Researchers identify new genes that may contribute to Alzheimer’s disease

Researchers from Boston University School of Medicine, working with scientists across the nation on the Alzheimer’s Disease Sequencing Project (ADSP), have discovered new genes that will further current understanding of the genetic risk factors that predispose people to the development of Alzheimer’s disease (AD). The ADSP was developed by the National Institutes of Health (NIH) in response to the National Alzheimer’s Project Act milestones to fight AD.

The incidence of AD is increasing each year and is the most common cause of dementia. Also, it is the fifth leading cause of death in those 65-years and older, according to the CDC. AD is characterized by the formation of senile plaques (extracellular deposits of β-amyloid protein) and neurofibrillary tangles (aggregates of hyper-phosphorylated tau protein) in the brain, leading to neurodegeneration and decline in memory, and eventually death. Despite the growing prevalence of AD and cost to society, the genetic and environmental factors that make some more susceptible to the development of AD is still not well understood.

“This large and deep gene sequencing study is an important part of identifying which variations may play a part in risk of getting Alzheimer’s or protection against it,” said Eliezer Masliah, MD, director of the Division of Neuroscience at the National Institute on Aging, part of NIH. “Big data efforts like the ADSP are really helping research move forward. Identifying rare variants could enhance our ability to find novel therapeutic targets and advance precision medicine approaches for Alzheimer’s disease.”

By comparing the exomes (gene-coding portions of entire genetic sequences) of nearly 6,000 individuals with AD and 5,000 cognitively healthy older adults, the researchers were able to find rare variations in genes that they believe may contribute to the development of common AD. These newly discovered genes may suggest an inflammatory response and changes in the protein production. These combined changes are thought to contribute to the overall neurodegeneration witnessed in AD.

The researchers hope their work will help bridge the knowledge gaps of the genetic architecture related to AD, which is a necessary step toward a better understanding of mechanisms leading to AD and eventual therapeutic treatments. “Many of our findings will provide insight into disease mechanisms and targets for biological experiments to gain further understanding about the role of these genes in AD pathogenesis,” explained corresponding author Lindsay A. Farrer, Ph.D., Chief of Biomedical Genetics and a professor of Medicine, Neurology, Ophthalmology, Epidemiology and Biostatistics at Boston University Schools of Medicine and Public Health.

The research team emphasizes that further research will need to be done to find other genes hidden throughout the genome, as the current paradigm is that many genes contribute to the development of AD.

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Discovery presents treatment hope for Alzheimer’s and other neurodegenerative diseases

There is new hope for the treatment of Alzheimer’s and other neurological diseases following a ground-breaking discovery made by an Australian-Chinese research collaboration.

Researchers from the University of South Australia and the Third Military Medical University in China have discovered a signal pathway within cells, and also invented a potential drug that could stop degeneration and actually improve learning and memory in affected patients.

UniSA’s Professor Xin-Fu Zhou and colleagues have been investigating tauopathies — which refers to a class of diseases caused by misfolding of the tau protein inside nerve cells that results in cell damage and eventually cell death.

These diseases include Alzheimer’s, Parkinson’s and Motor Neuron Disease, all of which presently have no cure.

Specifically, the team has looked into frontotemporal lobe degeneration (FTLD), a term representing a group of clinical syndromes related to cognitive impairment, behavioural abnormalities and speech disorders.

Professor Zhou says that previously it was unknown how the gene mutation was responsible for causing cell death or damage — referred to generally as neurodegeneration, and dementia in patients with FTLD and other motor neuron diseases. “Right now there is no treatment available at all,” Prof Zhou says. “We have been investigating how these tauopathies (diseases) have some common pathology, including a particular tau protein that plays a critical role in nerve cell function.”

Tau protein is a protein that stabilises microtubules and it is specifically abundant in neurons of the nervous system, but not in elsewhere.

“Our research found that in both the animal model and human brains, the signal of neurotrophins and receptors is abnormal in brains with FTLD,” Prof Zhou says.

