Tag: Alzheimer's disease

New Drug Targets for Memory Loss

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Researchers have identified specific drug targets within memory-encoding neural circuits, opening up possibilities for new treatments of a range of brain disorders.

Memory loss is a main feature of a number of neurological and psychiatric disorders including Alzheimer’s disease and schizophrenia. Presently, there are few, very limited memory loss treatments and the search for safe and effective drug therapies has, until now, borne little fruit.

The research was done in collaboration with colleagues at the international biopharmaceutical company Sosei Heptares. The findings, published in Nature Communications, identify specific receptors for the neurotransmitter acetylcholine that re-route information flowing through memory circuits in the hippocampus. Acetylcholine is released in the brain during learning and is critical for the acquisition of new memories. Until now, the only effective treatment for the symptoms of cognitive or memory impairment seen in diseases such as Alzheimer’s is using drugs that broadly boost acetylcholine. However, this leads to multiple adverse side effects. The discovery of specific receptor targets that have the potential to provide the positive effects whilst avoiding the negative ones is promising.

Lead author Professor Jack Mellor from the University of Bristol’s Center for Synaptic Plasticity, said: “These findings are about the fundamental processes that occur in the brain during the encoding of memory and how they may be regulated by brain state or drugs targeting specific receptor proteins. In the long-term, the discovery of these specific targets opens up avenues and opportunities for the development of new treatments for the symptoms of Alzheimer’s disease and other conditions with prominent cognitive impairments. The academic-industry partnership is important for these discoveries and we hope to continue working together on these projects.”

Dr Miles Congreve, Chief Scientific Officer at Sosei Heptares, added: “These important studies have helped us to design and select new, exquisitely targeted therapeutic agents that mimic the effects of acetylcholine at specific muscarinic receptors, without triggering the unwanted side effects of earlier and less-well targeted treatments. This approach has the exciting potential to improve memory and cognitive function in patients with Alzheimer’s and other neurological diseases.”

“It is fascinating how the brain prioritises different bits of information, working out what is important to encode in memory and what can be discarded. We know there must be mechanisms to pull out the things that are important to us but we know very little about how these processes work. Our future program of work aims to reveal how the brain does this using acetylcholine in tandem with other neurotransmitters such as dopamine, serotonin and noradrenaline,” said Professor Mellor.

Source: University of Bristol

Brain Cholesterol Production Linked to Alzehimer’s

Amyloid plaques and neurons. Source: NIAH

Cholesterol manufactured in the brain appears to play a key role in the development of Alzheimer’s disease, new research indicates.

Scientists found that cholesterol produced by cells called astrocytes is required for controlling the production of amyloid beta, a sticky protein which forms the characteristic plaques in patients with Alzheimer’s. These plaques have been the target of efforts to remove or prevent them  in the hopes that this could treat or prevent Alzheimer’s.

The new findings offer important insights into how and why the plaques form and may explain why genes associated with cholesterol have been linked to increased risk for Alzheimer’s. The results also provide scientists with important direction as they seek to prevent Alzheimer’s.

“This study helps us to understand why genes linked to cholesterol are so important to the development of Alzheimer’s disease,” Heather Ferris, MD, PhD, Researcher, UVA’s Division of Endocrinology and Metabolism. “Our data point to the importance of focusing on the production of cholesterol in astrocytes and the transport to neurons as a way to reduce amyloid beta and prevent plaques from ever being formed.”

The work sheds light on the role of astrocytes in Alzheimer’s disease. Scientists have known that these common brain cells undergo dramatic changes in Alzheimer’s, but they have been uncertain if the cells were suffering from the disease or contributing to it. The new results suggest the latter.

The scientists found that astrocytes help drive the progression of Alzheimer’s by making and distributing cholesterol to brain cells called neurons. This cholesterol buildup increases amyloid beta production and, in turn, fuels plaque accumulation.

Normally, the buildup of amyloid beta is limited because cholesterol is kept quite low in neurons. But in Alzheimer’s, the neurons are no longer able to regulate amyloid beta, leading to plaque formation.
Blocking the astrocytes’ cholesterol manufacturing “robustly” decreased amyloid beta production in lab mice, the researchers reported. While it is presently unknown whether this could be applied in people to prevent plaque formation, the researchers believe that further research is likely to yield important insights that will benefit the battle against Alzheimer’s.

