There has been a lot of buzz in the Huntington’s disease (HD) space recently with multiple updates from companies testing many different drugs in the clinic. As these drugs move closer to seeking approval from the regulators, this has raised some questions. Why are some trials held in certain countries and not others? What does it matter if a company applies to the European or US regulators? How does a drug really move from being tested in a lab to being approved for sale on pharmacy shelves? We spoke with Cristina Sampaio, MD, Chief Medical Officer at the CHDI Foundation and former longtime member of CHMP, a committee that evaluates applications to the European Medicines Agency (EMA) for new drugs to be approved to be sold in the European Union (EU). Here, we get into the nitty gritty of drug regulation and find some answers to these important questions.

Getting a drug to market

After a company has been busy in the lab and has worked with different animal models to test their drug, the next step is to begin testing their drug in people in clinical trials. Clinical trials are typically divided into Phases 1, 2, and 3. As a drug progresses through these phases, more participants are dosed for longer periods of time.
Each phase seeks to answer different questions about the drug being tested: Phase 1 is about what dose of the drug is safe for people; Phase 2 aims to work out if the drug is working and doing what it is designed to do while continuing to monitor safety; and Phase 3 seeks to confirm the effect of the drug, generally in a larger more diverse group of people, usually over a longer period of time, and looking out for possible side effects.

If a drug successfully moves through all phases of the clinical trial process, the company behind the drug will then apply to the regulators for approval which would allow them to market and sell their drug. This is the ideal outcome for companies, patients, and other stakeholders as it means we have a bigger arsenal of drugs to treat different diseases and conditions. In the case of HD, we’re hoping to soon have the first agency-approved, disease-modifying drug – what a thought!

Regulators – laying down the law on clinical trials and drug approvals

Testing new drugs in clinical trials is however a very risky business. Scientists do their utmost to make sure that new drugs they help develop are safe, effective, and could halt, slow, or alleviate symptoms of disease in humans, based on experiments they do in cell and animal models in the lab. However, there is always a risk that things might not go as well as everyone hoped when the drug is first given to people, with potentially very bad or disappointing outcomes, a scenario with which the HD community is unfortunately very familiar.

To work in the best interests of patient groups, it is important that all aspects of this process are carefully vetted and overseen by an independent panel of experts, from the very first people to be dosed with a drug, all the way to the final approval so that the drug can be made available. This is one of the roles the regulators play, helping to get drugs from the lab bench to the people who need them the most, the patient communities.

Most countries have drug regulatory agencies, although the scope, structure, and responsibilities of these agencies varies a lot. Regulators are responsible for ensuring the safety, efficacy, and quality of drugs, medical devices, and in some cases, other health-related products. All of these regulatory agencies serve different populations with different interests and needs, operating within different healthcare systems.

Regulators in Europe and the US

You are probably familiar with some of these regulators already – the European Medicines Agency (EMA) in the EU which is the central agency for approving and monitoring medicines across all 27 EU member states; and the Food and Drug Administration (FDA), which is responsible for regulating drugs, medical devices, and food safety, but is a federal agency representing the citizens of a single country, albeit a big one, the US.

As the FDA and EMA are currently the two big players in advancing HD drugs to market, they will be the focus of this article. The FDA and EMA are also two of the most important regulatory agencies in the world because of their global influence, scientific expertise, and high standards for drug evaluation and approval. This makes them key players in ensuring the safety, efficacy, and quality of pharmaceuticals and medical products in the global landscape of drug development.

However, it is important to note that there are many more regulators beyond those governing the US and the EU. This includes Health Canada (no points for guessing where they operate!), the National Medical Products Administration (NMPA) in China, the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan, and the Central Drugs Standard Control Organization (CDSCO) in India.

The FDA is an end-to-end authority on drug testing and regulation in the US

The FDA is a self-contained entity, with full control over drug approvals in the US in a very standardized process. The companies developing the drug will first file an investigational new drug (IND) application when they want to begin clinical trials. The FDA then reviews this huge dossier of information that comprises that application, detailing all of the pre-clinical data (experiments in cells and animal models) the company has worked to put together, and they then either approve it so the company to start clinical trials and begin testing their drug in people, or they don’t and things will pause.

The company might continue to have interactions with the FDA as needed and seek advice as drug development progresses through Phase 1 and Phase 2 trials. Then at the end of Phase 2 trials, all companies have to meet with the FDA and discuss plans for their Phase 3 trial. Together, this means that the FDA has a very prescriptive series of interactions with each company as they progress through the drug development pipeline. Because the FDA has been in the loop the whole way through this process, they should have the complete back story on each drug.

