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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 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 remove 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 , with disease prevalence increasing progressively from age 65 and up. Such cases are mostly sporadic, with no clear family 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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Chandrayaan-3’s measurements of sulfur open the doors for lunar science and exploration

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Chandrayaan-3's measurements of sulfur open the doors for lunar science and exploration

Chandrayaan-3's Pragyan rover has traveled 328 feet.
(100 meters) and measured the chemistry of the lunar soil.
ISRO

Jeffrey Gillis-Davis, Arts & Sciences at Washington University in St. Louis

In an exciting milestone for lunar scientists around the globe, India's Chandrayaan-3 lander touched down 375 miles (600 km) from the south pole of the Moon on Aug. 23, 2023.

In just under 14 Earth days, Chandrayaan-3 provided scientists with valuable new data and further inspiration to explore the Moon. And the Indian Space Research Organization has shared these initial results with the world.

While the data from Chandrayaan-3's rover, named Pragyan, or “wisdom” in Sanskrit, showed the lunar soil contains expected elements such as iron, titanium, aluminum and calcium, it also showed an unexpected surprise – sulfur.

India's lunar rover Pragyan rolls out of the lander and onto the surface.

Planetary scientists like me have known that sulfur exists in lunar rocks and soils, but only at a very low concentration. These new measurements imply there may be a higher sulfur concentration than anticipated.

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Pragyan has two instruments that analyze the elemental composition of the soil – an alpha particle X-ray spectrometer and a laser-induced breakdown spectrometer, or LIBS for short. Both of these instruments measured sulfur in the soil near the landing site.

Sulfur in soils near the Moon's poles might astronauts live off the one day, making these measurements an example of science that enables exploration.

Geology of the Moon

There are two main rock types on the Moon's surface – dark volcanic rock and the brighter highland rock. The brightness difference between these two materials forms the familiar “man in the moon” face or “rabbit picking rice” image to the naked eye.

The Moon, with the dark regions outlined in red, showing a face with two ovals for eyes and two shapes for the nose and mouth.
The dark regions of the Moon have dark volcanic soil, while the brighter regions have highland soil.
Avrand6/Wikimedia Commons, CC BY-SA

Scientists measuring lunar rock and soil compositions in labs on Earth have found that materials from the dark volcanic plains tend to have more sulfur than the brighter highlands material.

Sulfur mainly comes from volcanic activity. Rocks deep in the Moon contain sulfur, and when these rocks melt, the sulfur becomes part of the magma. When the melted rock nears the surface, most of the sulfur in the magma becomes a gas that is released along with vapor and carbon dioxide.

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Some of the sulfur does stay in the magma and is retained within the rock after it cools. This explains why sulfur is primarily associated with the Moon's dark volcanic rocks.

Chandrayaan-3's measurements of sulfur in soils are the first to occur on the Moon. The exact amount of sulfur cannot be determined until the data calibration is completed.

The uncalibrated data collected by the LIBS instrument on Pragyan suggests that the Moon's highland soils near the poles might have a higher sulfur concentration than highland soils from the equator and possibly even higher than the dark volcanic soils.

These initial results give planetary scientists like me who study the Moon new insights into how it works as a geologic system. But we'll still have to wait and see if the fully calibrated data from the Chandrayaan-3 team confirms an elevated sulfur concentration.

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Atmospheric sulfur formation

The measurement of sulfur is interesting to scientists for at least two reasons. First, these findings indicate that the highland soils at the lunar poles could have fundamentally different compositions, compared with highland soils at the lunar equatorial regions. This compositional difference likely from the different environmental conditions between the two regions – the poles get less direct sunlight.

Second, these results suggest that there's somehow more sulfur in the polar regions. Sulfur concentrated here could have formed from the exceedingly thin lunar atmosphere.

The polar regions of the Moon less direct sunlight and, as a result, experience extremely low temperatures compared with the rest of the Moon. If the surface temperature falls, below -73 degrees C (-99 degrees F), then sulfur from the lunar atmosphere could collect on the surface in solid form – like frost on a window.

Sulfur at the poles could also have originated from ancient volcanic eruptions occurring on the lunar surface, or from meteorites containing sulfur that struck the surface and vaporized on impact.

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Lunar sulfur as a resource

For long-lasting space missions, many agencies have thought about building some sort of base on the Moon. Astronauts and robots could travel from the south pole base to collect, process, store and use naturally occurring materials like sulfur on the Moon – a concept called in-situ resource utilization.

In-situ resource utilization means fewer trips back to Earth to get supplies and more time and energy spent exploring. Using sulfur as a resource, astronauts could build solar cells and batteries that use sulfur, mix up sulfur-based fertilizer and make sulfur-based concrete for construction.

Sulfur-based concrete actually has several compared with the concrete normally used in building projects on Earth.

For one, sulfur-based concrete hardens and becomes strong within hours rather than weeks, and it's more resistant to wear. It also doesn't require water in the mixture, so astronauts could save their valuable water for drinking, crafting breathable oxygen and making rocket fuel.

