actual age) have a higher risk of early mortality and tend to perform worse on measures of physical functioning (such as grip strength, lung function, walking speed).

However, we don’t yet know whether brainPAD can be used as a measure of cognitive ageing. If people with high brainPAD scores are shown to perform worse on tests of cognitive function, then brainPAD could potentially be used as a way of identifying such people at a very early stage, before cognitive decline is noticed using standard cognitive tests.

The next project in my PhD will look at developing an objective measure of cognitive reserve. Some people whose brains have the hallmarks of Alzheimer’s disease or other dementias seem to be able to maintain normal cognitive function. This has led researchers to try and understand why some people might have a buffer or some form of protection against certain neurodegenerative diseases. One theory is that people who are able to tolerate such neurodegeneration have high levels of what is called ‘cognitive reserve’.

Cognitive reserve refers to an individual’s ability to use their brain irrespective of their brains’ structural health. It is proposed that life experiences, such as education, occupational attainment, engagement in social, leisure, and mentally stimulating activities, and physical activity contribute to cognitive reserve.

However, currently, cognitive reserve is typically measured by questionnaires and interviews which measure these same factors (education, occupational attainment, etc.). This means that we might not have the most accurate measures, as people might not fully remember all the details of their education or social activities and their answers might be affected by response bias!

My goal is to use neuroimaging to develop an objective and standardised measure of cognitive reserve so that people with low cognitive reserve can be identified. This would allow for interventions to be directed at these people and it would also help in studies evaluating strategies to improve cognitive reserve.

What are the big questions or theories currently being debated in your subfield?

There are a couple of big questions which people are trying to answer in relation to cognitive reserve. Can cognitive reserve be objectively measured, and if so, how? What is the neural basis of cognitive reserve? Hopefully my project will help to shed some light on these questions.

What is a common misconception related to dementia that you often encounter?

One common misconception is that there nothing we can do to reduce our risk of dementia. Given our knowledge of cognitive reserve, one way we could reduce our risk of dementia is by increasing cognitive reserve! There is more and more evidence that taking part in mentally stimulating activities, being socially active, and regularly exercising can lower the risk of dementia. More generally, there is evidence that having a healthy diet, particularly a Mediterranean diet, not smoking, and cutting down on alcohol can also reduce the risk of dementia.

What recommendations would you give to people wanting to reduce their risk of Alzheimer’s disease?

Like a lot of things, the best recommendations for reducing risk of Alzheimer’s disease or other dementias are to live a healthy and active life. Specifically, try to exercise three times a week, particularly aerobic exercise like brisk walking, swimming, cycling. As well as that, try to stick to a Mediterranean diet, which is rich in fruits and vegetables, whole grains, beans and nuts, olive oil and fish.

Be socially active, join a group or club. In Ireland, we have a really great initiative called Men’s Sheds were men can meet up and work together on hobbies and meaningful projects. This is a great example of how people can keep socially engaged. As well as that, take part in mentally stimulating activities like puzzles and Sudoku. If you have access to a PC, there are now thousands of free online courses on websites like Coursera or EdX. By signing up for these, you can challenge yourself and learn something new, all while keeping your brain stimulated!

How can non-scientists contribute to the fight against Alzheimer’s?

Non-scientists could help in the fight against Alzheimer’s by taking part in research. Research studies are always on the lookout for participants. People without Alzheimer’s disease are always needed as well to form control groups. Have a look online or at any nearby universities!

On top of that, there are now even easier ways to take part in research. For example, downloading and playing the SeaHero Quest app allows researchers to collect valuable information about how the brain navigates in space, which is a key skill that declines early on in dementia.

When do you believe a viable Alzheimer’s treatment will be available?

I’m not sure, but I am hopeful that with all of the new techniques we will be able to identify people likely to develop Alzheimer’s or other dementias, earlier than ever before. This will allow for any interventions that can help with Alzheimer’s to be implemented at the early stages of the disease, where interventions are likely to be most specific. It will also help researchers test and monitor the effects of new interventions and treatments.

Is there any other information you’d like to add?

