Neurons in the brain of an Alzheimer’s patient, with plaques caused by tau proteins. Credit: NIH
A study led by researchers in the University of Florida College of Pharmacy has found that a pair of popular glucose-lowering medications may have protective effects against the development of Alzheimer’s disease and related dementias in patients with Type 2 diabetes.
In research published in JAMA Neurology on April 7, UF researchers studied Medicare claims data of older adults with Type 2 diabetes to assess the association among glucagon-like peptide-1 receptor agonists, or GLP-1RAs, sodium-glucose cotransporter-2 inhibitors, or SGLT2is, and the risk of Alzheimer’s disease and related dementias.
The research is supported by funding from the National Institute on Aging and the National Institute of Diabetes and Digestive and Kidney Diseases, both part of the National Institutes of Health.
The data showed a statistically significant association between a lower risk of Alzheimer’s and the use of GLP-1RAs and SGLT2is compared with other glucose-lowering medications. According to the researchers, the findings indicated that the two drugs may have neuroprotective effects for people without diabetes and may help slow the rate of cognitive decline in Alzheimer’s patients.
Serena Jingchuan Guo, MD, PhD, an assistant professor of pharmaceutical outcomes and policy and the study’s senior author, said these findings may point to new therapeutic uses for drugs commonly used to treat Type 2 diabetes and obesity.
“It’s exciting that these diabetes medications may offer additional benefits, such as protecting brain health,” Guo said. “Based on our research, there is promising potential for GLP-1RAs and SGLT2is to be considered for Alzheimer’s disease prevention in the future. As use of these drugs continues to expand, it becomes increasingly important to understand their real-world benefits and risks across populations.”
As the study only included patients with Type 2 diabetes, Guo said next steps include evaluating the effects of the two drugs in broader populations by using recent, real-world data that captures their growing use in clinical settings.
“Future research should focus on identifying heterogeneous treatment effects – specifically, determining which patients are most likely to benefit and who may be at greater risk for safety concerns,” Guo said.
In sports, the connection between head injuries and neurodegenerative diseases such as chronic traumatic encephalopathy, Alzheimer’s disease, and Parkinson’s disease is now well recognised.
Researchers at Tufts University and Oxford University have now uncovered mechanisms that may connect the dots between trauma events and the emergence of disease. They point to latent viruses lurking in most of our brains that may be activated by the jolt, leading to inflammation and accumulating damage that can occur over the ensuing months and years.
The results suggest the use of antiviral drugs as potential early preventive treatments post-head injury. The findings are published in a study in Science Signaling.
The microbiome aids in digestion, immune system development, and protection against harmful pathogens.
But the microbiome also includes dozens of viruses that swarm within our bodies at any given time. Some of these can be potentially harmful, but simply lie dormant within our cells. Herpes simplex virus 1 (HSV-1), found in over 80% of people, and varicella-zoster virus, found in 95% of people, are known to make their way into the brain and sleep within our neurons and glial cells.
Dana Cairns, GBS12, research associate in the Department of Biomedical Engineering and lead author of the study, had found evidence in earlier studies suggesting that activation of HSV-1 from its dormant state triggers the signature symptoms of Alzheimer’s disease in lab models of brain tissue: amyloid plaques, neuronal loss, inflammations, and diminished neural network functionality.
“In that study, another virus – varicella – created the inflammatory conditions that activated HSV-1,” said Cairns. “We thought, what would happen if we subjected the brain tissue model to a physical disruption, something akin to a concussion? Would HSV-1 wake up and start the process of neurodegeneration?”
The link between HSV-1 and Alzheimer’s disease was first suggested by co-author Ruth Itzhaki, visiting professorial fellow at Oxford University, who more than 30 years ago identified the virus in a high proportion of brains from the elderly population. Her subsequent studies suggested that the virus can be reactivated in the brain from a latent state by events such as stress or immunosuppression, ultimately leading to neuronal damage.
Blows to Brain-like Tissue
In the current study, the researchers used a lab model that reconstructs the environment of the brain to better understand how concussions may set off the first stages of virus reactivation and neurodegeneration.
The brain tissue model consists of a 6mm-wide donut-shaped sponge-like material made of silk protein and collagen suffused with neural stem cells, which are then coaxed into mature neurons, growing axons and dendrite extensions and forming a network. Glial cells also emerge from the stem cells to help mimic the brain environment and nurture the neurons.