The fact that amyloid beta production is normally tightly controlled suggests an important role in brain cells, the researchers said. Doctors may therefore need to be cautious about blockage or removal of amyloid beta. Additional research into the discovery could shed light on how to prevent the over-production of amyloid beta as a strategy against Alzheimer’s, the researchers believe.

“If we can find strategies to prevent astrocytes from over-producing cholesterol, we might make a real impact on the development of Alzheimer’s disease,” Dr Ferris said. “Once people start having memory problems from Alzheimer’s disease, countless neurons have already died. We hope that targeting cholesterol can prevent that death from ever occurring in the first place.”

Source: University of Virginia Health System

Small Study Hints at Omega-3 Protection of Memory in Alzheimer’s

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A first-of-its-kind study on Alzheimer’s disease found an indication that omega-3 fatty acids taken early on protect against Alzheimer’s disease, despite not finding biomarkers in patients’ cerebrospinal fluid.

The researchers published their findings in Journal of Alzheimer’s Disease.

“We are careful not to draw any wider conclusions, but we can see a difference in the results of the memory tests. Patients who were taking omega-3 supplements at an early stage of the disease scored better,” cautioned Yvonne Freund-Levi, researcher in neuroscience at Örebro University.

The small study enrolled 33 patients, 18 of which were given omega-3 supplements morning and evening, and15 were in the control group. Spinal fluid samples were collected, and patients performed a memory test at the start of the study and after six months.

“We can see that the memory function of the patients in the group that had taken omega-3 is stable, whereas the patients in the control group have deteriorated. That’s what the memory tests show,” said Yvonne Freund-Levi.

“But we can’t see any differences between the groups when we look at the various biomarkers in the spinal fluid samples.”

However there are differences within the group given omega-3: an increase of two of the markers that are linked to damaged nerve cells. There is no clinical link to the memory tests, however.

“Even if this data isn’t enough for us to change our recommendations to patients at this time, it is an interesting material for researchers to build on.”

This study is based on a larger study with over 200 patients with mild to moderate Alzheimer’s disease, initiated by Yvonne Freund-Levi and her research team 15 years ago. In that previous study, the researchers found that omega-3 transfers from the supplements to the brain.

“We are cautious about giving recommendations, but we know that starting early is by far the best thing – it is difficult to influence the disease at a later stage. The best piece of advice we have to offer at the moment is to be physically active and to include omega-3 in your diet – in the form of oily fish or as supplements.”

In future, researchers will be able to measure biomarkers in blood samples rather than having to perform spinal tap procedures.

“We have already tested this approach at Sahlgrenska University Hospital. Without a doubt, it is so much better for the patients.”

Source: Örebro University

Why REM Sleep is Important in Animals

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Researchers in Japan have discovered that capillary blood flow in the brain is increased in mice during the dream-active REM phase of sleep, possibly preventing a buildup of waste products.

Scientists have long wondered why almost all animals sleep, despite the disadvantages to survival of being unconscious. Now, researchers led by a team from the University of Tsukuba have found new evidence of brain refreshing that takes place during a specific phase of sleep: rapid eye movement (REM) sleep, where dreaming occurs.

Previous studies have seen conflicting results when measuring differences in blood flow in the brain between REM sleep, non-REM sleep, and wakefulness using various methods. For this study, the investigators used a technique to directly visualise red blood cell movement in the brain capillaries of mice during awake and asleep states.

“We used a dye to make the brain blood vessels visible under fluorescent light, using a technique known as two-photon microscopy,” explained the senior study author, Professor Yu Hayashi. “In this way, we could directly observe the red blood cells in capillaries of the neocortex in non-anaesthetised mice.”

The researchers also measured electrical activity in the brain to identify REM sleep, non-REM sleep, and wakefulness, and looked for differences in blood flow between these phases.