After the Phase 3 trial concludes, they will often privately advise companies on their potential chances of success if they were to file a new drug application (NDA), the final approval needed to bring their drug to market. This does not mean if a company files an NDA it will definitely be approved but more the opposite; that if the FDA suggests that a company NOT file for approval because the data for their drug are too weak, they will generally follow this advice.

The EU regulatory system works to serve all of its member states

In contrast to the US system, the EU system has multiple layers of organization, a reflection of the fact that it works to represent so many different countries.The EMA itself is not the regulator of clinical trials in the EU; this is controlled by each of the member states. This means that it is perfectly possible, although generally inadvisable, that the first time a drug company will interact with the EMA is when it starts the process to seek approval for its drug.

However, the EMA does offer scientific advice to companies, to support the development of new drugs. Scientific advice could be used to check with an independent body about the company’s choice of endpoints (what they plan to measure and benchmark against in the trial) or the population they plan to test in, and whether this all makes sense. This service helps companies do a better job designing and running their preclinical and clinical studies. This can help ensure that they meet regulatory criteria before submitting their drug for approval, reduce the risk of failure, and streamline the drug development process.

Once clinical trials are complete, in the EU system the companies will prepare a dossier with all kinds of information about the drug they have been testing to submit to the regulators. This is a huge administrative task and a lot of work for the companies to do and can take a very long time – up to 12 or 14 months! In fact, big pharmaceutical companies like Pfizer and Novartis will have dedicated teams whose sole job is to put applications like this together. We asked Cristina about the significance of this step in the drug approval process and what this might indicate about the likelihood that a drug would be approved. She clarified that submitting this package had little to do with the merit of the application, and it is a largely administrative milestone in the drug approval timeline.

EMA approval is directed by a committee of experts

The EMA also differs from the FDA as it does not itself hold the decision-making power about whether a drug is approved. The approval instead comes from another body called the European Commission (EC). Linking the EMA and EC is the committee for medicinal products for human use (CHMP) comprised of a representative from each member state, and experts in the fields of science relevant for the application. CHMP reviews all of the materials provided in the dossier submissions to the EMA by drug companies and gives an opinion on whether the drug should be approved to the EC. But it is the EC who makes a final decision on whether a license will be granted for a particular drug.

This is a complex process, not made any easier to understand by all the acronyms! Cristina sat on the CHMP for 13 years and is an expert on drug approval in the EU. She tells us that whereas just one faction is ultimately in charge of approvals at the FDA, there is a large and complex network of people in the EU system, making sure that the collective interests of all EU citizens are considered and represented in the process.

Despite this diversity of perspective, the CHMP works to ensure consensus of opinion in their recommendation, and does their best to avoid a split vote, which could open the door to applicant companies exploiting possible wedge issues. In practice, this can mean that CHMP could make a recommendation for approval, but with caveats, to ensure that consensus is reached. These caveats might be about permitted dosing strategies or who can receive the drug. For example, a breast cancer drug might be approved but only for patients with a certain genetic mutation instead of all breast cancer patients.

Do all drugs follow this same approval process?

Often, this is not the end of the process and there is considered to be a Phase 4 of clinical trials, as drugs are monitored for their effect after approval. This is to make sure that in much larger populations over longer periods of time, side effects or other occurrences which were not spotted in the course of the normal clinical trial time frame can be identified and assessed.

Sometimes, if the needs of patient groups are extreme and there are no drugs available yet, drugs might be approved even before a Phase 3 trial. This was the case for a PTC Therapeutics drug for Duchenne muscular dystrophy (DMD), Translarna (ataluren), which was conditionally approved by the EU regulators in 2014. Although the Phase 2 trial did not meet its primary endpoint, when the company sliced and diced the data, there did seem to be a somewhat promising effect in a subgroup of trial participants.

Translarna was approved by the EMA under the condition that additional data from a Phase 3 trial confirmed that the drug truly worked in the subgroup PTC had identified. Sadly, this Phase 3 trial did not reach its primary endpoint either. The application to the FDA for approval was denied and the EMA recommended the drug be withdrawn from the market. The EMA concluded that Translarna did not improve walking ability in patients sufficiently, resulting in the non-renewal of its marketing authorization in the EU. This decision was upheld despite appeals from PTC as well as from patient advocacy groups. PTC continues to seek FDA approval, but the inconsistency in clinical trial results remains a challenge for its approval.

This example demonstrates that even after agency approval, this is not the end of the road in drug regulation. However, companies with robust clinical trial data are unlikely to encounter such a turbulent back-and-forth with the regulators for approval of their drug as in this instance, especially if they’re backed by positive data from a Phase 3 trial showing endpoints were met.

Why might the EMA and FDA make different decisions?

In general, the EMA tends to be more restricted in their approvals, compared with the FDA. In fact, there is a growing divide in drugs approved and available in the US that are not approved in the EU. But not all of these differences in approvals are to the benefit of people in the US.