The neurons communicate with each other through their extensions similarly to how they would communicate in a brain. And just like cells in the brain, they can carry within them the DNA of dormant HSV-1 virus.
After enclosing the brain-like tissue in a cylinder and giving it a sudden jolt atop a piston, mimicking a concussion, Cairns examined the tissue under the microscope over time. Some of the tissue models had neurons with HSV-1, and some were virus-free.
Following the controlled blows, she observed that the infected cells showed re-activation of the virus, and shortly after that the signature markers of Alzheimer’s disease, including amyloid plaques, p-tau (a protein that creates fiber-like “tangles” in the brain), inflammation, dying neurons, and a proliferation of glial cells called gliosis.
More strikes with the pistons on the tissue models mimicking repetitive head injuries led to the same reactions, which were even more severe. Meanwhile, the cells without HSV-1 showed some gliosis, but none of the other markers of Alzheimer’s disease.
The results were a strong indicator that athletes suffering concussions could be triggering reactivation of latent infections in the brain that can lead to Alzheimer’s disease. Epidemiological studies have shown that multiple blows to the head can lead to doubling or even greater chances of having a neurodegenerative condition months or years down the line.
“This opens the question as to whether antiviral drugs or anti-inflammatory agents might be useful as early preventive treatments after head trauma to stop HSV-1 activation in its tracks, and lower the risk of Alzheimer’s disease,” said Cairns.
The problem goes far beyond the concerns for athletes. Traumatic brain injury is one of the most common causes of disability and death in adults, affecting about 69 million people worldwide each year, at an economic cost estimated at $400 billion annually.
“The brain tissue model takes us to another level in investigating these connections between injury, infection, and Alzheimer’s disease,” said David Kaplan, Stern Family Endowed Professor of Engineering at Tufts.
“We can re-create normal tissue environments that look like the inside of a brain, track viruses, plaques, proteins, genetic activity, inflammation and even measure the level of signalling between neurons,” he said. “There is a lot of epidemiological evidence about environmental and other links to the risk of Alzheimer’s. The tissue model will help us put that information on a mechanistic footing and provide a starting point for testing new drugs.”
A drug typically prescribed for arthritis halts brain-damaging seizures in mice that have a condition like epilepsy, according to researchers at the University of Wisconsin–Madison. The drug, called tofacitinib, also restores short-term and working memory lost to epilepsy in the mice and reduces inflammation in the brain caused by the disease.
If the drug proves viable for human patients, it would be the first to provide lasting relief from seizures even after they stopped taking it.
“It ticks all the boxes of everything we’ve been looking for,” says Avtar Roopra, a neuroscience professor in the UW–Madison School of Medicine and Public Health and senior author of the study, which appears in Science Translational Medicine.
Epilepsy is one of the most common neurological diseases, afflicting more than 50 million people around the world. While there are many known causes, the disease often appears after an injury to the brain, like a physical impact or a stroke.
Some days, months or even years after the injury, the brain loses the ability to calm its own activity. Normally balanced electrical activity through the brain goes haywire.
“The system revs up until all the neurons are firing all the time, synchronously,” says Roopra. “That’s a seizure that can cause massive cell death.”
And the seizures repeat, often at random intervals, forever. Some drugs have been useful in addressing seizure symptoms, protecting patients from some of the rampant inflammation and memory loss, but one-third of epilepsy patients do not respond to any known drugs, according to Olivia Hoffman, lead author of the study and a postdoctoral researcher in Roopra’s lab. The only way to stop the most damaging seizures has been to remove a piece of the brain where disruptive activity starts.
On their way to identifying tofacitinib’s potential in epilepsy, Hoffman and co-authors used relatively new data science methods to sift through the way thousands of genes were expressed in millions of cells in the brains of mice with and without epilepsy. They found a protein called STAT3, key to a cell signaling pathway called JAK, at the centre of activity in the seizure-affected mouse brains.
“When we did a similar analysis of data from brain tissue removed from humans with epilepsy, we found that was also driven by STAT3,” Hoffman says.
