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Research

Alzheimer’s and COVID-19 share a genetic risk factor

The discovery increases the risk of Alzheimer’s and severity of COVID-19

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An anti-viral gene that impacts the risk of both Alzheimer’s disease and severe COVID-19 has been identified by a research team.

The researchers estimate that one genetic variant of the OAS1 gene increases the risk of Alzheimer’s disease by up to six per cent in the population as a whole, while related variants of the same gene increase the likelihood of severe COVID-19 outcomes by up to 20 per cent.

The findings could open the door for new targets for drug development or tracking disease progression in either condition, and suggest that treatments developed could be used for both.

The findings also have potential benefits for other related infectious conditions and dementias.

Lead author Dr Dervis Salih, of UCL Queen Square Institute of Neurology and UK Dementia Research Institute at UCL, said: “While Alzheimer’s is primarily characterised by harmful build-up of amyloid protein and tangles in the brain, there is also extensive inflammation in the brain that highlights the importance of the immune system in Alzheimer’s. 

“We have found that some of the same immune system changes can occur in both Alzheimer’s disease and COVID-19.

“In patients with severe COVID-19 infection there can also be inflammatory changes in the brain. 

“Here we have identified a gene that can contribute to an exaggerated immune response to increase risks of both Alzheimer’s and COVID-19.”

For the study, the research team sought to build on their previous work, which found evidence from a large dataset of human genomes, to suggest a link between the OAS1 gene and Alzheimer’s disease.

The OAS1 gene is expressed in microglia, a type of immune cell that constitutes around ten per cent of all cells found within the brain. 

Investigating the gene’s link to Alzheimer’s further, they sequenced genetic data from 2,547 people, half of whom had Alzheimer’s disease. They found that people with a particular variation, called rs1131454, of the OAS1 gene were more likely to have Alzheimer’s disease, increasing carriers’ baseline risk of Alzheimer’s by an estimated 11 to 22 per cent. 

The new variant identified is common, as just over half of Europeans are believed to carry it, and it has a bigger impact on Alzheimer’s risk than several known risk genes.

Their findings add OAS1, an anti-viral gene, to a list of dozens of genes now known to affect a person’s risk of developing Alzheimer’s disease.

The researchers investigated four variants on the OAS1 gene, all of which dampen its expression. They found that the variants increasing the risk of Alzheimer’s disease are linked with OAS1 variants recently found to increase the baseline risk of needing intensive care for COVID-19 by as much as 20 per cent.

As part of the same research, in immune cells treated to mimic the effects of COVID-19, the researchers found that the gene controls how much the body’s immune cells release pro-inflammatory proteins. 

They found that microglia cells where the gene was expressed more weakly had an exaggerated response to tissue damage, unleashing what they call a ‘cytokine storm,’ which leads to an autoimmune state where the body attacks itself.

OAS1 activity changes with age, so further research into the genetic network could help to understand why older people are more vulnerable to Alzheimer’s, COVID-19, and other related diseases.

Following the outbreak of the COVID-19 pandemic, researchers from the UK Dementia Research Institute at UCL have pivoted their attention to investigating the long-term neurological consequences of the virus. 

Using biomarkers found in the blood and fluid surrounding the central nervous system, they are aiming to track neuroinflammation and injury to the neurons.

Dr Salih said: “If we could develop a simple way of testing for these genetic variants when someone tests positive for COVID-19, then it might be possible to identify who is at greater risk of needing critical care, but there is plenty more work to be done to get us there. 

“Similarly, we hope that our research could feed into the development of a blood test to identify whether someone is at risk of developing Alzheimer’s before they show memory problems.

“We are also continuing to research what happens once this immune network has been activated in response to an infection like COVID-19, to see whether it leads to any lasting effects or vulnerabilities, or if understanding the brain’s immune response to COVID-19, involving the OAS1 gene, may help to explain some of the neurological effects of COVID-19.”

Research

Women ‘under-represented in stroke trials for 30 years’

‘Put policy into practice so future research can address gaps in the understanding and treatment of stroke in women’

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Women have been under-represented in stroke clinical trials for the past 30 years, new research has found, making it harder to interpret what the findings really mean for them. 

