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Alzheimer’s disease is partly genetic − studying the genes that delay decline in some may lead to treatments for all

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Alzheimer's disease is partly genetic − studying the genes that delay decline in some may lead to treatments for all

Researchers are zeroing in on understanding what goes awry in the brains of people with Alzheimer's disease.
Tek Image/Science Photo Library via Getty Images

Steven DeKosky, University of Florida

Diseases that in families usually have genetic causes. Some are genetic mutations that directly cause the disease if inherited. Others are risk genes that affect the body in a way that increases the chance someone will develop the disease. In Alzheimer's disease, genetic mutations in any of three specific genes can cause the disease, and other risk genes either increase or decrease the risk of developing Alzheimer's.

Some genetic mutations or variants interact with other genetic alterations that to Alzheimer's disease. In some cases, gene alterations can interact with Alzheimer's-causing genetic variants in a way that proves beneficial; they actually suppress the pathological brain changes the other mutations would normally lead to. These protective gene variants can drastically slow or prevent cognitive decline. In two recent case reports on familial Alzheimer's disease, mutations delayed Alzheimer's symptoms for decades.

I am a neurologist and neuroscientist who has spent my career studying Alzheimer's disease and dementia both in the laboratory and in the clinic. Determining how genes affect brain chemistry is vital to understanding how Alzheimer's disease progresses and devising interventions to prevent or delay cognitive decline.

The amyloid hypothesis

In the early 1990s, scientists proposed the amyloid hypothesis to explain how Alzheimer's disease develops. The first neuropathological changes detected in the brain of Alzheimer's disease were the formation of amyloid plaques – clumps of protein pieces called beta-amyloid. Other changes in the Alzheimer's brain, such as the accumulation of another type of abnormal protein called neurofibrillary tangles, were thought to develop later in the course of the disease.

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Beta-amyloid begins to accumulate in the brain up to 15 years before symptoms emerge. Symptoms correlate with the number of neurofibrillary tangles in the brain – the more tangles, the worse the cognition. Researchers have tried to determine whether preventing or removing amyloid plaques from the brain would be an effective treatment.

Alzheimer's disease results from the accumulation of abnormal proteins in the brain.

Imagine the excitement of the scientific community in the 1990s when researchers identified three different genes causing familial Alzheimer's disease – and all three were involved with beta-amyloid.

The first was the amyloid precursor protein gene. This gene directs cells to produce the amyloid precursor protein, which breaks down into smaller fragments, the beta-amyloid that forms amyloid plaques in the brain.

The second gene was termed presenilin 1, or PSEN-1, a protein needed to cut the precursor protein into beta-amyloid.

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The third gene, presenilin 2, or PSEN-2, is closely related to PSEN-1 but found in a smaller number of families with familial Alzheimer's disease.

These findings added strength to the amyloid hypothesis explanation of the disease. However, uncertainty and opposition to the amyloid hypothesis have developed over the past several decades. This was in part tied to a recognition that several other processes – neurofibrillary tangles, inflammation and immune system activation – are also involved in the neurodegeneration seen in Alzheimer's.

The hypothesis also got significant pushback after many clinical trials attempting to block the effects of amyloid or it from the brain were unsuccessful. In some cases, treatments had significant side effects. Some researchers have come up with strong defenses of the hypothesis. But until a clinical trial based on the amyloid hypothesis could show definitive results, uncertainty would remain.

Genetic discoveries with treatment implications

The vast majority – more than 90% – of Alzheimer's cases occur in late life, with disease prevalence increasing progressively from age 65 and up. Such cases are mostly sporadic, with no clear history of Alzheimer's.

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However, a relatively small number of families have one of the three known genetic mutations that cause the disease to be passed down. In familial Alzheimer's, 50% of each generation will inherit the mutated gene and develop the disease much earlier, usually from their 30s to early 50s.

In 2019 and 2023, researchers identified changes in at least two other genes that markedly delayed the onset of disease symptoms in people with familial Alzheimer's disease mutations. These mutated genes were found in a very large family in Colombia whose members tended to develop Alzheimer's symptoms by their 40s.

A woman in the family carrying a mutated PSEN-1 gene did not have any cognitive symptoms until she was in her 70s. A genetic analysis showed that she had an additional mutation in a variant of the gene that codes for a protein called apolipoprotein E, or ApoE. Researchers believe the mutation, called the Christchurch variant – named after the in New Zealand where the mutation was first discovered – is responsible for interfering with and slowing down her disease.