“We were surprised by the results,” said Professor Hayashi. “There was a massive flow of red blood cells through the brain capillaries during REM sleep, but no difference between non-REM sleep and the awake state, showing that REM sleep is a unique state”

The research team then disrupted the mice’s sleep, resulting in ‘rebound’ REM sleep, which is a stronger form of REM sleep to compensate for the earlier disruption. During rebound REM sleep, blood flow was increased even further, suggesting an association between blood flow and REM sleep strength. However, when the researchers repeated the same experiments in mice without adenosine A2a receptors (blocking these receptors makes you feel more awake after a coffee), there was less of an increase in blood flow during REM sleep, even during rebound REM sleep.

“These results suggest that adenosine A2a receptors may be responsible for at least some of the changes in blood flow in the brain during REM sleep,” said Professor Hayashi.

Given that reduced blood flow in the brain and decreased REM sleep are correlated with the development of Alzheimer’s disease, in which waste products are seen to build up in the brain, this increased blood flow in the brain capillaries during REM sleep could be important for waste removal from the brain. This study highlights the role of adenosine A2a receptors in this process, perhaps leading to the development of new treatments for Alzheimer’s disease and other conditions.

Source: University of Tsukuba

Probe over Controversial Alzheimer’s Drug’s Approval

Amyloid plaques and neurons. Source: NIAH

The interim commissioner of the US Food and Drug Administration, Janet Woodcock, MD, last week requested the country’s Office of Inspector General to perform an independent investigation into the regulator’s decision to approve Biogen’s controversial Alzheimer’s drug Aduhelm.

Dr Woodcock noted in her letter that there “continues to be concerns raised” regarding the contact between FDA officials and Biogen ahead of the agency’s decision, “including some that may have occurred outside of the formal correspondence process.”

Dr Woodcock’s request comes after a bombshell report from Stat, which found that Biogen executives met with FDA officials, specifically Billy Dunn, MD, director of the FDA’s neuroscience unit, as early as 2019 to discuss a regulatory pathway for Aduhelm. The meetings took place even when it seemed there was no progress for the drug.

Earlier this week, a US House Representative, charged Biogen with “undue influence” over the FDA’s review process. Less than two weeks earlier, the House Committee on Oversight and Reform said it would conduct its own probe into the approval along with Biogen’s pricing strategies.

In the letter from Friday, Dr Woodcock said the agency would fully cooperate with the potential investigation to determine whether any of its interactions with Biogen were inconsistent with FDA policies and procedures.

“Given the ongoing interest and questions, today I requested that @OIGatHHS conduct an independent review and assessment of interactions between representatives of Biogen and FDA during the process that led to the approval of Aduhelm,” tweeted Dr Woodcock.

However, she maintained that she has “tremendous confidence” in the leadership at the FDA’s Center for Drug Evaluation and Research, which was involved in the review of Aduhelm.

“We believe this review and assessment will help ensure continued confidence in the integrity of FDA’s regulatory processes and decision-making,” Woodcock said in a tweet.

A spokesperson from Biogen told Fierce Pharma that the company would “of course” cooperate with “any inquiry in connection with a possible review of the regulatory process.”

The commissioner’s request is only the latest event in a bizarre and twisted story since the FDA’s Aduhelm approval just one month prior.

Facing fierce criticism of its wide-labelled approval, the FDA made the surprising move to narrow Aduhelm’s label last week Thursday, restricting the recommendation to just those with milder Alzheimer’s.

This comes after Biogen’s drug was essentially allowed access to the nation’s some 6 million Alzheimer’s patients. That decision was met with almost immediate pushback, as it was pointed out that the drug could overwhelm the payer budgets of most Alzheimer’s patients.

Source: Fierce Pharma

Are We Wrong About Amyloid Plaques in Alzheimer’s?

A recent study sheds new light on the disease and the highly debated aducanumab, a new drug recently approved by the FDA that treats the amyloid plaques.

Led by the University of Cincinnati and conducted in collaboration with the Karolinska Institute in Sweden, the study claims that the treatment of Alzheimer’s disease might lie in normalising levels of a brain protein called amyloid-beta peptide. This protein is needed in its original, soluble form to keep the brain healthy, but it sometimes hardens into ‘brain stones’ or clumps, called amyloid plaques.