For example, the Alzheimer’s drug, Aducanumab was initially approved by the FDA in 2021 under the accelerated approval pathway. However, its approval sparked significant controversy in regards to its efficacy, as clinical trials did not provide clear evidence of a clinical benefit​. This led to the company withdrawing the drug in 2022 as it was no longer commercially viable – the drug had a huge price tag and very few doctors were prescribing it. Following the withdrawal, Aducanumab became a notable example of the complexities and challenges involved in drug approvals, particularly for conditions like Alzheimer’s where treatment options are severely limited​.

These setbacks are indescribably disappointing for patient families. The rollercoaster of hope for those battling diseases like DMD, Alzheimer’s, and certainly HD is sufficiently fraying without regulatory approvals and withdrawals of medications that these families hope will modify the course of their disease. The hope, energy, and risk associated with advancing these ineffective medications could have been better spent with additional clinical testing to ensure endpoints are met, preventing such agency withdrawals.

Why are trials held in some countries and not others?

People from HD families have undoubtedly searched for clinical trials they may be eligible for only to be met with the disappointment that those trials aren’t taking place in their country. While certainly disheartening at the time, the decision to restrict trials to certain countries could actually help move drugs along more quickly, hopefully for the benefit of people with HD across the globe.

We recently heard positive Phase 1 trial news from Skyhawk Therapeutics, who is conducting their trial in Australia. Their decision to do this is likely a matter of cost. Healthcare costs in Australia are dwarfed in comparison to those in the US. So companies testing drugs there pay fewer fees to physicians and hospitals, making the trials a fraction of the cost. Although some drug companies are extremely wealthy organizations, smaller companies and start ups are often very cash-strapped. Spending less money to run a trial can improve their chances of survival, hopefully helping them advance their drug more quickly to convince more investors to pitch in and keep the program running.

In Europe, certain countries have faster or slower regulatory application review. Some countries, like Poland, Germany, or Hungary, have notoriously fast review processes. This allows them to attract different companies to their country for clinical trials. Other countries, like France, can be challenging to conduct clinical trials in for companies based in foreign countries, making it more common to see trials conducted there by French companies.

A company will consider trial costs and speed of regulatory approval when deciding where to conduct their trial. Ultimately though, these decisions should help a drug either fail more quickly or reach approval sooner. While we certainly don’t want drugs being tested for HD to fail, if they’re going to fail, we want that to happen as soon as possible. The sooner we know a drug won’t work, the sooner we can move on to something that will. And once we get to drugs that will work, we want those to move toward regulatory approval as quickly as possible.

On our way to triumphs

We would like to extend our heartfelt thanks to Cristina for sharing her expertise with us and talking through all of these complicated processes and considerations for drug approval so we could put this piece together. We are grateful to have experts like Cristina who dedicate their time and energy to helping the HD community.
Overall, the process of developing drugs isn’t easy. Rightfully so! It’s a risky business and we want to make sure drugs are effective, doing what is intended with little to no side effects, before they’re dolled out to the masses.

Right now is an exciting time in HD research – there are countless companies working on drugs for HD, many companies are testing their HD drugs in clinical trials, and some are at the stage of applying for regulatory approval. As more drugs reach this stage, we at HDBuzz want to make sure HD families understand that process, what each of the phases and stages of approval mean, and where we could see setbacks and, hopefully soon, triumphs.

The future undoubtedly holds regulatory approval for HD-modifying drugs. While we take that journey, HDBuzz will be here to help you understand the steps along the way in getting those drugs from the lab bench to the pharmacy shelves.

Scientists searching for new ways to stop Huntington’s disease (HD) have focused in on the repeating C-A-G letters of genetic code that cause the disease. That’s because the exact way these C-A-G letters repeat may have a big impact on when and whether someone develops HD. A group in Boston led by Dr. Jong-Min Lee recently applied a cutting-edge technology to try to change the letters of the C-A-G repeat in cells grown in a dish and mice that model HD. Were they successful? And what could this mean for future therapeutic approaches?

Three repeating letters – and an interruption to the repeat

The genetic code of every living organism is made up of 4 letters – C, A, G, and T. They’re combined in different ways to make every gene in our body, like letters on each page of a book. That’s a lot of diversity for just 4 letters!
HD is caused by a stretch of repeating C-A-G letters in the huntingtin gene – like three letters repeated on one specific page of the book. People who develop HD are born with 36 or more CAG repeats, one after the other at least 36 times, like this on the page: …CAG CAG CAG CAG CAG…

In most people, however, these repeating CAG letters actually have a slight imperfection near the end, which looks like this: …CAG CAG CAG CAA CAG. Notice those three CAA letters? Scientists call this the “CAG repeat interruption”, because it “interrupts” the repeating CAG letters. The CAG repeat interruption is found in the DNA of almost everyone, including people who have the gene that causes HD.