Importantly, her brain had a great deal of amyloid plaque but very few neurofibrillary tangles. This suggests that the link between the two was broken and that the suppressed number of neurofibrillary tangles also slowed down cognitive loss.

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Researchers have studied certain families in Colombia with rare genetic variants that slow the progression of Alzheimer's disease.

In May 2023, researchers reported that two siblings in the same large family also did not develop memory problems until their 60s or late 70s and were found to carry a mutation in a gene that codes for a protein called reelin. Studies in mice suggest that reelin has protective effects against amyloid plaque deposition in the brain. In these patients' brains, as with the patient who had the Christchurch variant, there were extensive amyloid plaques but very few neurofibrillary tangles. This observation confirmed that the tangles are responsible for the cognitive loss and that there are several ways to “disconnect” amyloid and neurofibrillary tangle accumulation.

Finding medicines that might mimic the protective effects of the Christchurch variant or the reelin mutation could delay Alzheimer's disease symptoms for all patients. Since the vast majority of nonfamilial Alzheimer's manifests after age 70 or 75, a 10-year delay in the emergence of first symptoms of Alzheimer's could have a massive effect in decreasing the prevalence of the disease.

These findings demonstrate that Alzheimer's can be slowed and will hopefully lead to additional new therapies that can someday not only treat the disease but prevent it as well.

Starts and stops

Despite over 20 years of doubts and therapy failures, the past several years have seen positive results from three different treatments – aducanumab, lecanemab and donanemab – that remove amyloid plaques and slow loss of cognitive function to some extent. Although there is still discussion of how much slowing of decline is clinically significant, these successes provide for the amyloid hypothesis. They also suggest that other strategies will be needed for optimal treatment.

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The FDA approved the Alzheimer's drug aducanumab (Aduhelm) in June 2021, to much controversy.

The U.S. Food and Drug Administration's 2021 approval of the first antibody treatment for Alzheimer's, aducanumab, sold under the brand name Aduhelm, was controversial. Only one of the two clinical trials testing its safety and effectiveness in people yielded positive results. The FDA approved the drug on the basis of that single study through an accelerated approval process in which treatments meeting an unmet clinical need can expedited approval.

The second antibody, lecanemab, sold as Leqembi, was approved in January 2023 via the same accelerated approval pathway. It was then fully approved in July 2023.

The third antibody, donanemab, completed a successful phase three clinical trial and is awaiting more safety data. When that is submitted to the FDA, the agency will consider the drug for approval.The Conversation

Steven DeKosky, Professor of Neurology and Neuroscience, University of Florida

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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The Conversation

Excavating data from digs done decades ago and connecting with today’s communities

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theconversation.com – Emily Fletcher, Ph.D. Candidate in Archaeology, Purdue University – 2024-06-18 07:39:20

Archaeologists excavate at the Gulkana Site in the 1970s.

Dr. William Workman Photo Collection

Emily Fletcher, Purdue University

The ancestors of Alaska Native people began using local copper sources to craft intricate tools roughly 1,000 years ago. Over one-third of all copper objects archaeologists have found in this region were excavated at a single spot, named the Gulkana Site.

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This is the site I've studied for the past four years as a Ph.D. student at Purdue University. In spite of its importance, the Gulkana Site is not well known.

To my knowledge, it isn't mentioned in any museums. Locals, Alaska Native Ahtna people, who descend from the site's original inhabitants, might recognize the name, but they don't know much about what happened there. Even among archaeologists, little information is available about it – just a few reports and passing mentions in a handful of publications.

However, the Gulkana Site was first identified and excavated nearly 50 years ago. What gives?

Archaeology has a data management problem, and it is not unique to the Gulkana Site. U.S. federal regulations and disciplinary standards require archaeologists to preserve records of their excavations, but many of these records have never been analyzed. Archaeologists refer to this problem as the “legacy data backlog.”

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As an example of this backlog, the Gulkana Site tells a story not only about Ahtna history and copperworking innovation, but also about the ongoing value of archaeological data to researchers and the public alike.

What happens after an excavation?

In the United States, most excavations, including those that have happened at the Gulkana Site, occur through a process called Cultural Resource Management. Since the 1960s, federal regulations in the U.S. have required archaeological excavations prior to certain development projects. Regulations also require that records of any finds be preserved for future generations.

One estimate suggests that this process has created millions of records in the legacy data backlog. Archaeological data is complex, and these records include many file formats, varying from handwritten maps to pictures and spatial data.