Meanwhile, Hoffman had unearthed a study of tens of thousands of arthritis patients in Taiwan aimed at describing other diseases associated with arthritis. It turns out, epilepsy was much more common among those arthritis patients than people without arthritis — but surprisingly less common than normal for the arthritis patients who had been taking anti-inflammatory drugs for more than five-and-a-half years.
“If you’ve had rheumatoid arthritis for that long, your doctor has probably put you on what’s called a JAK-inhibitor, a drug that’s targeting this signaling pathway we’re thinking is really important in epilepsy,” Hoffman says.
The UW researchers ran a trial with their mice, dosing them with the JAK-inhibitor tofacitinib following the administration of a brain-damaging drug that puts them on the road to repeated seizures. Nothing happened. The mice still developed epilepsy like human patients.
Remember, though, that epilepsy doesn’t often present right after a brain-damaging event. It can take years. In the lab mice, there’s usually a lull of weeks of relatively normal time between the brain damage and what the researchers call “reignition” of seizures. If it’s not really epilepsy until reignition, what if they tried the drug then? They devised a 10-day course of tofacitinib to start when the mouse brains fell out of their lull and back into the chaos of seizures.
“Honestly, I didn’t think it was going to work,” Hoffman says. “But we believe that initial event sort of primes this pathway in the brain for trouble. And when we stepped in at that reignition point, the animals responded.”
The drug worked better than they could have imagined. After treatment, the mice stayed seizure-free for two months, according to the paper. Collaborators at Tufts University and Emory University tried the drug with their own mouse models of slightly different versions of epilepsy and got the same, seizure-free results.
Roopra’s lab has since followed mice that were seizure-free for four and five months. And their working memory returned.
“These animals are having many seizures a day. They cannot navigate mazes. Behaviourally, they are bereft. They can’t behave like normal mice, just like humans who have chronic epilepsy have deficits in learning and memory and problems with everyday tasks,” Roopra says. “We gave them that drug, and the seizures disappear. But their cognition also comes back online, which is astounding. The drug appears to be working on multiple brain systems simultaneously to bring everything under control, as compared to other drugs, which only try to force one component back into control.”
Because tofacitinib is already FDA-approved as safe for human use for arthritis, the path from animal studies to human trials may be shorter than it would be for a brand-new drug. The next steps toward human patients largely await NIH review of new studies, which have been paused indefinitely amid changes at the agency.
For now, the researchers are focused on trying to identify which types of brain cells are shifted back to healthy behavior by tofacitinib and on animal studies of even more of the many types of epilepsy. Hoffman and Roopra have also filed for a patent on the use of the drug in epilepsy.
A decade of studies from labs around the world provide a growing evidence base that increasing the power of the brain’s gamma rhythms could help fight Alzheimer’s, and perhaps other, neurological diseases.
Source: Pixabay
A decade after scientists in The Picower Institute for Learning and Memory at MIT first began testing whether sensory stimulation of the brain’s 40Hz “gamma” frequency rhythms could treat Alzheimer’s disease in mice, a growing evidence base supporting the idea that it can improve brain health – in humans as well as animals – has emerged from the work of labs all over the world. A new review article in PLOS Biology describes the state of research so far and presents some of the fundamental and clinical questions at the forefront of the non-invasive gamma stimulation now.
“As we’ve made all our observations, many other people in the field have published results that are very consistent,” said Li-Huei Tsai, Picower Professor at MIT, director of MIT’s Aging Brain Initiative, and senior author of the new review with postdoc Jung Park. “People have used many different ways to induce gamma including sensory stimulation, transcranial alternating current stimulation or transcranial magnetic stimulation, but the key is delivering stimulation at 40 Hz. They all see beneficial effects.”
A decade of discovery at MIT
Starting with a paper in Nature in 2016, a collaboration led by Tsai has produced a series of studies showing that 40Hz stimulation via light, sound, a combination of the two, or tactile vibration reduces hallmarks of Alzheimer’s pathology such as amyloid and tau proteins, prevents neuron death, decreases synapse loss, and sustains memory and cognition in various Alzheimer’s mouse models. The collaboration’s investigations of the underlying mechanisms that produce these benefits has so far identified specific cellular and molecular responses in many brain cell types including neurons, microglia, astrocytes, oligodendrocytes and the brain’s blood vessels. Last year, for instance, the lab reported in Nature that 40Hz audio and visual stimulation induced interneurons in mice to increase release of the peptide VIP, prompting increased clearance of amyloid from brain tissue via the brain’s glymphatic “plumbing” system.