“It’s not the plaques that are causing impaired cognition,” said senior author Alberto Espay, professor of neurology at UC. “Amyloid plaques are a consequence, not a cause,” of Alzheimer’s disease, stated Prof Espay, who is also a member of the UC Gardner Neuroscience Institute.

Since its discovery, scientists have focused on treatments to eliminate the plaques. But the UC team, he said, viewed it differently: Cognitive impairment could be due to a decline in soluble amyloid-beta peptide instead of the corresponding accumulation of amyloid plaques. 
To test their hypothesis, they analyzed the brain scans and spinal fluid from 600 individuals enrolled in the Alzheimer’s Disease Neuroimaging Initiative study, who all had amyloid plaques. From there, they compared the amount of plaques and levels of the peptide in the individuals with normal cognition to those with cognitive impairment. They found that individuals with high levels of the peptide were cognitively normal, despite the numbers of plaques in their brains.

They also found that higher levels of soluble amyloid-beta peptide were associated with a larger hippocampus, the area of the brain most important for memory.

According to the authors, as we age most people develop amyloid plaques, but few people develop dementia. In fact, by the age of 85, 60% of people will have these plaques, but only 10% develop dementia.

“The key discovery from our analysis is that Alzheimer’s disease symptoms seem dependent on the depletion of the normal protein, which is in a soluble state, instead of when it aggregates into plaques,” said co-author Kariem Ezzat from the Karolinska Institute.

The most relevant future therapeutic approach for the Alzheimer’s program would then be to restore these brain soluble proteins to their normal levels, said Prof Espay.

The research team is now working to test their findings in animal models. If successful, future treatments may be very different from those tried over the last two decades. Treatment, says Espay, may consist of increasing the soluble version of the protein in a manner that keeps the brain healthy while preventing the protein from hardening into plaques.  

Source: University of Cincinnati 

Journal information: Andrea Sturchio et al, High cerebrospinal amyloid-β 42 is associated with normal cognition in individuals with brain amyloidosis, EClinicalMedicine (2021). DOI: 10.1016/j.eclinm.2021.100988

Lifestyle Changes Shown to Reduce Risk of Dementia

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After almost two decades, a new drug for Alzheimer’s disease has been approved in the US. However, some experts say it doesn’t really work — only treating amyloid plaques which are thought to cause the disease — and worry that it may cost a lot.

The amount of attention around this news reflects the importance of preventing dementia, with its devastating toll on families and patients. But millions of adults could lower their chances of needing such a drug by taking preventative measures.

That’s why a national panel of experts including the University of Michigan’s Deborah Levine, MD, MPH, recently published a guide for primary care providers on this topic as an official Scientific Statement from the American Heart Association.

People dread Alzheimer’s disease, she said. Helping people understand that they can prevent or slow future dementia by taking specific steps now could motivate them to increase their healthy behaviours for a positive effect.

The first step is to recognise that dementia risk is higher among people with seven major modifiable risk factors.

These are: depression, hypertension, physical inactivity, diabetes, obesity, hyperlipidaemia, poor diet, smoking, social isolation, excessive alcohol use, sleep disorders and hearing loss. Addressing each of these factors can, to varying extents, help reduce the risk of developing dementia, a fact backed by decades of research.

The second step is using medication, lifestyle change and other interventions to help patients reduce their dementia risk.

“Dementia is not inevitable,” said Dr Levine, a primary care provider at the University of Michigan Health, part of Michigan Medicine. “Evidence is growing that people can better maintain brain health and prevent dementia by following healthy behaviours and controlling vascular risk factors.”

These strategies can help preserve cognitive function and lower risk for heart attacks and strokes, said Dr Levine, who heads the Cognitive Health Services Research Program and sees patients at the Frankel Cardiovascular Center.

“We need to address the significant disparities that lead women, Black, Hispanic and less-educated Americans to have a much higher risk of dementia,” said Levine, a member of the U-M Institute for Healthcare Policy and Innovation.

She added that it’s never too late in life to start working on cognitive risk factor control.

“We have no treatments that will halt dementia – so it’s important to protect your brain health.”