The problem is worst for datasets that were created before computers were in common use. Research suggests that archaeologists are biased toward digital datasets, which are easier to access and use with modern methods. Ignoring nondigital datasets means not only abandoning the product of decades of archaeological work, it also silences the human experiences those datasets are meant to preserve. Once a site is excavated, this data is the only way the people who lived there can tell their story.

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Archaeologists aren't sure how to resolve this problem. Many have been proposed, including the creation of new data repositories, making new use of existing datasets whenever possible, and increasing collaboration with other disciplines and with public stakeholders. One of the more creative solutions, the Vesuvius , recently made headlines for awarding its US$700,000 grand prize to a team that successfully used artificial intelligence to read ancient text.

Digital archaeology excavates old data

Of course, such a complicated problem has no single miracle cure. In my work with the Gulkana Site, I'm employing many of these suggestions through a newer form of archaeology that some researchers are calling digital public archaeology. It combines digital archaeology, which uses computers in archaeological research, with public archaeology, which honors the public's interest in the past.

For me, archaeology looks different than what people might expect. Instead of spending my days excavating in some fabulous location, my work involves being parked at a computer for hours on end. I dig through old information instead of digging up new information.

As a digital archaeologist, I apply modern methods like AI to bring new to decades-old data about the Gulkana Site. I write software that converts 50-year-old handwritten excavation notes into a digital map that I can analyze with a computer.

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Although it is less glamorous, this work is arguably more important than excavation. Excavation is merely a data collection technique; on its own, it can't reveal much about a site. This is why there is still much to learn about the Gulkana Site, even though it was excavated decades ago.

Analysis is the way archaeologists learn about the past, and computers make more methods available to us than ever before. In my work, I use computational mapping techniques to study the copper artifacts recovered from the Gulkana Site. Studying where these objects were found will us understand if they were used by all people at the Gulkana Site or reserved for a select few.

Connecting archaeology to communities today

I am also a public archaeologist; I believe that the past is made meaningful through the people connected to it. This means that my study of the Gulkana Site would be insufficient were it conducted solely by me, alone at my computer 3,000 miles away from Alaska. Instead, I have designed my research in collaboration with descendants of the people who lived at the Gulkana Site to ensure my research holds value to them, not just to archaeologists.

In my research, this means embedding opportunities for youth involvement throughout my . Each year, I travel to Alaska to host a course about archaeology, Ahtna history, and technology in collaboration with Ahtna leadership and the local school district.

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In the course, we take field trips to archaeological sites and the Ahtna Cultural Center. Kids learn about the artifacts found at the Gulkana Site and have an to make their own. Ahtna share cultural knowledge with . At the end of the course, students integrate what they've learned into a game about the Gulkana Site.

The goal of my research is to bring new life to the Gulkana Site through digital methods and outreach. My experiences demonstrate that even a site excavated 50 years ago can reveal more to help us better understand the past. Perhaps more importantly, it can also help the next generation gain experience with technological skills and connect with their heritage. Old archaeological data is still meaningful in the digital age – we just have to pay attention to it.The Conversation

Emily Fletcher, Ph.D. Candidate in Archaeology, Purdue University

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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Keeping astronauts healthy in space isn’t easy − new training programs will prepare students to perform medicine while thousands of miles away from Earth

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theconversation.com – Arian Anderson, Emergency Medicine Physician, University of Colorado Anschutz Medical Campus – 2024-06-18 07:39:04

medicine professionals in consult with each other during a simulation exercise.

Katya Arquilla

Arian Anderson, University of Colorado Anschutz Medical Campus

In the coming decade, more people will go to space than ever before as human spaceflight enters a new era. NASA, the European Space Agency and other governmental agencies are partnering to develop crewed missions beyond the Moon. At the same time, these agencies are collaborating with private companies using new technologies to drive down the price of space exploration.

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Companies such as SpaceX, Blue Origin and Sierra Space have developed vehicles with reusable boosters, automated flight and lightweight materials to support these deep space missions. Some even have ambitions of their own to build private space stations, Moon bases or mining operations in the coming decades.

But as these technologies and partnerships rapidly make spaceflight more accessible, new challenges emerge. For one, maintaining the and performance of an astronaut crew. My team of researchers and educators at the University of Colorado and others around the world are looking to address this issue.

A group of people in orange jumpsuits stand around a table, with a person laying on it.

With spaceflight set to expand, astronauts will need access to medical care over longer voyages and on commercial flights.

