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Dementia

International Alzheimer’s clinical trial to test two drugs in combination

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Brain disease

Researchers leading a worldwide clinical trial aimed at finding treatments for Alzheimer’s disease are modifying an arm of the trial to evaluate a combination of drugs targeting two brain proteins – amyloid and tau. 

The trial – known as the Tau Next Generation Trial (Tau NexGen) – was initially announced with a focus on drugs that target tau, but with increasing evidence that targeting amyloid can reduce biomarkers of Alzheimer’s disease, the trial’s leaders have revised the first arm to include an experimental therapy targeting amyloid as well.

Tau NexGen is part of the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU), led by investigators at Washington University School of Medicine in St. Louis. 

The DIAN-TU is an international network of academic centres focused on finding therapies for Alzheimer’s disease by studying people who have rare, inherited mutations that will lead to a very high chance they will develop the disease at an early age.

“With growing evidence that removing amyloid plaques has biologically beneficial effects on amyloid and tau, we believe that targeting both Alzheimer’s disease pathologies — amyloid plaques and tau tangles — at the same time can provide the highest chance of success,” said principal investigator Dr Randall J. Bateman, director of DIAN-TU and the Charles F. and Joanne Knight Distinguished Professor of Neurology at Washington University.

The DIAN-TU launched in 2012 as the first prevention trial platform for Alzheimer’s disease. 

A trial platform allows multiple treatments to be evaluated using a single master protocol. The first therapies evaluated on the DIAN-TU platform were designed to target the buildup of amyloid plaques in the brain. Such plaques are thought to contribute to problems with memory and thinking. 

With the initiation of the Tau NexGen trial, the DIAN-TU has extended its focus to another Alzheimer’s disease pathology, tau tangles, that has been closely linked to cognitive decline.

The Tau NexGen trial is designed with three arms. Each arm will evaluate an investigational drug that targets tau; each drug is designed to work in different ways.

The first arm of the Tau NexGen trial will evaluate an experimental anti-amyloid drug called lecanemab (designed to target forms of amyloid called oligomers and protofibrils) and an investigational tau drug known as E2814 that is designed to target the spread of tau. Both drugs are developed by the Japanese pharmaceutical company Eisai Co Ltd. 

This will be the first Alzheimer’s prevention trial to target both amyloid and tau with two drugs at the same time.

For the other two arms, the research team plans to choose from two classes of tau drugs that act in different ways: by targeting other mechanisms of tau pathology, including small molecule drugs that inhibit tau aggregation; and genetic treatments that reduce the production of tau protein. 

Future tau drug arms may also be combined with amyloid drugs such as lecanemab.

The Tau NexGen trial is primarily funded by the National Institute on Aging of the National Institutes of Health (NIH), with significant support from Eisai, as well as the Alzheimer’s Association and philanthropic donations. Eisai is contributing E2814 and lecanemab to the trial.

The DIAN-TU trial platform is the first trial platform aimed at identifying drugs to prevent or slow Alzheimer’s in people who are nearly certain to develop the disease due to genetic mutations. 

People who inherit such mutations tend to develop symptoms at around the same age their affected parents did, often in their 50s, 40s or even 30s. While devastating for families, such mutations allow researchers to identify and study people in the earliest stages of the disease before their behaviour and memory begin to change.

Three trial arms were previously launched on the DIAN-TU trial platform to evaluate experimental drugs targeting amyloid. One, gantenerumab, reduced molecular markers of disease and slowed neurodegeneration in a phase 2/3 clinical trial. 

These promising results led the researchers to launch an exploratory open-label extension of the trial, meaning that participants in both the drug and placebo groups have been offered the drug, and the researchers continue to monitor their progress.

Although the trial focuses on people with rare mutations, drugs that are successful in this population would be promising candidates .

Dementia

Young-onset Alzheimer’s prevention trial to launch

The Primary Prevention Trial will target participants up to 25 years before the expected onset of dementia

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An international clinical trial is being launched aimed at preventing young-onset Alzheimer’s disease in people genetically destined to develop the illness. 