“We discovered an increase in the neurotrophin signalling pathway that is related to life and death of nerve cells, known as proNGF/p75, and then found blocking its functions was shown to reduce cell damage.

“Thus, in this paper we not only discovered a signaling pathway but also invented a potential drug for treatment of such diseases.”

Given this strong evidence now available, the next stage is a clinical trial and South Australian biotech company Tiantai Medical Technology Pty Ltd has recently acquired a licence to further develop and commercialise this medical technology.

Professor Zhou says this industry involvement means there is an opportunity to translate the discovery into a treatment of Alzheimer’s disease and other tauopathies.

The paper published in Molecular Psychiatry is a collaborative work between two laboratories led by Professor Xin-Fu Zhou, University of South Australia and Professor Yanjiang Wang, the Third Military Medical University.

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Discovery presents treatment hope for Alzheimer’s and other neurodegenerative diseases

There is new hope for the treatment of Alzheimer’s and other neurological diseases following a ground-breaking discovery made by an Australian-Chinese research collaboration.

Researchers from the University of South Australia and the Third Military Medical University in China have discovered a signal pathway within cells, and also invented a potential drug that could stop degeneration and actually improve learning and memory in affected patients.

UniSA’s Professor Xin-Fu Zhou and colleagues have been investigating tauopathies—which refers to a class of diseases caused by misfolding of the tau protein inside nerve cells that results in cell damage and eventually cell death.

These diseases include Alzheimer’s, Parkinson’s and Motor Neuron Disease, all of which presently have no cure.

Specifically, the team has looked into frontotemporal lobe degeneration (FTLD), a term representing a group of clinical syndromes related to cognitive impairment, behavioural abnormalities and speech disorders.

Professor Zhou says that previously it was unknown how the gene mutation was responsible for causing cell death or damage—referred to generally as neurodegeneration, and dementia in patients with FTLD and other motor neuron diseases.”Right now there is no treatment available at all,” Prof Zhou says.”We have been investigating how these tauopathies (diseases) have some common pathology, including a particular tau protein that plays a critical role in nerve cell function.”

Tau protein is a protein that stabilises microtubules and it is specifically abundant in neurons of the nervous system, but not in elsewhere.

“Our research found that in both the animal model and human brains, the signal of neurotrophins and receptors is abnormal in brains with FTLD,” Prof Zhou says.

“We discovered an increase in the neurotrophin signalling pathway that is related to life and death of nerve cells, known as proNGF/p75, and then found blocking its functions was shown to reduce cell damage.

“Thus, in this paper we not only discovered a signaling pathway but also invented a potential drug for treatment of such diseases.”

Given this strong evidence now available, the next stage is a clinical trial and South Australian biotech company Tiantai Medical Technology Pty Ltd has recently acquired a licence to further develop and commercialise this medical technology.

Professor Zhou says this industry involvement means there is an opportunity to translate the discovery into a treatment of Alzheimer’s disease and other tauopathies.

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Alzheimer’s disease and type 2 diabetes: Hope for inhibitors against amyloid plaques: Designed peptides as potential inhibitors of amyloid plaques

Effective therapeutics to counteract the formation of amyloid plaques in Alzheimer’s disease and type 2 diabetes are not yet available. Scientists at the Technical University of Munich (TUM) have now come a little bit closer to a solution: They have described a new class of designed macrocyclic peptides that are highly potent inhibitors of amyloid formation.

Amyloid plaques, which are protein deposits, play a crucial role in the development of Alzheimer’s disease and type 2 diabetes. Several teams of scientists around the world are working on finding ways to prevent amyloid plaque formation in the human brain.

The research team of Aphrodite Kapurniotu, Professor for Peptide Biochemistry (TUM) has been working on an idea for some time now in collaboration with the teams of Professor Martin Zacharias (TUM), Professor Gerhard Rammes (TUM Rechts der Isar Hospital) and Professor Jürgen Bernhagen (Institute for Stroke and Dementia Research (ISD) at Ludwig Maximilian University (LMU)). The researchers present now macrocyclic peptides (MCIPs) as potent inhibitors of amyloid formation; they reported their results in the journal Angewandte Chemie. The work has been supported by Deutsche Forschungsgemeinschaft (DFG) collaborative research center SFB 1035.