Katya Arquilla

Emerging medical challenges in space

NASA astronauts are some of the most accomplished people on the planet, and they're some of the healthiest. Astronauts undergo extensive medical and psychological testing that in one study disqualified 26% of final-round applicants. This rigorous screening and testing effectively limits the chance of a medical event occurring during a mission.

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But as spaceflight becomes more accessible, astronaut crews on commercial missions will likely make up the majority of space travelers in the coming years. Private missions will be short and stay in a close orbit around Earth in the near term, but private crews will likely have less training and more chronic medical conditions than the professional astronauts currently living and working in space.

While experiments aboard the International Space Station have extensively studied the normal physiological changes occurring to the human system in weightlessness, there is limited to no data about how common chronic diseases such as diabetes or high blood pressure behave in the space .

Mars, shown from space.

During Mars missions, astronauts will be away from Earth for long periods of time, with limited access to medical resources.

CU/LASP EMM/EXI ITF/Kevin M. Gill, CC BY

This industry boom is also creating opportunities for long-duration missions to the Moon and Mars. Because of the length of missions and the distance from Earth, professional astronauts on these missions will experience prolonged weightlessness, leading to bone and muscle loss, communication delays of a few seconds up to 40 minutes, and extreme isolation for months to years at a time.

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Crews must function autonomously, while being exposed to new hazards such as lunar or Martian dust. Because of the fuel required for these missions, resources will be limited to the lowest mass and volume possible.

As a result, mission planners will need to make difficult decisions to determine what supplies are truly necessary in advance, with limited or unavailable resupply opportunities for food, water and medicine. In space, for example, radiation and humidity inside a spacecraft can cause medications to deteriorate more quickly and become unavailable or even toxic to crew members.

Crews on the space station have access to a flight surgeon at Mission Control to manage medical care in the same way telehealth is used on Earth. Crews on distant planets, however, will need to perform medical care or procedures autonomously.

In the event of a medical emergency, crews may not be able to evacuate to Earth. Unlike the space station, where medical evacuations to Earth can occur in less than 24 hours, lunar evacuations may take weeks. Evacuations from Mars may not be possible for months or even years.

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Put simply, the current approaches to medical care in spaceflight will not meet the needs of future commercial and professional astronauts. Researchers will need to develop new technologies and novel training approaches to prepare future providers to treat medical conditions in space.

The current leaders in space medicine are either experts in aerospace engineering or in medicine, but rarely do experts have formal training or a complete understanding of both fields. And these disciplines often can't speak each other's language both literally and figuratively.

Training the next generation

To meet the evolving demands of human spaceflight, educators and universities are looking to develop a way to train specialists who understand both the limitations of the human body and the constraints of engineering design.

Some schools and hospitals, such as the University of Texas Medical Branch, have residency training programs for medical school graduates in aerospace medicine. Others, such as UCLA and Massachusetts General Hospital, have specialty training programs in space medicine, but these currently target fully trained emergency medicine physicians.

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My team at the University of Colorado has created a program that integrates human physiology and engineering principles to train medical to think like engineers.

Two domed tents connected by long tubes, in the desert.

The University of Colorado brings students to the desert to simulate a lunar base. Students work together to solve simulated medical issues that might occur during a space mission.

Katya Arquilla

This program aims to help students understand human health and performance in the spaceflight environment. It approaches these topics from an engineering design and constraints perspective to find to the challenges astronauts will face.

One of our most popular classes is called Mars in Simulated Surface Environments. This class puts students through engineering and medical scenarios in a simulated Mars environment in the Utah desert. Students deal with the challenges of working and providing care while wearing a spacesuit and on a desolate Mars-like landscape.

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The stress of the simulations can feel real to the students, and they learn to apply their combined skill sets to care for their fellow crew members.

Educational programs like these and others aim to create cross-trained specialists who understand both patient care and the procedural nature of engineering design and can merge the two, whether for space tourists in orbit or as a pioneer to the surface of another planet.

A new period of spaceflight is here, and these programs are already training experts to make space accessible and safe.The Conversation

Arian Anderson, Emergency Medicine Physician, University of Colorado Anschutz Medical Campus

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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The Hubble telescope has shifted into one-gyro mode after months of technical issues − an aerospace engineering expert explains

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theconversation.com – Panagiotis Tsiotras, Professor of Aerospace Engineering, Georgia Institute of Technology – 2024-06-17 07:13:24

The Hubble Telescope is nearing its 35th birthday.