Unlike most other Alzheimer’s prevention trials, this will enrol people before the disease has taken hold, up to 25 years before the expected onset of dementia. 

The Primary Prevention Trial, led by Washington University School of Medicine in St. Louis, will investigate whether gantenerumab — an investigational antibody under development for Alzheimer’s disease by Roche and Genentech — can clear a key Alzheimer’s protein called amyloid beta, and slow or stop the disease. 

Amyloid is the chief component of plaques that dot the brains of people with the disease.

Many scientists suspect the disease originates from the buildup of amyloid plaques in the brain that start to develop up to two decades before symptoms of dementia begin.

“Overwhelming evidence suggests that the most effective way to slow or stop amyloid beta is to prevent it from building up in the first place, but most of the drugs targeted to this protein have been tested in people who already have at least some early signs of the disease, such as memory loss – when the disease is far enough along that reducing amyloid alone isn’t likely to stop it,” said Dr Eric McDade, an associate professor of neurology and the trial’s principal investigator. 

“We’ll be recruiting participants as young as 18. In many ways, this trial will be a necessary test of the amyloid hypothesis, which has had a major influence on Alzheimer’s research and drug development over the past 30 years.”

The new trial involves families with rare genetic mutations that cause Alzheimer’s at a young age – typically in a person’s 50s, 40s or even 30s. 

A parent with such a mutation has a 50 per cent chance of passing the genetic mutation to a child, and any child who inherits the mutation is all but guaranteed to develop symptoms of dementia near the same age as his or her parent. 

This certainty gives researchers an opportunity to evaluate the effectiveness of drugs designed to prevent Alzheimer’s.

More than $130million has been earmarked for the trial, including grants totalling an estimated $97.4million from the National Institute on Aging (NIA) of the National Institutes of Health (NIH), $14million from the Alzheimer’s Association and the GHR Foundation, and up to $11.5million from longtime Washington University benefactor Joanne Knight of St. Louis and family, who have long supported Alzheimer’s research at Washington University. In addition, the university has pledged to raise an additional $6.5 million. 

The trial is being conducted in close partnership with Roche and Genentech, which also is providing significant funding.

“We are thrilled to be part of this important clinical trial in one of the earliest stages of Alzheimer’s studied to date,” said Dr Rachelle Doody, global head of neurodegeneration at Roche and Genentech. 

“Our vision has always been to detect Alzheimer’s early, before damage in the brain is irreversible, offering tools and treatment all along the journey for people at risk of the disease. 

“Close collaboration between industry, academia and patients is so critical to achieve this and tackle the complex challenge of this disease.”

The trial will recruit people with rare, early-onset forms of the disease, but the results also will further understanding of Alzheimer’s overall, which could benefit the millions of people living with the more common form, which affects people later in life. 

Dr McDade and his team are studying about 230 participants from families that carry genetic mutations that lead to early-onset Alzheimer’s disease. 

The participants come from sites on five continents and have no or very few amyloid deposits. 

The trial will test gantenerumab over four years, with a goal of determining whether early treatment will prevent the buildup of the toxic protein.

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Brain injury

COVID ‘can cause more signs of brain damage than Alzheimer’s’

New research found higher levels of seven markers of neurodegeneration in hospitalised COVID patients

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Patients hospitalised for COVID-19 had higher levels over the short term of blood proteins known to rise with neurological damage than non–COVID-19 patients diagnosed with Alzheimer’s disease, a new study has found.

The research – conducted over two months early in the COVID-19 pandemic – found higher levels of seven markers of brain damage, or neurodegeneration, in patients with COVID-19 with neurological symptoms than those without them, and much higher levels in patients that died in the hospital than in those discharged and sent home.

A second analysis by the team from NYU Grossman School of Medicine found that a subset of the damage markers in patients hospitalised with COVID-19, over the short term, were significantly higher than in patients diagnosed with Alzheimer’s disease, and in one case more than twice as high.