Meanwhile, at MIT and at the MIT spinoff company Cognito Therapeutics, phase II clinical studies have shown that people with Alzheimer’s exposed to 40Hz light and sound experienced a significant slowing of brain atrophy and improvements on some cognitive measures compared to untreated controls. Cognito, which has also measured significant preservation of white matter in volunteers, has been conducting a pivotal, nationwide phase III clinical trial of sensory gamma stimulation for more than a year.
“Neuroscientists often lament that it is a great time to have AD if you are a mouse,” Park and Tsai wrote in the review. “Our ultimate goal, therefore, is to translate GENUS discoveries into a safe, accessible, and non-invasive therapy for AD patients.” The MIT team often refers to 40Hz stimulation as “GENUS” for Gamma Entrainment Using Sensory Stimulation.
A growing field
As Tsai’s collaboration, which includes MIT colleagues Edward Boyden and Emery N. Brown, has published its results, many other labs have produced studies adding to the evidence that various methods of non-invasive gamma sensory stimulation can combat Alzheimer’s pathology. Among many examples cited in the new review, in 2024 a research team in China independently corroborated that 40Hz sensory stimulation increases glymphatic fluid flows in mice. In another example, a Harvard Medical School-based team in 2022 showed that 40Hz gamma stimulation using Transcranial Alternating Current Stimulation significantly reduced the burden of tau in three out of four human volunteers. And in another study involving more than 100 people, researchers in Scotland in 2023 used audio and visual gamma stimulation (at 37.5Hz) to improve memory recall.
Open questions
Amid the growing number of publications describing preclinical studies with mice and clinical trials with people, open questions remain, Tsai and Park acknowledge. The MIT team and others are still exploring the cellular and molecular mechanisms that underlie GENUS’s effects. Tsai said her lab is looking at other neuropeptide and neuromodulatory systems to better understand the cascade of events linking sensory stimulation to the observed cellular responses. Meanwhile the nature of how some cells, such as microglia, respond to gamma stimulation and how that affects pathology remains unclear, Tsai added.
Even with a national Phase III clinical trial underway, it is still important to investigate these fundamental mechanisms, Tsai said, because new insights into how non-invasive gamma stimulation affects the brain could improve and expand its therapeutic potential.
“The more we understand the mechanisms, the more we will have good ideas about how to further optimize the treatment,” Tsai said. “And the more we understand its action and the circuits it affects, the more we will know beyond Alzheimer’s disease what other neurological disorders will benefit from this.”
Indeed the review points to studies at MIT and other institutions providing at least some evidence that GENUS might be able to help with Parkinson’s disease, stroke, anxiety, epilepsy, and the cognitive side effects of chemotherapy and conditions that reduce myelin such as multiple sclerosis. Tsai’s lab has been studying whether it can help with Down syndrome as well.
The open questions may help define the next decade of GENUS research.
Most treatments being pursued today to protect against Alzheimer’s disease focus on amyloid plaques and tau tangles that accumulate in the brain, but new research from Mass General Brigham and Washington University School of Medicine in St. Louis points to a novel – and noble – approach: using xenon gas. The study found that xenon gas inhalation suppressed neuroinflammation, reduced brain atrophy, and increased protective neuronal states in mouse models of Alzheimer’s disease. Results are published in Science Translational Medicine, and a phase 1 clinical trial of the treatment in healthy volunteers will begin in early 2025.
“It is a very novel discovery showing that simply inhaling an inert gas can have such a profound neuroprotective effect,” said senior and co-corresponding author Oleg Butovsky, PhD, at Brigham and Women’s Hospital (BWH). “One of the main limitations in the field of Alzheimer’s disease research and treatment is that it is extremely difficult to design medications that can pass the blood-brain barrier – but senon gas does. We look forward to seeing this novel approach tested in humans.”
“It is exciting that in both animal models that model different aspects of Alzheimer’s disease, amyloid pathology in one model and tau pathology in another model, that Xenon had protective effects in both situations,” said senior and co-corresponding author David M. Holtzman, MD, from Washington University School of Medicine in St. Louis.