New class of amyloid inhibitors

In its new study, the team presents macrocyclic peptides, developed as a new class of amyloid inhibitors. “We have discovered an MCIP that is stable in human blood plasma and can also overcome the human blood-brain barrier in an in vitro cell culture model,” explains Professor Kapurniotu. She adds: “So far we were ‘only’ able to demonstrate these properties in the test tube — thus further research is necessary. But these are two highly desirable properties for inhibitors of Alzheimer’s amyloid.”

TUM has already applied for a patent for the newly developed macrocyclic peptides. “They could be a good alternative to the currently pursued antibody-based approaches as therapeutics against Alzheimer’s amyloid plaque formation because they are easy to produce, have promising properties and, due to their peptidic nature, they will be significantly cheaper than antibodies,” says Professor Kapurniotu.

“Therefore, further investigations are now planned to verify whether the MCIPs are also effective in in vivo models. Furthermore, the MCIPs could also be suitable as templates for the development of small molecule peptidomimetics (molecules mimicking peptide chains), which might also find application as anti-amyloid drugs in Alzheimer’s and type 2 diabetes.

The research work was funded by the German Research Foundation (DFG) within the SFB 1035.

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Eye conditions provide new lens screening for Alzheimer’s disease

Alzheimer’s disease is difficult to diagnose as well as treat, but researchers now have a promising new screening tool using the window to the brain: the eye.

A study of 3,877 randomly selected patients found a significant link between three degenerative eye diseases—age-related macular degeneration, diabetic retinopathy and glaucoma—and Alzheimer’ disease.

The results offer physicians a new way to detect those at higher risk of this disorder, which causes memory loss and other symptoms of cognitive decline. .

The researchers, from the University of Washington School of Medicine, the Kaiser Permanente Washington Health Institute and the UW School of Nursing, reported their findings Aug. 8 in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.

“We don’t mean people with these eye conditions will get Alzheimer’s disease,” said lead researcher Dr. Cecilia Lee, assistant professor of ophthalmology at the UW School of Medicine. “The main message from this study is that ophthalmologists should be more aware of the risks of developing dementia for people with these eye conditions and primary care doctors seeing patients with these eye conditions might be more careful on checking on possible dementia or memory loss.”

The participants in the study were age 65 and older and did not have Alzheimer’s disease at the time of enrollment. They were part of the Adult Changes in Thought database started in 1994 by Dr. Eric Larson, who is at Kaiser Permanente Washington Health Research Institute. Over the five-year study, 792 cases of Alzheimer’s disease were diagnosed by a committee of dementia experts. Patients with age-related macular degeneration, diabetic retinopathy, or glaucoma were at 40 % to 50% greater risk of developing Alzheimer’s disease compared to similar people without these eye conditions. Cataract diagnosis was not an Alzheimer’s disease risk factor.

“What we found was not subtle,” said Dr. Paul Crane, professor of medicine, Division of General Internal Medicine, at the UW School of Medicine. “This study solidifies that there are mechanistic things we can learn from the brain by looking at the eye.”

More than 46 million older adults are affected by dementia worldwide and 131.5 million cases are expected by 2050, the researchers said. Alzheimer’ disease is the most common dementia,and discovering risk factors may lead to early detection and preventive measures, they said in their paper.

Lee said anything happening in the eye may relate to what’s happening in the brain, an extension of the central nervous system. The possible connections need more study. She said a better understanding of neurodegeneration in the eye and the brain could bring more success in diagnosing Alzheimer’s early and developing better treatments.

The researchers said several factors suggest the effects they uncovered were specific to ophthalmic conditions and not merely age-related phenomenon.

Larson said for years Alzheimer’s researchers were focused on amyloid buildup in brain tissue, but that hasn’t brought much benefit to patients.