My PhD research is funded by the Irish Research Council, in partnership with Altoida AG. I am very grateful for the support of both of these organisations. Altoida AG has developed an app that uses computerised and gamefied tests of cognitive performance to evaluate perceptual and memory function in older adults. This app may ultimately allow for early screening of mild cognitive impairment and identification of people who are at risk of developing Alzheimer’s disease. We have tested this app on a number of older adults here in Trinity College, and hopefully we will have some interesting data from these tests in the next year!

 

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Rory Boyle is a PhD candidate in the Whelan Lab in Trinity College Dublin. He graduated with a BSc in Psychology from Dublin City University in 2014, and an MSc in Brain Sciences from the University of Glasgow in 2016. His BSc research project compared the effects of aerobic exercise and caffeine consumption on measures of mood and cognitive performance. His MSc research project used EEG to investigate the age-related differences in the visual processing of faces. Specifically, his project examined whether there were differences in the information content of brain activity during the visual processing of faces.

 

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Interview with a Dementia Researcher: Dr. Aida Suarez Gonzalez, Clinical Neuropsychologist

What areas of research are you currently pursuing?

I am a clinical neuroscientist with a strong translational focus. I have a passion for non-pharmacological interventions and evidence-based services to help people to live well with dementia.

What are the big questions or theories currently being debated in your field?

The development of new multicomponent functional interventions in dementia (such as disease education, counselling, goal-setting, goal-oriented cognitive rehabilitation, coping strategies training, etc.) is a hot topic. These interventions have the potential to increase autonomy, quality of life, and mental health in patients and families.

Another big concept is the need to develop more suitable methods to produce high quality evidence in support of non-pharmacological interventions. The traditional methods used in classic drug trials do not always makes sense when applied to non-pharmacological approaches.

I am also interested in the introduction of a new generation of purpose-built assistive technologies (such as specific communication aids, adapted e-readers, memory aids, etc.). These tools are revolutionizing the way we provide support, so people can remain independent for longer. IDEAL and GREAT are two examples of programs that support the concept of living well with dementia.

What is a common misconception related to dementia that you often encounter?

There are two big misunderstandings that particularly trouble me because they produce undesirable consequences when a diagnosis of dementia is provided.

First, we always highlight that dementia is not a natural part of aging, that it is a disease. However, we usually forget to add that this is a very common disease in old age and that we, as longer-living societies, have lived with age-related diseases for centuries (and hey, here we are after all).

I don’t mean we should belittle the seriousness of dementia, but rather encourage more acceptance and reconciliation with life and trust in the resilience of what we human beings are capable of. I think this way of thinking moves the focus from the frustration of the current absence of a treatment to reflecting on what we can do to live well with the disease. And of course this way of seeing things is not incompatible with increasing research efforts towards finding a cure.

Secondly, calling the dementias “dementias” contributes the stigma and misunderstanding of the disease. In many societies across the world, the word dementia means losing yourself, your reasoning, judgement, understanding and contact with reality. And this is not true. This is a false and unfair misconception that every day strips millions of people around the world from their social roles and right to decide about their lives, and exposes them to patronization.

Of course, advanced stages of the disease do impair your thinking skills severely, but this is not the case in the early and even moderate stages (that can last for many years) and it also depends a lot on the dementia subtype that you have. With the right support, many people with progressive cognitive impairment can lead fairly independent lives for a long time.

Look for example at the UK Network of Dementia Voices, which is a community of 100 groups of people living with dementia that seeks to magnify their own views, make their voices being heard and pressure the public administration to include their advice in matters that affect them.

The same applies to the 3 Nations Dementia Working Group, who are a powerful group of people living with dementia transforming the way we perceive dementia and progressive cognitive impairment by making an extraordinary contribution to society through education and raising awareness. They do public speaking, provide input to public policy bodies and bring value, advice and information about what is like the experience of living with dementia. They have dementiayes, and also they are inspiring, powerful and they are transforming the world.

What recommendations would you give to people wanting to reduce their risk of Alzheimer’s disease?

There is quite a lot of scientific consensus around the main preventive measures: healthy diet, good control of vascular risk factors such as cholesterol, diabetes and hypertension, regular physical exercise, remaining mentally active, and maintaining strong and good quality social bonds and social networks.