The causes of Alzheimer’s disease are not fully understood; there is currently no cure, and more effective treatments are desperately needed. Characterised by protein buildups in the brain, including tau and amyloid, Alzheimer’s disease disrupts nerve cell communication and causes progressive brain abnormalities that lead to neuronal damage and ultimately to death. Microglia, the brain’s primary and most prominent immune cells, act as ‘first responders’ when something goes awry in the brain, and they play a key role in regulating brain function in all phases of development. Microglial dysregulation is a key component of Alzheimer’s disease. Butovsky’s lab previously designed a way to study how microglia respond to neurodegeneration and confirmed that a specific phenotype of microglia can be modulated in a way that is protective in Alzheimer’s disease.
In this study, mouse models of Alzheimer’s disease were treated with xenon gas that has been used in human medicine as an anesthetic and as a neuroprotectant for treating brain injuries. Xenon gas penetrates the blood-brain barrier, passing from the bloodstream directly into the fluid surrounding the brain. The team found that xenon gas inhalation reduced brain atrophy and neuroinflammation and improved nest-building behaviours in the Alzheimer’s disease mouse models. It also induced and increased a protective microglial response that is associated with clearing amyloid and improving cognition. Together, these findings identify the promising potential of xenon inhalation as a therapeutic approach that could modify microglial activity and reduce neurodegeneration in Alzheimer’s disease.
The clinical trial at Brigham and Women’s Hospital, which will initially only enrol healthy volunteers, is set to begin in the next few months.
As early phases of the clinical trial get underway to establish safety and dosage, the research team plans to continue to study the mechanisms by which xenon gas achieves its effects in addition to its potential for treating other diseases such as multiple sclerosis, amyotrophic lateral sclerosis, and eye diseases that involve the loss of neurons. The team is also devising technologies to help use xenon gas more efficiently as well as potentially recycle it.
“If the clinical trial goes well, the opportunities for the use of Xenon gas are great,” said co-author Howard Weiner, MD, co-director of the Ann Romney Center for Neurologic Diseases at BWH and principal investigator of the upcoming clinical trial. “It could open the door to new treatments for helping patients with neurologic diseases.”
Neurons in the brain of an Alzheimer’s patient, with plaques caused by tau proteins. Credit: NIH
University of Pittsburgh researchers uncovered a surprising link between Alzheimer’s disease and herpes simplex virus-1 (HSV-1), suggesting that viral infections may play a role in the disease. The study results were published in Cell Reports.
The study also revealed how tau protein, often viewed as harmful in Alzheimer’s, might initially protect the brain from the virus but contribute to brain damage later. These findings could lead to new treatments targeting infections and the brain’s immune response.
“Our study challenges the conventional view of tau as solely harmful, showing that it may initially act as part of the brain’s immune defence,” said senior author Or Shemesh, assistant professor in the Department of Ophthalmology at Pitt. “These findings emphasise the complex interplay between infections, immune responses and neurodegeneration, offering a fresh perspective and potential new targets for therapeutic development.”
The scientists identified forms of HSV-1-related proteins in Alzheimer’s brain samples, with greater amounts of viral proteins co-localised with tangles of phosphorylated tau—one of the hallmarks of Alzheimer’s pathology—in brain regions especially vulnerable to Alzheimer’s across disease stages.
Further studies on miniature models of human brains in a Petri dish suggested that HSV-1 infection could modulate levels of brain tau protein and regulate its function, a protective mechanism that seemed to decrease post-infection death of human neurons.
While the precise mechanisms by which HSV-1 influences tau protein and contributes to Alzheimer’s disease are still unknown, Shemesh and his colleagues plan to explore those questions in future research. They aim to test potential therapeutic strategies that target viral proteins or fine-tune the brain’s immune response and investigate whether similar mechanisms are involved in other neurodegenerative diseases, such as Parkinson’s disease and amyotrophic lateral sclerosis.
Neurons in the brain of an Alzheimer’s patient, with plaques caused by tau proteins. Credit: NIH
Brain shrinkage observed in people receiving drugs for Alzheimer’s treatment actually reflects their efficacy, suggests to a new study from University College London. The researchers analysed data from a dozen different trials of amyloid-targeting immunotherapy – including lecanemab, recently approved in the UK for Alzheimer’s treatment but not yet used by the NHS.