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Microfluidic system incorporates neuroinflammation into ‘Alzheimer’s in a dish’ model

Building on their development of the first culture system to replicate fully the pathology behind Alzheimer’s disease, a Massachusetts General Hospital (MGH) research team has now produced a system that includes neuroinflammation, the key biological response that leads to the death of brain cells. The investigators describe their system, which incorporates the glial cells that that not only surround and support neurons but also provide some immune system functions, in a paper published in Nature Neuroscience.

“Our original ‘Alzheimer’s in a dish ‘ system recapitulated the plaques and tangles typically seen the brains of patients with Alzheimer’s disease, but did not induce neuroinflammation,” says Rudolph Tanzi, Ph.D., director of the Genetics and Aging Research Unit in the MassGeneral Institute for Neurodegenerative Disease (MIND) and co-senior author of the current paper. “Studies have shown that we can have many plaques and tangles in our brains with no symptoms, but when neuroinflammation kicks in, exponentially more neurons die and cognitive impairment leading to dementia is induced. A complete model of Alzheimer’s pathology needs to incorporate that ‘third leg of the stool’.”

In their 2014 Nature paper, the MGH team described using a gel-based, three-dimensional culture system—developed by Doo Yeon Kim, Ph.D., of the Genetics and Aging Unit, also a co-senior author of the current study—to induce the formation of both amyloid-beta plaques and neurofibrillary tangles in human neural cells carrying gene variants associated with early-onset, familial Alzheimer’s disease (FAD). That study confirmed that amyloid deposition was the essential first step leading to the formation of tangles containing the pathogenic form of the protein tau

The updated system also brings in technology developed by co-senior author Hansang Cho, Ph.D., now of the University of North Carolina at Charlotte, when he was a postdoctoral fellow in the MGH BioMEMS Resource Center . In a 2013 Scientific Reports paper, Cho and his co-authors reported using a microfluidic device consisting of two circular chambers, one inside the other, to measure the migration of microglia—glial cells that function as nervous system immune cells—from the outer chamber into the amyloid-loaded inner chamber by means of connecting channels.

For the current study Cho and lead author Joseph Park, Ph.D., of the MGH Genetics and Aging Unit, used the ‘Alzheimer’s in a dish’ system to culture neural stem cells with FAD variants in the central chamber of Cho’s device. Several weeks later, the neurons and astrocytes, glial cells that support and insulate neurons, that had differentiated were found to contain elevated levels of amyloid-beta and tau, as well as inflammatory factors known to contribute to the neuroinflammation seen in Alzheimer’s disease.

When human microglia were added to the outer chamber of the device, they soon began to show structural changes signifying their activation and migrate through the channels into the inner chamber. Once the microglia arrived in the inner chamber, they directly attacked neurons, causing visible damage to key structures, while levels of inflammatory factors like TNF-alpha, IL-6 and IL-8 rose significantly. Six days later the central chambers had lost 20 percent of both their neurons and their astrocytes.

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Alzheimer’s drug may stop disease if used before symptoms develop

About 50 percent of people who reach the age of 85 will develop Alzheimer’s disease. Most will die within about five years of exhibiting the hallmark symptoms of the disease – severe memory loss and a precipitous decline in cognitive function.

But the molecular processes that lead to the disease will have begun years earlier.

Currently, there are no known ways to prevent the disease or to stop its progression once it has begun. But research at the University of Virginia offers new understanding of how the disease develops at the molecular level, long before extensive neuronal damage occurs and symptoms show up.

Additionally, the researchers have found that an FDA-approved drug, memantine, currently used only for alleviating the symptoms of moderate-to-severe Alzheimer’s disease, might be used to prevent or slow the progression of the disease if used before symptoms appear. The research also offers, based on extensive experimentation, a hypothesis as to why this might work.

The findings are published currently online in the journal Alzheimer’s & Dementia.