Two words, one meaning

Letters in the genetic code are grouped by threes to create “words” that code for building blocks to create proteins. C-A-G codes for a protein building block called “glutamine”. This is why you may have heard of the CAG repeats referred to as a “polyglutamine” stretch – there’s lots of glutamines in a row.

But C-A-G isn’t the only word that codes for glutamine. C-A-A does as well! This means when the CAG repeat is interrupted by CAA, it doesn’t change the protein word that’s spelled. It still codes for glutamine.

It’s noteworthy that if you get a genetic test for HD and you’re told that you have a certain number of repeats, like 42 for example, that number is the pure CAG repeats. They’re not including any CAG repeat interruptions you may have in your genetic code. There may be more glutamines present, but the CAG repeat stretch, uninterrupted, is 42.

More interruptions please

Not long ago, HD researchers discovered that some people with HD have no CAG repeat interruption – and some even have an extra interruption in the CAG repeat!

What is especially interesting about people without the CAG repeat interruption is that they develop HD much earlier than expected – about 12 years earlier. And people with an extra interruption appear to develop HD later – perhaps 5 year later. So there may be something special about those CAA letters that interrupt the repeated CAG letters. Losing the interruption in the middle of CAG letters might make HD symptoms appear earlier – and an extra interruption in the middle of CAG letters might make HD symptoms appear later.

Could adding extra CAG repeat interruptions into the DNA of people with HD help delay or slow symptoms? Changing the DNA of a person is no easy task, but a group of scientists led by Dr. Lee decided to try a cutting-edge approach to introduce more CAG repeat interruptions into cells grown in a dish and mice, as a proof-of-concept to seeing if it would be possible in people.

Changing bases

Dr. Lee’s group teamed up with Dr. Ben Kleinstiver, an expert in “base editing”, to try out their idea of adding more CAG repeat interruptions. What’s base editing? It’s basically a new technology that allows you to change a specific letter on a specific page of the book. It’s targeted to a specific letter like a homing missile. The technology is based on CRISPR discoveries that have been used to create medicines that recently received regulatory agency approval. Base editing is basically based on CRISPR. Ok, I’ll stop with the bad puns.

Base editing is hot-off-the-press technology, so scientists are still working out the kinks. They don’t really know which ingredients of base editing work best to change specific letters in DNA sequences. So Dr. Lee’s group tried a bunch of different combinations of ingredients to see what happened in cells in a dish that have a CAG repeat resembling the repeat in people who have the gene for HD.

In a few combinations of base editing ingredients, up to 50% of cells in a dish had CAA interruptions added to the CAG repeat sequence. That’s pretty amazing! Scientists can’t yet control exactly where these interruptions are added in the CAG repeat, but a few of the letter changes even looked like the extra interruption we see in people with delayed onset of HD symptoms.

Not quite ready for prime time

Getting all the ingredients to make base editing work into people is a big task, similar to the hurdles facing CRISPR therapeutics for HD. This is really hard if you’re trying to get all those ingredients into the brain, where people who have the gene for HD need them.

But scientists are a tenacious bunch of people and Dr. Lee’s group was not about to let the challenge stop them from trying. His group tried the best combinations of base editing ingredients in mice that have the CAG repeat from people that have the gene for HD, with some early indicators that the approach may be working to add interruptions.

We will no doubt hear more about this work in the future, and learn more about whether adding interruptions to the CAG repeat would be a new promising approach to slow HD. Stay tuned!

Since its inception in 2010, HDBuzz has existed with the financial support of non-profit organizations within the Huntington’s disease (HD) space. In our 14 years of service, we have never directly asked the HD community for donations. However, recently during a tenuous time in the existence of HDBuzz, we lost the support of one of our largest and longest standing backers. This seriously jeopardized the existence of HDBuzz. We want to ensure that this never happens again. So that HDBuzz will continue to exist and report science in plain language for the global HD community, we’re asking for your help.

Where does HDBuzz get funding?

To date, HDBuzz has been funded by a consortium of HD community organizations. Our founding partners are the Huntington’s Disease Association of England and Wales, the Huntington Society of Canada, and the Huntington’s Disease Society of America. The Griffin Foundation, a non-profit educational foundation, is a major funding partner. More recently, we’ve received vital financial and stewardship support from the Michael Berman Family Foundation and the Hereditary Disease Foundation (HDF). Currently, we are housed as a project within the HDF until we can get our footing.

These organizations have funded and supported HDBuzz as a service to the entire HD community, but have never received special access to its content, which is freely available to all. They have never had any editorial control over our content, nor have they ever asked for it.