While brain shrinkage is usually an undesirable outcome, the team found that the excess volume loss was consistent across studies and correlated with how effective the therapy was in removing amyloid and was not associated with harm.
As a result, the researchers believe that the removal of amyloid plaques, which are abundant in Alzheimer’s patients, could account for the observed brain volume changes. And, as such, the volume loss should not be a cause for concern.
To describe this phenomenon, the research team coined a new phrase: “amyloid-removal-related pseudo-atrophy” or ARPA. The team published their findings in published in Lancet Neurology.
Senior author and Director of the UCL Dementia Research Centre, Professor Nick Fox said: “Amyloid-targeting monoclonal antibodies represent a significant therapeutic breakthrough in the treatment of Alzheimer’s disease. These agents work by binding to and triggering the removal of amyloid plaques from the brain.
“One area of controversy has been the effect of these agents on brain volumes. Brain volume loss is a characteristic feature of Alzheimer’s disease, caused by progressive loss of neurons.
“Amyloid immunotherapy has consistently shown an increase in brain volume loss – leading to concerns in the media and medical literature that these drugs could be causing unrecognised toxicity to the brains of treated patients.
“However, based on the available data, we believe that this excess volume change is an anticipated consequence of the removal of pathologic amyloid plaques from the brain of patients with Alzheimer’s disease.”
In August, the Medicines and Healthcare Products Regulatory Agency (MHRA) licensed lecanemab, for use in the early stages of Alzheimer’s disease in the UK *.
The drug works by targeting beta amyloid – a protein that builds up in the brains of people with Alzheimer’s disease and is thought to be the triggering event leading to neuronal dysfunction and cell death.
The National Institute for Health and Care Excellence (NICE) that decide whether drugs should be made available on the NHS have published draft guidance advising that the benefits of lecanemab are too small to justify the cost to the NHS. However, the decision will be reviewed following a public consultation and a second independent committee meeting later this year.
This is a pseudo-colored image of high-resolution gradient-echo MRI scan of a fixed cerebral hemisphere from a person with multiple sclerosis.
Credit: Govind Bhagavatheeshwaran, Daniel Reich, National Institute of Neurological Disorders and Stroke, National Institutes of Health
The question of what causes complex neurological diseases such as Alzheimer’s or multiple sclerosis continues to confound scientists and doctors, with the unknowns standing in the way of early diagnoses and effective treatments.
Even among identical twins who share the same genetic risk factors, one may develop a particular neurological disease while the other does not.
That’s because unlike diseases such as cystic fibrosis or sickle-cell anaemia, which are caused by a single gene, most neurological disorders are associated with many, sometimes hundreds, of rare genetic variants. And on their own, these variants can’t predict who will develop disease, as neurological conditions are also strongly influenced by environmental factors and vascular risks such as high blood pressure, aging, heart disease, or obesity.
But there’s one often-overlooked thread that connects most neurological diseases, says Katerina Akassoglou, PhD, a senior investigator at Gladstone Institutes: They’re marked by a toxic immune reaction caused by blood that leaks into the brain through damaged blood vessels.
“Interactions between the brain, blood vessels, and the immune system are a common thread in the development and progression of many neurological diseases that have been traditionally viewed as very different conditions,” says Akassoglou. “Knowing that leaked blood is a key driver of brain inflammation, we can now approach these diseases from a different angle.”
She and her collaborators share their insights on this topic in a commentary article published in Cell’s 50th anniversary “Focus on Neuroscience” issue.
Neutralising the Culprit
Akassoglou and her lab have long investigated how blood that leaks into the brain triggers neurologic diseases, essentially by hijacking the brain’s immune system and setting off a cascade of harmful often-irreversible effects that result in damaged neurons.
One blood protein in particular, fibrin, normally involved in blood coagulation, is responsible for setting off this detrimental cascade. The process has been observed in conditions as diverse as Alzheimer’s, traumatic brain injury, multiple sclerosis, premature birth, and even COVID-19. However, Akassoglou and her team found that the process could be prevented or interrupted by “neutralising” fibrin to deactivate its toxic properties – an approach that appears to protect against many neurological diseases when tested in animal models.