“Based on what we’ve learned so far, it is my opinion that we will never be able to cure Alzheimer’s disease by treating patients once they become symptomatic,” said George Bloom, a UVA professor and chair of the Department of Biology, who oversaw the study in his lab. “The best hope for conquering this disease is to first recognize patients who are at risk, and begin treating them prophylactically with new drugs and perhaps lifestyle adjustments that would reduce the rate at which the silent phase of the disease progresses.

“Ideally, we would prevent it from starting in the first place.”

As Alzheimer’s disease begins, there is a lengthy period of time, perhaps a decade or longer, when brain neurons affected by the disease attempt to divide, possibly as a way to compensate for the death of neurons. This is unusual in that most neurons develop prenatally and then never divide again. But in Alzheimer’s the cells make the attempt, and then die.

“It’s been estimated that as much as 90 percent of neuron death that occurs in the Alzheimer’s brain follows this cell cycle reentry process, which is an abnormal attempt to divide,” Bloom said. “By the end of the course of the disease, the patient will have lost about 30 percent of the neurons in the frontal lobes of the brain.”

Erin Kodis, a former Ph.D. student in Bloom’s lab and now a scientific editor at AlphaBioCom, hypothesized that excess calcium entering neurons through calcium channels on their surface drive those neurons back into the cell cycle. This occurs before a chain of events that ultimately produce the plaques found in the Alzheimer’s brain. Several experiments by Kodis ultimately proved her theory correct.

The building blocks of the plaques are a protein called amyloid beta oligomers. Kodis found that when neurons are exposed to toxic amyloid oligomers, the channel, called the NMDA receptor, opens, thus allowing the calcium flow that drives neurons back into the cell cycle.

Memantine blocks cell cycle reentry by closing the NMDA receptor, Kodis found.

“The experiments suggest that memantine might have potent disease-modifying properties if it could be administered to patients long before they have become symptomatic and diagnosed with Alzheimer’s disease,” Bloom said. “Perhaps this could prevent the disease or slow its progression long enough that the average age of symptom onset could be significantly later, if it happens at all.”

Side effects of the drug appear to be infrequent and modest.

Bloom said potential patients would need to be screened for Alzheimer’s biomarkers years before symptoms appear. Selected patients then would need to be treated with memantine, possibly for life, in hopes of stopping the disease from ever developing, or further developing.

“I don’t want to raise false hopes,” Bloom said, but “if this idea of using memantine as a prophylactic pans out, it will be because we now understand that calcium is one of the agents that gets the disease started, and we may be able to stop or slow the process if done very early.”

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Alzheimer’s Drug Trial Offers New Hope, But Uncertainty, Too

THURSDAY, July 26 — There have been many setbacks on the long road to finding a treatment that might slow or stop Alzheimer’s disease, but a new trial offers a glimmer of hope.

Researchers report that an experimental drug called BAN2401 slowed mental decline by as much as 30 percent in Alzheimer’s patients. It also appeared to clear away the amyloid protein plaques in the brain that have long been linked to the devastating illness.

However, the trial — a follow-up to data on the drug released in 2017 — was small, and questions and caveats remain.

“That said, these two studies indicate that amyloid remains an important therapeutic target to pursue in Alzheimer’s disease,” the Alzheimer’s Association said in a statement.

The trial included 856 patients with either mild cognitive impairment (often a precursor to Alzheimer’s) or mild Alzheimer’s disease. The 161 participants who received the highest dose of the drug every two weeks for 18 months had much slower mental decline than the 245 patients who received a placebo, the Associated Press reported.

The highest dose of the drug also removed much of the Alzheimer’s-associated plaque in the brains of patients, according to the findings presented by the drug’s makers Wednesday at the Alzheimer’s Association’s annual meeting in Chicago.

BAN2401, which has been developed by Eisai and Biogen, works by undermining the string-like amyloid tendrils that form in the brain before they clump together to create plaques. It is thought that intervening very early in the disease process — long before dementia sets in — is the best path to a successful treatment.

The drug did not meet its stated statistical goals by the end of one year — making the trial a failure overall.

However, gains in curbing cognitive decline were seen by 18 months, the researchers said in a news conference on Wednesday.