Source: University of Michigan

A Neurologist Confronts His Alzheimer’s Disease

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Neurologist Daniel Gibbs, MD, PhD, related his experiences of having been diagnosed with Alzheimer’s disease and taking part in clinical trials of possible treatments for it.

“I’m fascinated by this disease that, for my entire career as a scientist and a neurologist, I could only observe from the outside,” Dr Gibbs wrote in his new book, A Tattoo on my Brain: A Neurologist’s Personal Battle against Alzheimer’s Disease. “Now I’ve got a front-row seat — or rather, I’m in the ring with the tiger.”

Dr Gibbs stumbled upon his diagnosis accidentally, when he and his wife tested their DNA to learn about their ancestry that he discovered he had two copies of the APOE4 allele, the most common genetic risk factor for Alzheimer’s disease.

Because he had an early diagnosis, Dr Gibbs has volunteered to participate in several Alzheimer’s clinical trials in recent years, including one for aducanumab, the controversial Alzheimer’s treatment the FDA is expected to decide upon in June.

During a trial of aducanumab, he developed a serious amyloid-related imaging abnormality (ARIA) involving both brain oedema and intracerebral haemorrhage, which he recovered from. Dr Gibbs went on to co-author a case report about the clinical course and treatment of his complication. In the wake of much controversy, aducanumab has today received FDA approval.

MedPage Today interviewed Dr Gibbs on his experiences and perspectives since his Alzheimer’s diagnosis.

Dr Gibbs said that “as a patient and as a neurologist” it is a coping mechanism which gives hime “a huge advantage” to be able to look at the disease through his two “masks”. “Looking at it from the neurologist scientist’s point of view is a lot less threatening and is intellectually very satisfying. I enjoy reading and writing about it,” he said.

Regarding his future, he said: “One of the messages I try to get across in the book is that you need to plan for the future while you are still cognitively intact, and make very clearly known what you want done when you’re unable to give instructions about your care. I’ve done that. My family knows, my doctor knows: I don’t want anything done if I can’t participate in making decisions.” 

Dr Gibbs said he was excited to volunteer for the aducanumab study partly because of the way aducanumab was discovered; a reverse-engineered antibody found in cognitively normal aged people. Another reason was the more aggressive nature of the trial. He explained the meaning of “tattoo on my brain” alluded to in the title of his book, an adverse effect of the experimental drug.

“For me, a ‘tattoo on my brain’ has two forms. In the ARIA — the amyloid-related imaging abnormality complication I had from aducanumab — there was both leakage of fluid causing swelling in my brain and leakage of blood, microhaemorrhages. Those went away, as did the swelling in my brain, but they left behind this haemosiderin, this iron-containing pigment which is not dissimilar to tattoo ink, if you will.

“I haven’t had a recent MRI scan, but at least the last one I looked at a year or two ago still showed those little dots of hemosiderin. In a literal sense, that is the tattoo on my brain. In the figurative sense, the tattoo is a symbol of a kind of coming out of the closet and showing something that you’re not ashamed of.” 

The book, he said, is about people with early disease and the children of people with Alzheimer’s disease because they’re at risk. The aim is to “loosen up the conversation” so that interventions such as lifestyle changes can take place.

He suspects that the first disease-modifying drugs will be effective in early stages, which are going to be really hard studies to do. Recruiting participants without cognitive impairment but the pathology of  of Alzheimer’s disease is extremely difficult.
Finally, he offered some advice on dealing with Alzheimer’s.

“What I would recommend is for everybody to start doing things that are good for them. A heart-healthy diet is good for you in so many ways. It’s hard to say that’s not a good idea, although we’re a country of hamburger-loving people. And exercise — I don’t know how you overcome that bar of convincing people if you want to be a healthy 70- or 80-year-old, you have to exercise and get a good diet. And good sleep.”

Source:MedPage Today

Alzheimer’s Disease Disrupts Blood Vessels in Vicious Circle

Researchers have discovered a new mechanism of Alzheimer’s disease, one that disrupts the blood vessels around the disease’s characteristic amyloid plaques and worsens the disease progression. 