“As a first step, we know that neutralizing fibrin reduces the burden posed by vascular dysfunction,” Akassoglou says. Regardless of what initially caused the blood leaks, be it a head injury, autoimmunity, genetic mutations, brain amyloid or infection, neutralizing fibrin appears to be protective in multiple animal models of disease.
The scientists previously developed a drug, a therapeutic monoclonal antibody, that specifically targets fibrin’s inflammatory properties without affecting its essential role in blood coagulation. This fibrin-targeting immunotherapy has shown, in mice, to protect from multiple sclerosis and Alzheimer’s, and to treat neurological effects of COVID-19. A humanized version of this first-in-class fibrin immunotherapy is already in Phase 1 safety clinical trials by Therini Bio, a biotech company launched to advance discoveries from Akassoglou’s lab.
A New Era of Brain Research
In the Cell commentary, Akassoglou and her colleagues make the case that seemingly disparate neurological diseases must be viewed differently in light of new research on the blood-brain-immune interface.
They say that in the coming decade, scientific breakthroughs will emerge from collaborative networks of immunologists, neuroscientists, haematologists, geneticists, computer scientists, physicists, bioengineers, drug developers, and clinical researchers. These partnerships, forged across academia, industry, and foundations, will catalyse innovation in drug discovery and transform medical practice for neurological diseases.
“This is a new opportunity for drug discovery that goes beyond addressing genes alone or environmental factors alone,” Akassoglou says. “To usher in this new era, we must leverage new technologies and embrace an interdisciplinary approach that accounts for the important roles of immune and vascular systems in neurodegeneration.”
Over 30% of older adults take five or more medications daily, which is termed polypharmacy. It is associated with poor health outcomes like falls, medication interactions, hospitalisations and even death. Multiple chronic conditions in older adults increases the risk of polypharmacy. While polypharmacy is more common in older adults with Alzheimer’s disease and related dementias, there is little research examining the impact on symptoms, health outcomes and physical function.
Researchers from Drexel University’s College of Nursing and Health Professions recently published a study in Biological Research For Nursing examining symptoms, health outcomes and physical function over time in older adults with and without Alzheimer’s disease and related dementias and polypharmacy.
Led by Martha Coates, PhD, the research team found that individuals who are experiencing polypharmacy and have Alzheimer’s disease and related dementias experience more symptoms, falls, hospitalisations, mortality and had lower physical function – indicating that polypharmacy can also negatively impact quality of life for older adults with Alzheimer’s disease and related dementias.
“The cut-off of point of five or more medications daily has been associated with adverse health outcomes in previous research, and as the number of medications increase the risk of adverse drug events and harm increases,” said Coates.
The research team used a publicly available dataset from the National Health and Aging Trends Study – a nationally representative sample of Medicare beneficiaries in the United States from Johns Hopkins University. Since 2011, data is collected yearly to examine social, physical, technological and functional domains that are important in aging.
For this study, the research team used data from 2016 through 2019 to compare changes in symptoms, health outcomes and physical function among four groups: 1) those with Alzheimer’s disease and related dementias and polypharmacy; 2) those with Alzheimer’s disease and related dementias only; 3) those with polypharmacy only; and 4) those without either Alzheimer’s disease and related dementias or polypharmacy.
Coates explained that the researchers used analytic weights to analyse the data, which generates national estimates, making the sample of 2052 individuals representative of 12 million Medicare beneficiaries in the US, increasing the generalisability of the findings.
“We found that older adults with Alzheimer’s disease and related dementias and polypharmacy experienced more unpleasant symptoms, increased odds of falling, being hospitalised and mortality compared to those without Alzheimer’s disease and related dementias and polypharmacy,” said Coates. “They also experienced more functional decline, required more assistance with activities of daily living like eating, bathing and dressing, and were more likely to need an assistive device like a cane or walker.”
Coates noted that there are tools available to help health care providers review and manage medication regimens for older adults experiencing polypharmacy and possibly taking medications that are potentially inappropriate or no longer provide benefit. However, currently there are no specific tools like that for older adults with Alzheimer’s disease and related dementias.
The findings from this research shed light on the negative impact polypharmacy can have on older adults with Alzheimer’s disease and related dementias. But Coates added that further research is needed to develop strategies to reduce the occurrence of polypharmacy in people with Alzheimer’s disease and related dementias.