“On behalf of the millions living with Alzheimer’s disease and other dementias now and the millions more at risk, the Alzheimer’s Association finds these results important to report and share with the scientific community,” the association’s statement said.

The study was led by company scientists and has not yet been reviewed by outside experts. One issue is that participants’ progress in the trial was tracked using a cognitive assessment devised by Eisai and Biogen. It remains to be seen if those measures hold up to outside scrutiny, experts said.

Overall, dementia experts said that because the trial was too small to provide conclusive evidence and used a new way to assess mental decline, the findings need to be confirmed with further research.

Even so, some said the results offered hope after decades of failed attempts.

“We’re cautiously optimistic,” Maria Carrillo, chief science officer of the Alzheimer’s Association, told the AP.

“A 30 percent slowing of decline is something I would want my family member to have,” and the drug’s ability to clear brain plaques “looks pretty amazing,” she added.

“That’s a very hopeful outcome. It means we may be on the right track,” Dr. Stephen Salloway, neurology chief at Brown University, told the AP.

Speaking to the New York Times, neurologist Dr. Samuel Gandy said the 30 percent slowing of cognitive loss seen in the study might not be enough to make a difference in patients’ everyday function.

Would such an effect mean the difference, for example, between allowing a patient to dress or feed themselves without the aid of a caregiver? That’s not clear from the study, said Gandy, who is associate director of the Mount Sinai Alzheimer’s Disease Research Center in New York City.

“I wouldn’t say this is a quantum leap,” he said. “It is a convincing moving of the needle. But it’s not clear that the needle has moved far enough to make a difference in people’s lives.”

In any case, even if further studies proved successful, bringing BAN2401 to market would still take years, although Eisai chief executive Ivan Cheung said that both his company and Biogen have submitted requests to meet with the U.S. Food and Drug Administration to talk over steps needed for approval.

“It’s a bit premature to talk about at this point, but our goal is to bring BAN2401 to patients and families as soon as possible,” Cheung told the Times.

Alzheimer’s is the most common type of dementia, which affects about 50 million people worldwide. There is no cure. Current medicines just treat symptoms.

More information

Find out more about Alzheimer’s disease at the U.S. National Institute on Aging.

Posted: July 2018

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Alzheimer’s drug trial offers new hope, but uncertainty, too

(HealthDay)—There have been many setbacks on the long road to finding a treatment that might slow or stop Alzheimer’s disease, but a new trial offers a glimmer of hope.

Researchers report that an experimental drug called BAN2401 slowed mental decline by as much as 30 percent in Alzheimer’s patients. It also appeared to clear away the amyloid protein plaques in the brain that have long been linked to the devastating illness.

However, the trial—a follow-up to data on the drug released in 2017—was small, and questions and caveats remain.

“That said, these two studies indicate that amyloid remains an important therapeutic target to pursue in Alzheimer’s disease,” the Alzheimer’s Association said in a statement.

The trial included 856 patients with either mild cognitive impairment (often a precursor to Alzheimer’s) or mild Alzheimer’s disease. The 161 participants who received the highest dose of the drug every two weeks for 18 months had much slower mental decline than the 245 patients who received a placebo, the Associated Press reported.

The highest dose of the drug also removed much of the Alzheimer’s-associated plaque in the brains of patients, according to the findings presented by the drug’s makers Wednesday at the Alzheimer’s Association’s annual meeting in Chicago.

BAN2401, which has been developed by Eisai and Biogen, works by undermining the string-like amyloid tendrils that form in the brain before they clump together to create plaques. It is thought that intervening very early in the disease process—long before dementia sets in— is the best path to a successful treatment.

The drug did not meet its stated statistical goals by the end of one year—making the trial a failure overall.

However, gains in curbing cognitive decline were seen by 18 months, the researchers said in a news conference on Wednesday.

“On behalf of the millions living with Alzheimer’s disease and other dementias now and the millions more at risk, the Alzheimer’s Association finds these results important to report and share with the scientific community,” the association’s statement said.