Critically, HDBuzz has never accepted funding or support from drug companies. HDBuzz loves drug companies – we’re hoping they help us cure HD! But taking money from any organization dedicated to a particular therapy could give the impression of bias in our reporting, which we diligently aim to avoid.

Why is HDBuzz’s funding model changing?

In 2024, HDBuzz operations transferred from the UK to the US. This made sense considering the leadership of HDBuzz was no longer located in the UK, but rather in North America.

While this transition was happening, we lost financial sponsorship, stewardship, and support from one of our largest and longest standing donors within the HD nonprofit space. It became clear that solely relying on donations from other HD nonprofits was a finicky model with the potential to jeopardize the existence of HDBuzz.

We realized that we need to explore other models that are more sustainable and are a better reflection of the value that we bring to the HD community. This will allow us to maintain HDBuzz long into the future.

However, our mission remains the same – to report science in an unbiased, easy-to-understand way so that the HD community can better understand HD, research, and clinical trials. Particularly as we advance toward disease modifying drugs, we hope that our services will enable HD families to make educated decisions about their lives, treatment, and care.

Our ask

To build a long-lasting, sustainable model, we are now directly asking our readers to consider contributing to the mission of HDBuzz. With enough generosity, this will allow us to be completely independent from other organizations in the HD space.

Please consider making a donation if you value the services that HDBuzz provides. We want HDBuzz to be sustainable so that we can continue to report unbiased science to the HD community. With your support, we can ensure the continuity of our services. Nothing is expected, but everything is appreciated and sustains what we do at HDBuzz. Please consider giving what you’re able.

What will my donation be used for?

HDBuzz will never be behind a paywall. If you don’t donate, you will still have access to HDBuzz’s content. We strongly believe that science should be accessible to everyone in every way. We do our best to make complicated science easy to understand, and will always provide that without required fees.

We will continue to operate under a creative commons attribution license, offering our content freely for syndication to reach as many people as possible. We strongly encourage you to share our content with anyone who you feel may benefit from it.

Donations will be used to maintain our website, to update our website, to translate our articles into various languages, for travel to conferences so that we can live tweet research, for travel to meetings so that we can present and directly interface with the HD community, and for the time our writers and editors spend reading, writing, developing content, putting together presentations, and presenting to the HD community.

Additionally, we want to expand our content, add writers, increase the number of countries we serve, and interact directly with the HD community in more ways. We are excited to continue the work that we already do and expand that!

Thank you!

We are deeply committed to the HD community and deeply ingrained within it. We have spent the early (and late!) hours of our lives toiling away in labs learning as much as we can about HD. Trying to understand it. Trying to find a treatment for it. We are HD family members, researchers, scientists, supporters, and friends.

We hope that the content you find on HDBuzz brings you information, education, comfort, and hope. Both in dark times, and in sunnier ones. Our goal is to be the conduit through which anyone can access the information HD researchers have. We strongly feel that the job of a scientist isn’t done until the people that need that information most – HD families – also have that information.

It is the honor of everyone who contributes to HDBuzz to report on the stellar HD science being carried out in labs around the world to advance us toward an HD-free future. We profoundly appreciate that the HD community trusts us for relaying the research, the truth behind the science, and what that means for HD families.

To contribute to the mission of HDBuzz, please click the donation button below. Even a $20 monthly donation will go a long way in helping us ensure that HDBuzz is sustainable and will allow us to expand. Thank you for being our new partners in this endeavor!

In this article, we’re bringing you advice from the 2024 Lancet Commission on dementia prevention, intervention, and care – a group of experts who have combed through massive amounts of previous research collected over decades to highlight 14 risk factors associated with dementia. The good news? Those 14 factors are things that can be modified. So making lifestyle changes around the factors identified here can help improve brain health, and potentially keep people that have the gene for Huntington’s disease (HD) healthy for longer.

Dementia vs HD

While HD and dementia may have different root causes, underlying factors that are beneficial for one will be beneficial for the other. Dementia is a general term for a reduced cognitive ability – the ability to think, remember, and reason.

A reduction in cognition is only one component of HD, which is caused by an inherited expansion of the genetic code in the huntingtin (HTT) gene. HD also affects a person’s mood and has a movement component similar to Parkinson’s disease, called chorea.

While there are currently no disease-modifying treatments for HD, there are several very promising ongoing clinical trials, such as those by uniQure, Wave Life Sciences, PTC Therapeutics, and Skyhawk Therapeutics. These companies are directly targeting the cause of HD, aiming to lower the HTT message. There are also companies with ongoing trials for drugs that would treat the cognitive aspect of HD, like Sage Therapeutics.

But we want to make sure that folks with the gene for HD stay as healthy as possible until we do have a disease-modifying treatment for HD in hand. So what active changes can people make to ensure that happens?