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The gray surface of the Moon as seen from above, with a box showing the rover's location in the center.
The Chandrayaan-3 lander, pictured as a bright white spot in the center of the box. The box is 1,108 feet (338 meters) wide.
NASA/GSFC/Arizona

While seven missions are currently operating on or around the Moon, the lunar south pole region hasn't been studied from the surface before, so Pragyan's new measurements will help planetary scientists understand the geologic history of the Moon. It'll also allow lunar scientists like me to ask new questions about how the Moon formed and evolved.

For now, the scientists at Indian Space Research Organization are busy processing and calibrating the data. On the lunar surface, Chandrayaan-3 is hibernating through the two--long lunar night, where temperatures will drop to -184 degrees F (-120 degrees C). The night will last until September 22.

There's no guarantee that the lander component of Chandrayaan-3, called Vikram, or Pragyan will survive the extremely low temperatures, but should Pragyan awaken, scientists can expect more valuable measurements.The Conversation

Jeffrey Gillis-Davis, Research Professor of Physics, Arts & Sciences at Washington University in St. Louis

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

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Spyware can infect your phone or computer via the ads you see online – report

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Spyware can infect your phone or computer via the ads you see online – report

A new type of spyware means those online ads could go from annoying to menacing.
AP Photo/Julio Cortez

Claire Seungeun Lee, UMass Lowell

Each day, you digital traces of what you did, where you went, who you communicated with, what you bought, what you're thinking of buying, and much more. This mass of data serves as a library of clues for personalized ads, which are sent to you by a sophisticated network – an automated marketplace of advertisers, publishers and brokers that operates at lightning speed.

The ad networks are designed to shield your identity, but companies and governments are able to combine that information with other data, particularly phone location, to identify you and track your movements and online activity. More invasive yet is spyware – malicious software that a agent, private investigator or criminal installs on someone's phone or computer without their knowledge or consent. Spyware lets the user see the contents of the target's device, calls, texts, email and voicemail. Some forms of spyware can take control of a phone, including turning on its microphone and camera.

Now, according to an investigative report by the Israeli newspaper Haaretz, an Israeli technology company called Insanet has developed the means of delivering spyware via online ad networks, turning some targeted ads into Trojan horses. According to the , there's no defense against the spyware, and the Israeli government has given Insanet approval to sell the technology.

Sneaking in unseen

Insanet's spyware, Sherlock, is not the first spyware that can be installed on a phone without the need to trick the phone's owner into clicking on a malicious link or downloading a malicious file. NSO's iPhone-hacking Pegasus, for instance, is one of the most controversial spyware tools to emerge in the past five years.

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Pegasus relies on vulnerabilities in Apple's iOS, the iPhone operating system, to infiltrate a phone undetected. Apple issued a security update for the latest vulnerability on Sept. 7, 2023.

Diagram showing the different entities involved in real time bidding, and the requests and responses
When you see an ad on a web page, behind the scenes an ad network has just automatically conducted an auction to decide which advertiser won the right to present their ad to you.
Eric Zeng, CC BY-ND

What sets Insanet's Sherlock apart from Pegasus is its exploitation of ad networks rather than vulnerabilities in phones. A Sherlock user creates an ad campaign that narrowly focuses on the target's demographic and location, and places a spyware-laden ad with an ad exchange. Once the ad is served to a web page that the target views, the spyware is secretly installed on the target's phone or computer.

Although it's too early to determine the full extent of Sherlock's capabilities and limitations, the Haaretz report found that it can infect Windows-based computers and Android phones as well as iPhones.

Spyware vs. malware

Ad networks have been used to deliver malicious software for years, a practice dubbed malvertising. In most cases, the malware is aimed at computers rather than phones, is indiscriminate, and is designed to lock a user's data as part of a ransomware attack or steal passwords to access online accounts or organizational networks. The ad networks constantly scan for malvertising and rapidly block it when detected.

Spyware, on the other hand, tends to be aimed at phones, is targeted at specific people or narrow categories of people, and is designed to clandestinely obtain sensitive information and monitor someone's activities. Once spyware infiltrates your system, it can record keystrokes, take screenshots and use various tracking mechanisms before transmitting your stolen data to the spyware's creator.

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While its actual capabilities are still under investigation, the new Sherlock spyware is at least capable of infiltration, monitoring, data capture and data transmission, according to the Haaretz report.

The new Sherlock spyware is likely to have the same frightening capabilities as the previously discovered Pegasus.

Who's using spyware

From 2011 to 2023, at least 74 governments engaged in contracts with commercial companies to acquire spyware or digital forensics technology. National governments might deploy spyware for surveillance and gathering intelligence as well as combating and terrorism. enforcement agencies might similarly use spyware as part of investigative efforts, especially in cases involving cybercrime, organized crime or national security threats.

Companies might use spyware to monitor employees' computer activities, ostensibly to protect intellectual property, prevent data breaches or ensure compliance with company policies. Private investigators might use spyware to gather information and evidence for clients on legal or personal matters. Hackers and organized crime figures might use spyware to steal information to use in fraud or extortion schemes.