The study found that more than three quarters of the trials enrolled less women than the expected proportion that experience stroke in the community.

George Institute researchers looked at 281 stroke trials that had at least 100 participants and were conducted between 1990 and 2020. 

The total number of participants was 588,887, of whom 37.4 per cent were women, but the average prevalence of stroke in women across the countries included was 48 per cent. 

“It’s now time to put policy into practice so that future research can address our knowledge gaps in the understanding and treatment of stroke in women,” said study co-author Dr Katie Harris. 

While there have been studies showing varying degrees of representation of women in cardiovascular trials, this issue has only recently started to be examined in relation to stroke trials.

The greatest differences were seen in trials involving a particular type of stroke known as intracerebral haemorrhage, those where the mean age of participants was less than 70. 

Lead author Dr Cheryl Carcel, from The George Institute for Global Health and a Heart Foundation Fellow, said that while both women and men had the same one-in-four risk of experiencing a stroke in their lifetime, women were much older and in worse health at the time they have a stroke.

“These findings have implications for how women with stroke may be treated in the future, as women typically have worse functional outcomes after stroke and require more supportive care,” said Dr Carcel.

Dr Carcel said the reasons for this under-representation were complex and most likely due to a number of factors, including recruitment criteria that unintentionally exclude women like age and having other health conditions.

“Patient attitudes and beliefs can also be a factor, and there can even be a potential bias among the clinical staff conducting the study,” she said. 

“Our previous research indicated that how women were treated in hospital and whether they had been on the right medications before their stroke, could be responsible for their poorer outcomes.”

Dr Harris said that barriers and facilitators to women’s participation in stroke trials needed to be explored both at the trial and patient level to help redress the balance.

“Achieving a better gender representation in stroke trials can provide a more reliable assessment of the treatment benefits and harms, and inform treatment guideline recommendations for women affected by this serious condition,” she said.

While the United States, Canada and some European countries, adopted policies to boost the number of women in clinical trials over the course of the study, the results showed no change over this time.

“Our study suggests those efforts have clearly not translated into action,” Dr Harris added. 

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Brain injury

‘Take urgent action on rugby player safety’

Rugby’s authorities must act now to protect players at all levels, following publication of the landmark BRAIN study

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rugby players in a scrum with their heads and shoulders down

Rugby’s governing authorities are being urged to take “urgent preventative action” to protect players at all levels of the sport after new research suggests the game may have been safer in the pre-professional era. 

The BRAIN study, published today, found that former elite rugby players who experienced three or more concussions during their career did not have worse cognitive function before the age of 75 than those who had experienced no, or just one or two, concussions. 

The study found no overall group association between concussion history and worse cognitive function, but did find that 29 per cent of over 75s who had sustained three or more rugby-related concussions during their career had significantly worse cognitive function.

However, results from the BRAIN study – funded by The Drake Foundation, which worked with 146 former elite rugby players in England aged 50 and over, most of whom played in the pre-professional era – call into question whether safety standards in the sport have worsened since the game became professional.  

Several retired players from the modern era have recently been diagnosed with early-onset neurodegenerative disease and likely Chronic Traumatic Encephalopathy (CTE). 

In addition, the neuroimaging results of the Drake Rugby Biomarker Study, published earlier this year, found that 23 per cent of current elite adult rugby players tested had abnormalities in brain structure, and half showed an unexpected change in brain volume.

The Foundation has also been vocal in its campaign to make recommendations around safety in rugby and football enforceable rules, and is now calling for further immediate emphasis on player welfare. 

“These findings are broadly reassuring for players from the amateur era,” says Lauren Pulling, CEO of The Drake Foundation. 

“However, given the findings of the Drake Rugby Biomarker Study and recent cases of early-onset brain disease in ex-players from the professional era, the new study results do call into question how long-term health might differ in players from the modern era.

“The evidence we have so far suggests that the sport may actually be travelling in the wrong direction in terms of player welfare and brain health. 

“In addition to further research, we therefore also urge the sport’s governing bodies to review the modern game’s laws and protocols and take urgent, preventative action to universally reduce players’ exposure to head impacts both in matches and training.”