14 factors that affect brain health

1. Less education

People who have more childhood education and those who go on to attain higher education have a reduced risk of developing dementia. This could be because these groups are more likely to obtain more cognitively stimulating jobs, challenging their brain more frequently. Less education is considered a risk factor from early life that if rectified, would reduce the cases of dementia by 5%.

2. Hearing loss

It seems like a strange correlation, but the Commission found an association between dementia and hearing loss. While this is a factor typically associated with older people, age wasn’t the variable contributing to the risk of dementia here since they accounted for age. The authors think there could be social factors at play, such as isolation due to the inability to hear in social situations, leading to low mood and motivation. They also floated the idea of biological factors, such as vascular disease that could affect both the cochlea of the ear and the brain. However, none of those theories relating hearing loss to dementia have been proven. Hearing loss is considered a midlife risk factor, and eliminating it, for example with hearing aids, would reduce the number of dementia cases by 7%.

3. High blood pressure

People with untreated high blood pressure, aka hypertension, have an increased risk of dementia. However, this risk is lost when hypertension is treated with medication. The study specifically notes that risk of dementia increases when systolic pressure (the top number) is over 130. So getting blood pressure in check by age 40 so that it’s closer to 120/80 is good for your brain. Hypertension is a midlife risk factor that accounts for a 2% increase in dementia cases.

4. Physical inactivity

Exercise is tricky to measure since it varies so much across a person’s life, between cultures and socioeconomic status, and occurs at different intensity levels. However, the study shows that physical activity, particularly sustained physical activity across a person’s life, is associated with better cognition by the age of 69. The thought behind why exercise is so good for us is that it improves blood flow and reduces blood pressure, which could improve brain plasticity and reduce brain swelling – certainly things that could be beneficial for HD! Eliminating this midlife risk factor by living more active lifestyles could reduce the number of dementia cases by 2%.

5. Diabetes

While there’s a correlation between diabetes and increased risk for dementia, this appears to only be the case for diabetes acquired in midlife, not later than age 70. No one is sure why there is a correlation between diabetes and dementia, but they think it may be because of the effect that diabetes has on blood vessels, which run throughout the brain. It could also be because the brain requires insulin for metabolism and insulin resistance can lead to brain swelling. Improving health to eliminate type 2 diabetes in midlife could reduce dementia cases by 2%.

6. Social isolation

Infrequent social contact shows an increased risk for dementia. Criteria that counted toward social isolation were living alone, visits with friends and family less than once per month, and lack of participation in weekly group activities. Studies have found that socialization can improve the brain’s resilience to damage, promote healthy behavior, lower stress, and reduce inflammation. Eliminating social isolation in later life could reduce the number of dementia cases by 5%.

7. Excessive alcohol consumption

The report finds that heavy drinking comes with an increased risk for developing dementia compared to light drinking. Interestingly, not drinking at all had a higher risk for dementia than light drinking. A reason to imbibe?! Probably not. The jury is still out on how sound those findings are since various factors could be at play here, like not drinking because of alcoholism or other non-related health issues. Reducing alcohol consumption by midlife could reduce dementia cases by 1%.

8. Air pollution

Air quality is determined by the amount and size of particles in the air. Fine particles equal to or smaller than 2.5 μm are notoriously dangerous. The report found that sustained breathing of particles that are equal to or smaller than 10 μm increases the risk of developing dementia. Since there is a strong link between air quality and socioeconomic circumstance, developing policies and regulations around clean air will be important for reducing this risk for people from various social and geographical backgrounds. Having access to healthy air to breath later in life accounts for a 3% reduction in dementia cases.

9. Smoking

We now have an overwhelming amount of data to show that smoking is unequivocally bad for your health, and that includes your brain. Smoking increases the risk of dementia, with a higher risk for those who start smoking earlier. The good news is that this risk is only associated with current smokers; there was no increased risk of dementia between ex-smokers and people who had never smoked. Quitting smoking habits by midlife can reduce the cases of dementia by 2%.

10. Obesity

While obesity is associated with increased risk for dementia, this is a tricky factor to measure. Obesity is associated with other factors on this list, such as physical inactivity, diabetes, and high blood pressure. So it’s hard to tease out which is the factor really associated with dementia risk. However, most studies adjust for these other factors and obesity is still associated with higher dementia risk. Even a modest weight loss of 5 pounds improved cognition, suggesting that keeping an eye on your weight is good for your brain. Maintaining a healthy weight by midlife would reduce dementia cases by 1%.

11. Traumatic brain injury

Perhaps unsurprisingly, a bad knock on your noodle is bad for your brain! The study found that people who got a traumatic brain injury at younger ages were more likely to develop dementia. Avoiding traumatic brain injuries by midlife could reduce the number of dementia cases by 3%.