The study was led by company scientists and has not yet been reviewed by outside experts. One issue is that participants’ progress in the trial was tracked using a cognitive assessment devised by Eisai and Biogen. It remains to be seen if those measures hold up to outside scrutiny, experts said.

Overall, dementia experts said that because the trial was too small to provide conclusive evidence and used a new way to assess mental decline, the findings need to be confirmed with further research.

Even so, some said the results offered hope after decades of failed attempts.

“We’re cautiously optimistic,” Maria Carrillo, chief science officer of the Alzheimer’s Association, told the AP.

“A 30 percent slowing of decline is something I would want my family member to have,” and the drug’s ability to clear brain plaques “looks pretty amazing,” she added.

“That’s a very hopeful outcome. It means we may be on the right track,” Dr. Stephen Salloway, neurology chief at Brown University, told the AP.

Speaking to the New York Times, neurologist Dr. Samuel Gandy said the 30 percent slowing of cognitive loss seen in the study might not be enough to make a difference in patients’ everyday function.

Would such an effect mean the difference, for example, between allowing a patient to dress or feed themselves without the aid of a caregiver? That’s not clear from the study, said Gandy, who is associate director of the Mount Sinai Alzheimer’s Disease Research Center in New York City.

“I wouldn’t say this is a quantum leap,” he said. “It is a convincing moving of the needle. But it’s not clear that the needle has moved far enough to make a difference in people’s lives.”

In any case, even if further studies proved successful, bringing BAN2401 to market would still take years, although Eisai chief executive Ivan Cheung said that both his company and Biogen have submitted requests to meet with the U.S. Food and Drug Administration to talk over steps needed for approval.

“It’s a bit premature to talk about at this point, but our goal is to bring BAN2401 to patients and families as soon as possible,” Cheung told the Times.

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Eight new mouse models for Alzheimer’s disease available to researchers

The MODEL-AD Center, an ambitious project to develop and distribute precise mouse models of late-onset Alzheimer’s disease (AD), has released eight new models carrying genetic mutations found in patients.

In past decades, most AD researchers had to rely on mouse models that carried a genetic mutation associated with the relatively rare, early-onset, familial version of the disease. But at least 95 percent of the more than 5.4 million Alzheimer’s patients in the U.S. have the late-onset version of the disease, which has not yet been successfully modeled in mice.

Enter MODEL-AD (which stands for Model Organism Development and Evaluation for Late-onset AD), a joint program of the Indiana University School of Medicine (IU), The Jackson Laboratory (JAX), Sage Bionetworks and the University of California, Irvine. MODEL-AD was launched in September 2016 by a five-year grant totaling $25 million from the National Institute on Aging, to address the critical lack of precision mouse models for late-onset AD.

“This effort is all about creating and sharing the mouse and data resources and protocols that research, pharma and biotech need for preclinical AD drug development,” says Bruce Lamb, Ph.D., executive director of IU’s Stark Neurosciences Research Institute, a principal investigator of MODEL-AD and a member of the Alzheimer’s Association Medical and Scientific Advisory Council.

In addition to AD mouse model development, MODEL-AD is working to establish standardized and rigorous processes for the characterization and preclinical testing of animal models, and to align the pathophysiological features of AD models with corresponding stages of clinical disease using translatable biomarkers.

“MODEL-AD would not have been possible even five years ago,” says JAX Research Scientist Michael Sasner, Ph.D. “Patient genetic testing, now commonplace, has generated massive databases to mine for gene variants associated with late-onset AD. CRISPR/Cas9 technology enables us to quickly create new mouse models with precise genetic mutations—even multiple mutations in a single mouse. And we now have a wide range of -omics, biomarker, and imaging technologies to evaluate how well a given mouse models late-onset AD.”

The project’s leaders expect to create more than 40 new mouse models based on human data sets, screen more than 24 models including deep phenotyping of at least eight new models, and establish a preclinical testing pipeline.

MODEL-AD has already created and made available models with humanized mutations in the strongest genetic risk factors for late-onset AD, including APOE ε4 and Trem2.

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