The research team anticipates this study will help guide future analysis of the impact of specific medications on health outcomes in individuals with Alzheimer’s disease and related dementias and that it provides a foundation to support intervention development for medication optimisation in older adults with Alzheimer’s disease and related dementias and polypharmacy.
Neurons in the brain of an Alzheimer’s patient, with plaques caused by tau proteins. Credit: NIH
Alzheimer’s disease may damage the brain in two distinct phases, based on new research funded by the National Institutes of Health (NIH) using sophisticated brain mapping tools. According to researchers who discovered this new view, the first, early phase happens slowly and silently – before people experience memory problems – harming just a few vulnerable cell types. In contrast, the second, late phase causes damage that is more widely destructive and coincides with the appearance of symptoms and the rapid accumulation of plaques, tangles, and other Alzheimer’s hallmarks.
“One of the challenges to diagnosing and treating Alzheimer’s is that much of the damage to the brain happens well before symptoms occur. The ability to detect these early changes means that, for the first time, we can see what is happening to a person’s brain during the earliest periods of the disease,” said Richard J. Hodes, MD, director, NIH National Institute on Aging. “The results fundamentally alter scientists’ understanding of how Alzheimer’s harms the brain and will guide the development of new treatments for this devastating disorder.”
Scientists analysed the brains of 84 people, and the results, published in Nature Neuroscience, suggest that damage to one type of cell, called an inhibitory neuron, during the early phase may trigger the neural circuit problems that underlie the disease. Additionally, the study confirmed previous findings about how Alzheimer’s damages the brain and identified many new changes that may happen during the disease.
Specifically, the scientists used advanced genetic analysis tools to study the cells of the middle temporal gyrus, a part of the brain that controls language, memory and vision. The gyrus has been shown to be vulnerable to many of the changes traditionally seen during Alzheimer’s. It is also a part of the brain that researchers have thoroughly mapped for control donors. By comparing control donor data with that from people who had Alzheimer’s, the scientists created a genetic and cellular timeline of what happens throughout the disease.
Traditionally, studies have suggested that the damage caused by Alzheimer’s happens in several stages characterized by increasing levels of cell death, inflammation and the accumulation of proteins in the form of plaques and tangles. In contrast, this study suggests that the disease changes the brain in two “epochs” – or phases – with many of the traditionally studied changes happening rapidly during the second phase. This coincides with the appearance of memory problems and other symptoms.
The results also suggest that the earliest changes happen gradually and “quietly” in the first phase before any symptoms appear. These changes include slow accumulation of plaques, activation of the brain’s immune system, damage to the cellular insulation that helps neurons send signals and the death of cells called somatostatin (SST) inhibitory neurons.
The last finding was surprising to the researchers. Traditionally, scientists have thought that Alzheimer’s primarily damages excitatory neurons, which send activating neural signals to other cells. Inhibitory neurons send calming signals to other cells. The paper’s authors hypothesised how loss of SST inhibitory neurons might trigger the changes to the brain’s neural circuitry that underlie the disease.
Recently, a separate NIH-funded brain mapping study by researchers at MIT found that a gene called REELIN may be associated with the vulnerability of some neurons to Alzheimer’s. It also showed that star-shaped brain cells called astrocytes may provide resilience to or resist the harm caused by the disease.
Researchers analysed brains that are part of the Seattle Alzheimer’s Disease Brain Cell Atlas, which is designed to create a highly detailed map of the brain damage that occurs during the disease. The project was led by Mariano I. Gabitto, PhD, and Kyle J. Travaglini, PhD, from the Allen Institute, Seattle. The scientists used tools – developed as part of the NIH’s BRAIN Initiative – Cell Census Network – to study more than 3.4 million brain cells from donors who died at various stages of Alzheimer’s disease.
“This research demonstrates how powerful new technologies provided by the NIH’s BRAIN Initiative are changing the way we understand diseases like Alzheimer’s. With these tools, scientists were able to detect the earliest cellular changes to the brain to create a more complete picture of what happens over the entire course of the disease,” said John Ngai, Ph.D., director of The BRAIN Initiative®. “The new knowledge provided by this study may help scientists and drug developers around the world develop diagnostics and treatments targeted to specific stages of Alzheimer’s and other dementias.”