Image source: Wikimedia

Presently, Alzheimer’s disease is the leading cause of dementia worldwide. As economies develop and people live longer lives, its incidence is increasing dramatically as the population ages and yet, unfortunately, the origin of the disease is still unknown and there is no truly effective treatment.

The study was published in the international journal Nature Communications, and led by Dr Alberto Pascual’s laboratory, from the Neuronal Maintenance Mechanisms Group at the Biomedicine Institute of Seville (IBiS) and was chiefly carried out by María Isabel álvarez Vergara and Alicia E Rosales-Nieves.

Blood vessel formation disrupted

The study focuses on the dysfunction of a physiological process called angiogenesis, which is important during development to form the vessels of the brain, and in adulthood to repair any damage to pre-existing vessels. The researchers found that Alzheimer’s disease induces angiogenesis dysfunction, resulting in the loss of vessels instead of the formation of new ones and worsening the progression of the disease. Identification of the molecular pathways involved will enable new therapeutic strategies to alleviate the effects of this disease can be rationally designed. Their data also links familial (genetic) Alzheimer’s to problems in the formation of new blood vessels, which demonstrates the importance of the vascular component of the disease.

A vicious circle

A characteristic feature of Alzheimer’s patients is the accumulation of highly toxic substances in their brains, known as senile plaques. Normally, the brain is capable of cleaning out these toxic substances by carrying them away in the bloodstream. Therefore, the loss of the vessels due to plaques creates a vicious circle: having fewer vessels reduces the brain’s cleaning ability and so allowing more toxic substances to accumulate, which in turn continue to destroy the vessels and worsen the situation further. Additionally, since the human brain is a major consumer of the body’s oxygen and nutrients a local reduction in the supply of these substances through the blood represents an additional strain on it.

Source: News-Medical.Net

Journal information: Alvarez-Vergara, M.I., et al. (2021) Non-productive angiogenesis disassembles Aß plaque-associated blood vessels. Nature Communications. doi.org/10.1038/s41467-021-23337-z.

Phase 1 Clinical Trial of a Gene Therapy for Alzheimer’s

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Researchers at University of California San Diego School of Medicine have received a grant to conduct a first-in-human Phase 1 clinical trial of a gene therapy for treating Alzheimer’s disease (AD) or Mild Cognitive Impairment (MCI), a condition often preceding dementia.

Gene therapy is an experimental technique that uses genes or gene products for the treatment or prevention of diseases by altering the DNA of living cells. Viral vectors are commonly used to insert the DNA changes into the target cells’ nuclei, but non-viral vectors also exist though they are generally less efficient.

The clinical trial, developed by principal investigator Mark Tuszynski, MD, PhD, professor of neuroscience and director of the Translational Neuroscience Institute at UC San Diego School of Medicine, delivers the brain-derived neurotrophic factor (BDNF) gene into the brains of qualifying trial participants where it is hoped it will stimulate BDNF production in cells.

BDNF belongs to a family of growth factors (proteins) found in the brain and central nervous system that support existing neurons and promote growth and differentiation of new neurons and synapses. BDNF is particularly important in brain regions susceptible to degeneration in AD.

“We found in earlier studies that delivering BDNF to the part of the brain that is affected earliest in Alzheimer’s disease — the entorhinal cortex and hippocampus — was able to reverse the loss of connections and to protect from ongoing cell degeneration,” said Tuszynski. “These benefits were observed in aged rats, aged monkeys and amyloid mice.”

The three-year-long trial seeks to recruit 12 participants with either diagnosed AD or MCI to receive AAV2-BDNF treatment, with another 12 persons serving as a control group over that period.

This will be the first safety and efficacy assessment of AAV2-BDNF in humans. A previous gene therapy trial from 2001 to 2012 using AAV2 and a different protein called nerve growth factor (NGF) found increased growth, axonal sprouting and activation of functional markers in the brains of participants.

“The BDNF gene therapy trial in AD represents an advance over the earlier NGF trial,” said Tuszynski. “BDNF is a more potent growth factor than NGF for neural circuits that degenerate in AD. In addition, new methods for delivering BDNF will more effectively deliver and distribute it into the entorhinal cortex and hippocampus.”

Source: UC San Diego