On top of the revelation that Israeli cybersecurity firms have developed a defense-proof technology that appropriates online advertising for civilian surveillance, a key concern is that Insanet's advanced spyware was legally authorized by the Israeli government for sale to a broader audience. This potentially puts virtually everyone at risk.

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The silver lining is that Sherlock appears to be expensive to use. According to an internal company document cited in the Haaretz report, a single Sherlock infection costs a client of a company using the technology a hefty US$6.4 million.The Conversation

Claire Seungeun Lee, Associate Professor of Criminology and Justice Studies, UMass Lowell

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

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NASA’s Mars rovers could inspire a more ethical future for AI

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Cracking down on slavery and human trafficking in NSW

Responses to violence through human trafficking and demand a multifaceted approach including governments, according to a new .
shutterstock

Jennifer Burn, University of Technology Sydney

The NSW Community Relations Commission released a report which found the NSW is failing to adequately acknowledge or respond to reports of human trafficking and slavery.

While many in the community think of a trafficked person as a woman working in sexual servitude, the report found that human trafficking and slavery affects men, women and children.

Exploitation through trafficking and forced labour occurs in many industries including hospitality, agriculture and factory work. Some victims are criminally exploited in private homes; others are subjected to forced marriage.

Recent cases

Over the last few weeks and months, media reports of people experiencing such exploitation worldwide have put a spotlight on slavery, human trafficking and practices such as forced marriage and forced labour.

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There were distressing reports of a high profile case in the United Kingdom where three women were allegedly held in slavery or slavery like-conditions for 30 years in an ordinary house in an ordinary residential area.

While the facts of the case are still unclear and highlight difficulties in understanding the dimension of abuse – particularly in private domestic settings – the said that the women were controlled by “invisible handcuffs” demonstrating a “complicated and disturbing picture of emotional control”.

Back in Australia, the ABC reported in July on the case of a group of Filipino boxers who were trafficked to Sydney. It was alleged the boxers' passports were confiscated and they were prevented from leaving until their debts were paid off. They lived in substandard conditions in a small garage and were given food scraps for meals.

As a result of investigation, the Australian Federal Police charged three members of a family with people-trafficking offences. The case has not yet been heard.

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In an earlier Australian case, a couple were charged and convicted of slavery offences involving the trafficking of a vulnerable Filipina woman to Australia to work in their takeaway food shop and as a domestic worker for their family. The woman worked in the family's takeaway food shop and the family's home in a Queensland country town every day for up to 18 hours a day.

After work, she returned to the family's home, cleaned and looked after the couple's three children and undertook other household duties. She was paid very little and was further abused. Eventually she escaped, leading to an investigation by police and charges and convictions of slavery offences.

Putting an end to slavery

New laws introduced by the Commonwealth earlier this year criminalise forced labour and forced marriage and boost the Australian legislative response to human trafficking, slavery and slavery-like practices.

People affected by trafficking and slavery must be supported in their recovery and to achieve justice. As such, the NSW Community Relations Commission has recommended that the NSW attorney-general review the current Victims Rights and Support Act 2013 scheme to include crimes related to human trafficking and slavery.

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It also recommended the Commonwealth establish a national compensation scheme for victims of trafficking and slavery, recognising that such crimes are primarily Commonwealth offences.

People can be enslaved through subtle forms of coercion, and work in domestic servitude for very little money.
AAP/Jenny Evans

The inquiry suggested the Department of Family and Community Services assess existing services and develop an action plan to co-ordinate services for people who have experienced trafficking and slavery. Non-residents in NSW are currently ineligible for housing support, for instance, so the inquiry asked Housing NSW to provide housing services for the small number of people who are ineligible for other forms of housing support and who are in desperate need of accommodation.

The inquiry also recommended a number of simple, practical measures. Visa applicants and entrants to Australia, for instance, should be provided with more information about the Australian legal system. They should also be given law enforcement contact details, information about the role of the Fair Work Ombudsman and a brief statement about Australian laws against slavery and trafficking, including forced marriage.

The inquiry noted the Commonwealth had initiated a community awareness program to boost general and specific awareness about human trafficking in slavery in Australian communities. Clearly, there is a role for NSW to work with the Commonwealth and to develop campaigns and information resources for the NSW community, in schools, and to be made available to vulnerable groups.

The inquiry also recommended the NSW government invest in more of police, frontline government agency staff – especially in and social services – to ensure we have the best chance of identifying trafficked and enslaved people in NSW and extending support to the trafficked person.

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Responses to violence through human trafficking and slavery demand a multifaceted approach by governments and non-government agencies, and include the private sector. The inquiry sets out a pathway for NSW to co-ordinate and develop an effective -based response to these abuses.The Conversation

Jennifer Burn, Associate Professor, Faculty of Law and Director of Anti-Slavery Australia, University of Technology Sydney

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

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