“Our findings suggest that patients hospitalised for COVID-19, and especially in those experiencing neurological symptoms during their acute infection, may have levels of brain injury markers that are as high as, or higher than, those seen in people who have Alzheimer’s disease,” says lead author Dr Jennifer A. Frontera, professor in the Department of Neurology at NYU Grossman School of Medicine.

“Traumatic brain injury, which is also associated with increases in these biomarkers, does not mean that a patient will develop Alzheimer’s disease or related dementias later on, but does increase the risk of it,” says senior author Dr Thomas M. Wisniewski, the Gerald J. and Dorothy R. Friedman Professor in the Department of Neurology and director of the Center for Cognitive Neurology at NYU Langone. 

“Whether that kind of relationship exists in those who survive severe COVID-19 is a question we urgently need to answer with ongoing monitoring of these patients.”

The study, conducted from March to May 2020, identified 251 people who, although 71 years on age on average, had no record or symptoms of cognitive decline or dementia before being hospitalised for COVID-19. 

These patients were then divided into groups with and without neurological symptoms during their acute COVID-19 infection, when patients either recovered and were discharged, or died.

The research team also, where possible, compared marker levels in the COVID-19 group to patients in the clinical core cohort of NYU Langone’s Alzheimer’s Disease Research Center, an ongoing, long-term study at NYU Langone Health. 

None of these 161 control patients (54 cognitively normal, 54 with mild cognitive impairment, and 53 diagnosed with Alzheimer’s disease) had COVID-19. Brain injury was measured using single-molecule array (SIMOA) technology, which can track the minute blood levels of neurodegeneration markers in picograms (one trillionth of a gram) per millilitre of blood (pg/ml), where older technologies could not.

Three of the study markers—ubiquitin carboxy-terminal hydrolase L1 (UCHL1), total tau, and phosphorylated-tau-181 (ptau181)—are known measures of the death or disabling of neurons, the cells that enable nerve pathways to carry messages. 

Levels of neurofilament light chain increase with damage to axons, which are extensions of neurons. Glial fibrillary acidic protein (GFAP) is a measure of damage to glial cells, which support neurons. Amyloid beta 40 and 42 are proteins known to build up in people who have Alzheimer’s disease. 

Past study results argue that total tau and ptau181 are also specific measures of Alzheimer’s disease, but their role in the disease remains a matter of debate.

Blood markers in the COVID-19 patient group were measured in blood serum (the liquid part of blood that has been made to clot), while those in the Alzheimer’s disease study were measured in plasma (the liquid blood fraction that remains when clotting is prevented). 

For technical reasons, the difference meant that neurofilament light chain, GFAP, and UCHL1 levels could be compared between the COVID-19 group and patients in the Alzheimer’s disease study, but total tau, ptau181, amyloid beta 40, and amyloid beta 42 could only be compared within the COVID-19 patient group (neuro symptoms or not; death or discharge).

Further, the main measure of neurological damage in patients with COVID-19 was toxic metabolic encephalopathy, or TME, with symptoms that range from confusion to coma, and caused during severe infections by toxins generated as the immune system overreacts (sepsis), kidneys fail (uremia), and oxygen delivery is compromised (hypoxia). 

Specifically, the average percentage increase in levels of the seven markers for hospitalised patients with TME compared to those without neurological symptoms was 60.5 per cent. 

For the same markers within the COVID-19 group, average percentage increase when comparing those successfully discharged home from the hospital to those who died in the hospital was 124 per cent.

A secondary set of findings came from comparing neurofilament light chain, GFAP, and UCHL1 levels in the serum of people with COVID-19 against levels of the same markers in the plasma of non–COVID-19 Alzheimer’s disease patients. 

Neurofilament light chain was, over the short-term, 179 per cent higher (73.2 versus 26.2 pg/ml) in patients with COVID-19 than those with Alzheimer’s disease. GFAP was 65 per cent higher (443.5 versus 275.1 pg/ml) in patients with COVID-19 patients than those with Alzheimer’s disease, while UCHL1 was 13 per cent higher (43 versus 38.1 pg/ml).