12. Depression

The report noted that the correlation between depression and dementia was bidirectional – that depression could be both a cause and consequence of cognitive changes. Theories about how depression could affect cognition relate to less self care and social contact, as well as biological factors like increased levels of the stress hormone cortisol that could affect the brain. Encouragingly, seeking treatment, like therapy, for depression by midlife could reduce dementia cases by 3%.

13. Vision loss

Vision loss was a new factor added since the 2020 Commission report. Specifically, they found an increased risk for dementia related to untreated vision loss. For conditions like cataracts where people sought treatment, there was no increased risk. But for people who had cataracts or diabetic retinopathy and didn’t seek treatment, there was an increased chance they would develop dementia. The report specifically noted the correlation wasn’t seen for other eye conditions, like glaucoma or age-related macular degeneration. Getting a handle on preventable vision loss by late life could reduce dementia cases by 2%.

14. High cholesterol

High LDL cholesterol is also a new addition since the 2020 report. Since then, studies have been done to show that high cholesterol is indeed associated with an increased risk for dementia. Taking a lipid-lowering drug, like statins that are widely prescribed to lower cholesterol, was not associated with an increased dementia risk. So the correlation seems to be with untreated high cholesterol. High LDL cholesterol is a midlife risk factor that if eliminated could reduce dementia cases by 7%.

What wasn’t included?

Notably absent from this list is sleep. HDBuzz has previously written about the importance of sleep for managing HD, tips and tricks for a good night’s sleep for people with HD, and biological reasons for why people with HD might have trouble sleeping. We also recently heard about sleep issues caused by HD and new drugs being developed for treatment at the Hereditary Disease Foundation conference.

However, there doesn’t yet seem to be a conclusive link between sleep disturbances and an increased risk for dementia. So far, studies haven’t been able to tease out how the risk for developing dementia might be associated with various facets of sleep, like duration compared to quality of sleep.

Diet was also not included as a risk factor in the report. While diet heavily plays into several factors on the list, like obesity and diabetes, there isn’t yet enough evidence for specific diets like the Mediterranean diet. However there’s lots of evidence that reducing consumption of ultra processed foods is good for overall health, so opting for an apple over chips will always be a good decision!

Surprisingly, even genetics can be overcome

The more surprising findings from the report are that developing dementia can be modified even for people who are at an increased genetic risk. The paper states that, “for the first time, it is clear that risk can be modified even in people with increased genetic risk of dementia.” It’s likely that these findings can be applied to HD as well – even if someone has the gene for HD, modifiable lifestyle choices could delay onset, increase healthy years, and reduce disease burden.

Since the previous report in 2020, the field has seen a massive expansion in the use and utility of biomarkers – biological changes that track with a disease and can be used to measure progression. Shockingly, there are many older people who have biomarkers of dementia, like amyloid plaques within their brains, who never go on to develop dementia. These findings strongly suggest that brain changes associated with dementia don’t mean that the disease is inevitable, supporting the 14 modifiable factors highlighted here.

Unsurprisingly, being healthy is good for you

This report from the Lancet Commission on dementia can not only be used by individuals to improve their own brain health, but it’s also used to guide policy changes at the national and international governmental levels. This could take the form of prioritizing early education across socioeconomic backgrounds, destigmatizing and encouraging seeking help for mental health, and enacting helmet laws for contact sports and bicycles.

Overall, the report shows what people certainly already know – living a healthy lifestyle and being kind to yourself will give you more healthy years. Things that are good for your brain, like education and preventing brain injury, will keep your brain healthy. And things that are good for your heart, like exercise, not smoking, and less alcohol, are also good for your brain.

You may have also noticed that each of these factors is relatively small by comparison – a few percentage points here or there, with the highest being 7%. So even if someone can’t check off every factor on the list, their chances of developing dementia are still low. It’s when health issues compound that the risk for developing dementia really increases. The take home message here is take care of – and be kind to – yourself.

Today, on International Ataxia Awareness Day, we’re bringing awareness to a group of brain disorders known as Ataxia, which can take many forms. Like Huntington’s disease (HD), Ataxia is degenerative; it damages brain cells, causes changes in movement, and involves complex symptoms that worsen over time. HD and some forms of Ataxia have a shared genetic origin, and we’ll talk about medical and research overlap.

What is Ataxia?

Like HD, Ataxia is a rare form of neurological disease. It can lead to a variety of symptoms including lack of coordination, slurred speech, and difficulty walking – this can appear similar to the effects of alcohol. Ataxia is usually caused by damage to a part of the brain that coordinates movement, known as the cerebellum, which is located at the back of the head right above the neck.