Additional research carried out this month on behalf of The Drake Foundation by Censuswide, via an online survey of 508 respondents in the UK who are involved in rugby union, found that 62 per cent of adults who either play amateur rugby or have a child who plays rugby are concerned about the long-term effects of the sport on their or their child’s brain health. 

This figure rises to 73 per cent for parents who do not play the game themselves, but who have a child that does.

Over 60 per cent agree that rugby has become a more dangerous sport at all levels since it turned professional in 1995, whilst 66 per cent believe that rugby union would be safer if fundamental law changes were introduced to better reflect the way the sport was played in the pre-professional era.

James Drake, founder of The Drake Foundation, says: “As a passionate sports fan who loves rugby, I’ve witnessed first-hand the way the game has evolved since turning professional. 

“In my view it’s a sport that has become ostensibly less safe for the players involved and my concerns are reflected by our research this month, which reveals 61 per cent of adults who either play the game or have children that do, are concerned about the sport’s long-term effect on brain health.

“A further two thirds of adults believe the sport could be made safer if law changes were introduced to return it to the game as it was played in the amateur era. The Drake Foundation is calling on rugby’s authorities to give this immediate consideration to protect the sport we love and the current and future generations who play it.”

The BRAIN study is the first to carry out detailed measurements of cognitive function in a large number of former players and to relate this to their concussion and playing history. 

It was conducted by the London School of Hygiene & Tropical Medicine, Queen Mary University of London and the Institute of Occupational Medicine with researchers from UCL and the University of Oxford, and with assistance from the Rugby Football Union (RFU). 

It is also the first to include substantial numbers from the over-75 age-group. Previous studies which have focussed on younger players have found little or no association between concussions and reduced cognitive function.

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Research

Research reveals how brain cells talk

Breakthrough could help in the treatment of mental health and early-stage neurodegenerative diseases

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New understanding of how brain cells talk could help in the treatment of mental health conditions and early-stage neurodegenerative diseases. 

Researchers have discovered that reversing the modification of molecular messages at synapses in the human brain may contribute to conditions including anxiety and dementia. 

The findings, published today, are hailed as a major step in our understanding of how brain cells communicate, and could help to identify new treatments for neurological and psychiatric conditions.

The research was led by Dr Helen Miranda Knight in the School of Life Sciences at the University of Nottingham, along with researchers across the Schools of Medicine, Life Science, and Bioscience.

She said: “The implications are very important for normal brain function but also for reversible psychiatric mental conditions such as anxiety and addiction disorders and early-stage neurodegenerative diseases such as dementias.”

Nerve cells in the human brain talk to each other at sites called synapses, where molecules are released to signal to the next cell. 

When people learn or remember things, this signalling is strengthened. When communication between synapses goes wrong, circuits become broken. 

As more circuits are lost, this changes how people can think and perform everyday tasks. This is seen in cognitive disorders, such as forms of dementia and some mental health conditions.

The function of nerve cells and synapses depends on proteins that are made using information encoded in genetic material called RNA. It is thought that RNAs are located exactly where and when they are needed for synaptic signalling because some kind of synaptic ‘tag’ labels the correct active synapse. 

Scientists have recently learnt that RNA can have a methyl group or molecule added to one of the RNA bases which ‘marks’ the RNA message. Such adding of methyl groups can influence proteins binding to DNA or RNA and consequently stop proteins being produced.

This new study shows that RNA marking can be reversed at synapses and hence may act as a ‘synaptic tag’. The findings suggest, that if disrupted, this could cause synapses and nerve cells to malfunction by influencing the formation of toxic protein clumps.

The researchers used advanced microscopy to examine changes in marked RNAs in time and location at synapses, and a sequencing technique to characterise ‘marked’ RNAs in brain tissue from the hippocampus, a region of the brain very important for memory formation.

Dr Knight said: “In this new study, we are able to gain a new understanding of the genomic mechanisms which regulate how nerve cells communicate at synapses. These genomic mechanisms involve methyl groups being put on RNA messages and importantly taken off when a synapse is active.”

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