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Dementia

Dementia protein changes discovered in terminal childhood disease

‘These findings challenge the view that changes to the brain that underlie these forms of dementia are merely age-associated’

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A world-first study has revealed that protein changes seen in dementia are also present in a terminal childhood disease. 

The pioneering research found that the brains of infants who passed away with an extremely rare genetic condition, Krabbe disease, have similar changes to those seen in two age-related brain diseases, dementia with Lewy bodies and Parkinson’s disease.

The study, from Newcastle University and funded by Alzheimer’s Research UK, shows alpha-synuclein has the potential to spread throughout the brain. 

Dementia with Lewy bodies (DLB) and Parkinson’s disease are both neurodegenerative diseases associated with older age. 

In both diseases, a protein called alpha-synuclein builds up in the brain into structures called Lewy bodies, causing damage to nerve cells.

In contrast, Krabbe disease is a rare inherited childhood disorder – with only one case in every 100,000 births. 

The disease destroys the protective coating surrounding nerve cells in the brain and throughout the nervous system. It is caused by a mutation in the GALC gene, with symptoms showing within the first few months of life.

Sadly, the disease typically leads to death in those affected by the age of two.

The team at Newcastle studied postmortem brain tissue of four infants who died of Krabbe disease. While they did not identify Lewy bodies in the brain tissue of those infants, they did identify changes to the protein alpha-synuclein that are normally associated with DLB and Parkinson’s disease.

In particular, the researchers noted that the alpha-synuclein protein in Krabbe disease had the ability to stick together and spread through the brain, a key change associated with dementia with Lewy bodies and Parkinson’s disease that is thought to drive the progression of both diseases.

Dr Daniel Erskine, Alzheimer’s Research UK Research Fellow at Newcastle University, who is an expert in Lewy bodies and led the study, said: “Looking at the brains of four infants with Krabbe disease compared to four infants without Krabbe disease, we performed a series of experiments to establish the behaviour of the alpha-synuclein protein. 

Dr Daniel Erskine

“We found that alpha-synuclein in Krabbe disease shared key qualities that are normally only associated with age-associated neurodegenerative disease like dementia with Lewy bodies.

“This phenomenon has only been reported previously in the brains of older people with neurodegenerative diseases, so seeing it in the brains of these infants is highly remarkable.

“These findings challenge the view that changes to the brain that underlie these forms of dementia are merely age-associated, but are instead the result of dysfunction of specific biological pathways. 

“This is an important message, as while we cannot stop ageing, we can potentially fix something that is not working properly.

“These research findings have only been made possible from the support of the families donating their loved ones’ brains for research and I would like to pay tribute to them for their generosity in helping others in a time of unparalleled grief.

“Thankfully, Krabbe disease is a relatively rare condition, however it is devastating for the families affected. Dementia with Lewy bodies affects roughly 100,000 people in the UK.

“Building on these findings to help develop new drugs that target this common biological pathway could change the lives of people with both conditions.”

Dr Rosa Sancho, head of research at the charity Alzheimer’s Research UK, said: “In dementia with Lewy bodies, the protein alpha-synuclein forms clumps called Lewy bodies inside brain nerve cells. 

“While Lewy bodies were not found in the brains of infants in this study, researchers have shown for the first time that alpha-synuclein had a similar capacity to spread through the brain in Krabbe disease.

“At Alzheimer’s Research UK we often hear dementia dismissed as a normal part of ageing. 

“We know dementia is caused by brain diseases, and this research offers more evidence that the disease that cause dementia are caused by biological processes going awry rather than as a by-product of old age.

“Learning about the diseases that cause dementia from other neurodegenerative conditions and sharing this knowledge with other fields is important. 

“We’re incredibly grateful to the families of those whose brains were studied in this research, and who made this important discovery possible.”

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