The symptoms of ataxia can vary a lot by the person, and they can also vary by the type of Ataxia. Some forms are passed down from one parent, as with HD – just one copy of the faulty gene causes disease. This is known as autosomal dominant inheritance. Other forms of Ataxia are passed down only when a person inherits two copies of a faulty gene – the parents don’t have ataxia, but they are each a “carrier” of the gene. Ataxia can also be caused by a brain injury or infection (acquired), or have unknown causes (idiopathic/sporadic).

Why should the HD community be aware of Ataxia?

Ataxia can refer to a group of disorders, but it can also simply refer to uncoordinated movements. If you’ve ever had too much to drink, you’ve likely experienced alcoholic ataxia. And many people with HD experience ataxia at some point over the course of their disease. Ask many healthcare workers with HD expertise, and they’ll tell you that when you’ve seen one person with Huntington’s disease, you’ve seen one person with Huntington’s disease. We all know that HD is complex and that symptoms can vary from day to day, let alone between individuals. Symptoms of ataxia can affect people with HD, especially in later stages.

HD affects the part of the brain that is important for voluntary movements, and it is more likely to cause chorea, which can appear jerky and dance-like. Ataxia affects the part of the brain that coordinates movement, and it is more likely to cause movements that appear unstable or slow. Both diseases worsen over time and cause people to have difficulties with speech, walking, and day-to-day tasks. There are even case reports where a person with HD was misdiagnosed with ataxia because their early symptoms involved difficulties with balance and coordination.

The genetics of HD and Ataxia

The greatest area of overlap in HD and Ataxia research is within a group of Ataxias that is caused by the same genetic error. We know that HD is inherited dominantly (from one parent), and that it is always caused by the expansion of CAG repeats within a gene called huntingtin. Some ataxias are also inherited dominantly, including a group of disorders known as spinocerebellar ataxia (SCA), and several of these are also caused by the expansion of CAG repeats.

In HD, the extra CAGs are found within the huntingtin gene, whereas SCA is caused by CAG repeats within other genes. Some examples are ataxin-1, ataxin-3, and ataxin-7, but there are a whole family of genes with CAG repeat expansions that are known to cause rare Ataxias (among other diseases). We recently heard about research into SCA from Dr. Harry Orr at the Hereditary Disease Foundation conference, which we covered.

New genetic causes of Ataxia have been discovered very recently, including ones caused by triplet repeats. In fact, in 2024 a new 5-letter DNA repeat was revealed as the cause of many hereditary Ataxia cases. Like the discovery of the gene that causes HD in 1993, this is a huge step forward for folks who have this type of Ataxia! Bill Nye the Science Guy, a well-known science communicator (and source of inspiration to us at HDBuzz) has family members who have this form of Ataxia, known as SCA27B. He has partnered with the National Ataxia Foundation in the USA to create several videos about this condition.

Historical research overlap

Historically, genetic research in HD and Ataxia has followed a similar path. There were initial efforts in the 1980s and 1990s to narrow down the “neighborhood” followed by the exact location of the genes that led to disease. There followed the creation of animal models in the 1990s and 2000s allowing scientists to study the development, progression, and treatment of HD and hereditary Ataxias. These paths involved similar laboratory techniques that built upon one another across fields.

Importantly, research developments in the HD and Ataxia fields involved similar collaborative efforts between researchers and family members who agreed to donate their time, samples, and brain tissue for the benefit of future generations.

Research today

The shared nature of the CAG repeat in HD and several hereditary Ataxias means that researchers can continue to learn from one another, working together and in parallel, and employing a shared set of tools and ideas. Bi-annual international conferences continue to gather global scientists studying CAG repeat disorders, and many labs work on HD in addition to hereditary Ataxias like SCA. The phenomenon of CAG repeats getting longer in some cells (somatic expansion) holds true for these Ataxias in addition to HD, knowledge that can be leveraged towards treatments.

What’s more, we’re already reaping the benefits of shared insights in drug research. The development of ASOs for huntingtin-lowering has led to similar efforts in the Ataxia field, which also involves an extra-long, clumpy protein. Similarities between diseases in how CAGs repeat themselves has even led to the development of a drug by VICO Therapeutics that may be used to treat people with Huntington’s disease, SCA1, or SCA3. Stay tuned for a deeper dive into the recent positive momentum of that human trial, which involves participants with all three disorders.

The takeaway

Ataxia and HD share many similarities. It’s productive for researchers to gain insights from one another across disease fields, especially those with common genetic features. And it’s gratifying to know that other families challenged with an inherited disease have built their own supportive networks whose parallel efforts drive clinical research and advocacy.

HDBuzz is proud to acknowledge the Ataxia community on Ataxia Awareness Day. We’d also like to give a shout-out to Dr. Celeste Suart at the National Ataxia Foundation (NAF) for her input. The NAF hosts SCAsource, a site similar to HDBuzz which provides plain-language research news written by scientists. If you’re interested in learning more, SCAsource is a great place to start.