How can non-scientists contribute to the fight against Alzheimer’s?

The lay public can make a powerful contribution by trying to educate themselves about dementia, understanding better the changes experienced by a person with the disease, and committing to contribute towards a more dementia-friendly society.

For example, if you run a fruit shop in a neighborhood with an aged population, it’s very likely that some of your clients may be living with memory problems. You can seek information to educate yourself to understand better what that means and place a sign in your shop window explaining that this is a “memory problems friendly shop” and that people can come and speak to you about how to better support them to continue doing their shopping safely and independently.

When do you believe a viable Alzheimer’s treatment will be available?

I wish I had a response for that and I wish that response was “soon.” However, it is possible that we still have to live with Alzheimer’s in our lives for a long time, so I would encourage researchers and policy-makers to double efforts on finding a treatment, but also on helping us having good, purposeful, meaningful and fulfilling lives even if carrying a diagnosis of Alzheimer’s. There is a lot of life beyond the diagnosis, let’s also embrace that and make the best of it.

Is there any other information you’d like to add?

I would like to encourage other scientists to join a movement for change that focuses more on people and less on the disease, at least in the case of the diseases for which a cure has not been found yet. We hardly have any relevant tools to use in clinical studies to measure the impact of non-pharmacological interventions on people’s real lives and this needs to change. Current methods in this area are so quantitatively constrained and disease-oriented that allow little flexibility and, their resulting scientific outputs are usually difficult to translate into clinically practice.

 

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Dr. Aida Suarez Gonzalez is a clinical neuropsychologist at University College London’s Dementia Research Centre. She earned her Masters degrees in Gerontology and Clinical Neuropsychology, as well as her PhD in Neuropsychology, from the University of Salmanca in Spain.

 

 

 

 

 

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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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Saliva Test for Alzheimer’s Disease Shows Encouraging Results

A small study suggests that saliva tests for amyloid-beta could be a useful method for diagnosing Alzheimer’s disease.

As we discussed in last week’s article, Alzheimer’s disease is notoriously difficult to diagnose, particularly in its early stages. Some estimates suggest that up to half of all Alzheimer’s diagnoses are incorrect. Currently-available tests for Alzheimer’s are often expensive and invasive, and in many cases they still can’t offer a completely accurate diagnosis.

In a recent study published in BMC Neurology, researchers investigated whether saliva could be used to detect the hallmarks of Alzheimer’s disease. The test quantifies levels of amyloid-beta, a toxic protein that accumulates in the brains of Alzheimer’s disease patients. Since detecting amyloid-beta inside the brain can be difficult, its levels in the saliva could be a useful proxy to aid in diagnosis.

The study included 15 patients with mild to moderate Alzheimer’s disease and 8 patients with normal cognition. The researchers collected saliva samples and used a highly sensitive protein test called an ELISA to quantify how much amyloid-beta each sample contained. They found that the saliva of Alzheimer’s patients contained more than twice as much amyloid-beta than that of the healthy patients.

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This figure from the paper shows that Alzheimer’s disease patients (represented as diamonds) all had higher salivary amyloid-beta levels than the normal patients (represented as squares). This relationship held true regardless of the patients’ age.

The results of this study suggest that the levels of amyloid-beta in the saliva could be a cheap and easy method for improving the accuracy of Alzheimer’s disease diagnoses. Since the current diagnostic methods require a spinal tap or blood sample, a saliva test could help encourage people to get tested for Alzheimer’s, considering an estimated 3-10% of individuals have a phobia of needles.

Due to the small sample size, this study needs to be repeated and expanded before we can draw broader conclusions. However, the preliminary results are encouraging and help to corroborate previous studies that have shown similar accuracy for these saliva tests. Perhaps in the future, diagnosing Alzheimer’s disease will be as simple as spitting into a tube.

 

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Computer Algorithm Diagnoses Alzheimer’s Disease from Brain Scans

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

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

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

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

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

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

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

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

 

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

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

What Is Niemann-Pick Disease?

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

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

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

The Cholesterol Connection

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

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

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

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

Where We Go From Here

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

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

 

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