NASA via AP

Panagiotis Tsiotras, Georgia Institute of Technology

Imagine keeping a laser beam trained on a dime that's 200 miles away. Now imagine doing that continuously for 24 hours, while riding a merry-go-round. Seem difficult? Well, that's basically what the Hubble Space Telescope does.

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After months of technical issues, NASA announced June 4 that Hubble would shift into one-gyroscope mode. This essentially means that the telescope will have to rely on just one of the several gyroscopes – devices that measure an object's orientation in space – it normally uses to track and follow objects in space.

Named after astronomer Edwin Hubble, the Hubble telescope launched in 1990 into low Earth orbit. Here, it's above Earth's atmosphere, which interferes with the observations from Earth-based telescopes. During its three decades of operation, it has provided us with stunning pictures of distant galaxies and scientists to look closer to the beginning of the universe.

Hubble takes clear, high-resolution pictures of billions of light years away. To collect enough photons – light “particles” – for a high-quality picture, it essentially acts as a very low-speed camera. It keeps its aperture – that is, the opening in the lens that lets light pass through – open for up to 24 hours to take a single picture.

Anyone who has taken a at a low shutter speed knows how difficult it is to avoid ending up with a blurry image. Hubble takes this to an extreme. It needs to stay pointed at the same distant point in space with an accuracy within a few milliarcseconds – where one milliarcsecond equals one 3,600,000th of a degree – for up to 24 hours. And it needs to keep this accuracy while orbiting the Earth at 17,000 miles per hour (27,000 kilometers per hour) through extreme heat and cold.

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To keep track of its target and generate clear pictures, Hubble uses what aerospace engineers like me call attitude control . All spacecraft and aircraft have an attitude control system to them point in the right direction.

What's a gyro, anyway?

An attitude control system consists of a suite of sensors measuring the orientation of the spacecraft, a set of actuators – thrusters, reaction wheels or control moment gyroscopes – that move the spacecraft around, and a flight computer. The flight computer takes the measurements from the sensors and generates the commands for the actuators.

A diagram of the Hubble, showing three boxes labeled gyros, three labeled fine guidance sensors and two labeled reaction wheels in its interior.

The gyros work in tandem with fine guidance sensors and reaction wheels to control the telescope's orientation in space.

NASA/STSci

A gyroscope is a device that measures an object's attitude, or orientation in space. In other words, it measures how much the object has rotated from some fixed point. For Hubble to know where it's pointing to take a picture, it has to know where it is in space. It needs at least three gyros – one per axis.

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Hubble initially had six gyros: three main ones and three more as extras. But after more than 30 years in orbit, four of the gyros have failed from complications related to aging.

From the two remaining gyros, NASA has reserved one as a backup, so Hubble is now operating with a single gyro. But if you need at least three gyros – one per axis – to know where you are, how can Hubble figure out where it is with only one gyro?

One of Hubble's gyroscopes.

The clever answer that NASA engineers came up with is actually very simple. You can use other sensors on the telescope, such as magnetometers and star sensors, to make up for the lack of gyros.

Gyro stand-ins

Magnetometers measure Earth's local magnetic field, which scientists understand pretty accurately. You can use the magnetometers to get a rough idea of the attitude with respect to the known magnetic field direction, pretty much the same way you use a compass. A three-axis magnetometer can take measurements of the strength and direction of the Earth's magnetic field as the satellite moves along its orbit to find its orientation in space.

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Or you can use star trackers or sun sensors, which are much more accurate than magnetometers. These sensors use a map of the sky and align what they see with what's on the map to figure out where they are pointing.

By combining the star trackers, sun sensors, magnetometers and a single gyro, Hubble can maintain a pointing accuracy that is very close to the three-gyro configuration – although the one-gyro configuration will limit how fast Hubble can track objects in space.

Hubble has one of the most accurate pointing attitude control systems ever built, and it has provided people with stunning pictures of the early universe. But losing all but two gyros is just another reminder that Hubble's days are numbered.

Hubble's successor, the James Webb Space Telescope, launched on Dec. 25, 2021. It is stationed 1,000,000 miles (1,609,344 km) away from Earth at what is called the second Lagrange point (L2).

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At this point, the telescope, the Earth and the Sun are always aligned, and the telescope's protective sun shield blocks the Sun's rays. This feature allows its infrared camera to operate at chilly temperatures to much better-quality pictures.

While the long-enduring Hubble's discoveries opened the universe to astronomers, Webb will allow us to look deeper into the cosmos than ever before.The Conversation

Panagiotis Tsiotras, Professor of Aerospace Engineering, Georgia Institute of Technology

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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