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New Alzheimer’s Prevention Trial in Young People

AHA Publisher — Thu, 23 Dec 2021 08:00:56 +0000

Washington University in St. Louis via Newswise – Washington University School of Medicine in St. Louis is launching an international clinical trial aimed at preventing Alzheimer’s disease in people genetically destined to develop the illness at a young age. Unlike most other Alzheimer’s prevention trials, this one will enroll people before the disease has taken hold – up to 25 years before the expected onset of dementia. Called the Primary Prevention Trial, the new study will investigate whether gantenerumab — an investigational antibody under development for Alzheimer’s disease by Roche and Genentech, a member of the Roche Group — can clear a key Alzheimer’s protein called amyloid beta, and slow or stop the disease. Amyloid is the chief component of plaques that dot the brains of people with the disease. Many scientists suspect the disease originates from the buildup of amyloid plaques in the brain that start to develop up to two decades before symptoms of dementia begin. “Overwhelming evidence suggests that the most effective way to slow or stop amyloid beta is to prevent it from building up in the first place, but most of the drugs targeted to this protein have been tested in people who already have at least some early signs of the disease, such as memory loss – when the disease is far enough along that reducing amyloid alone isn’t likely to stop it,” said Eric McDade, DO, an associate professor of neurology and the trial’s principal investigator. “We’ll be recruiting participants as young as 18. In many ways, this trial will be a necessary test of the amyloid hypothesis, which has had a major influence on Alzheimer’s research and drug development over the past 30 years.” The new trial involves families with rare genetic mutations that cause Alzheimer’s at a young age – typically in a person’s 50s, 40s or even 30s. A parent with such a mutation has a 50% chance of passing the genetic mutation to a child, and any child who inherits the mutation is all but guaranteed to develop symptoms of dementia near the same age as his or her parent. This certainty gives researchers an opportunity to evaluate the effectiveness of drugs designed to prevent Alzheimer’s. Forestalling the earliest signs of disease could be game changing in the world of Alzheimer’s prevention, and the study has garnered support from all quarters: a U.S. governmental agency, nonprofit organizations, individual benefactors, and the health-care company Roche and Genentech. More than $130 million has been earmarked for the trial, including grants totaling an estimated $97.4 million from the National Institute on Aging (NIA) of the National Institutes of Health (NIH), $14 million from the Alzheimer’s Association and the GHR Foundation, and up to $11.5 million from longtime Washington University benefactor Joanne Knight of St. Louis and family, who have long supported Alzheimer’s research at Washington University. In addition, the university has pledged to raise an additional $6.5 million. The trial is being conducted in close partnership with Roche and Genentech, which also is providing significant funding. “We are thrilled to be part of this important clinical trial in one of the earliest stages of Alzheimer’s studied to date,” said Rachelle Doody, MD, PhD, global head of neurodegeneration at Roche and Genentech. “Our vision has always been to detect Alzheimer’s early, before damage in the brain is irreversible, offering tools and treatment all along the journey for people at risk of the disease. Close collaboration between industry, academia and patients is so critical to achieve this and tackle the complex challenge of this disease.” The trial will recruit people with rare, early-onset forms of the disease, but the results also will further our understanding of Alzheimer’s overall, which could benefit the millions of people living with the more common form, which affects people later in life. The processes that lead to memory loss and cognitive impairment in Alzheimer’s are thought to be similar, whether the disease is caused by an inherited mutation or by the complex combination of genetics and environment that causes most Alzheimer’s cases. McDade and colleagues are studying about 230 participants from families that carry genetic mutations that lead to early-onset Alzheimer’s disease. The participants come from sites on five continents and have no or very few amyloid deposits. The trial will test gantenerumab over four years, with a goal of determining whether early treatment will prevent the buildup of the toxic protein. “This trial is the first of its kind in that it aims to intervene before the onset of significant neuropathology in those young adults who are at a very high risk of developing the debilitating symptoms of Alzheimer’s dementia,” said Laurie Ryan, PhD, chief of the Clinical Interventions and Diagnostics Branch in NIA’s Division of Neuroscience. “We now know that changes in the brain can begin a decade or more before symptoms appear, so this trial is designed to provide another piece in the Alzheimer’s prevention puzzle.” The new trial is the second international Alzheimer’s prevention trial led by Washington University School of Medicine. The first trial, known as the Dominantly Inherited Alzheimer Network-Trials Unit-001 (DIAN-TU-001), began in 2012 and is ongoing. That trial was testing the effectiveness of drug treatments, including gantenerumab, in people who were likely to develop the disease during the trial because nearly all had some amyloid plaques at the time they entered it. Earlier this year, trial leaders reported from the DIAN-TU-001 study that, while the effects on clinical outcomes such as cognitive function were not clear, gantenerumab improved biomarkers of the disease. As a consequence, trial leaders have offered the drug to participants as part of an exploratory open-label extension and continue to monitor changes in measures of Alzheimer’s disease in those participants who are receiving the investigational drug. “Multiple drugs are being tested in the ongoing Knight Family DIAN-TU prevention trial, which involves people who are expected to develop symptoms within 10 years,” said Randall J. Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology and the principal investigator and program director of the Knight Family DIAN-TU. “Initiating a new prevention trial alongside the DIAN-TU-001 trial gives family members an opportunity to attempt to stop the disease even earlier – 10 years or more before symptoms are likely to arise, which is before or just as the first brain changes begin. It’s the ultimate approach for prevention.” This new trial will draw from this same group of families and is aimed at determining whether targeting amyloid can prevent familial Alzheimer’s disease. Success would give researchers additional reasons to continue pursuing amyloid-based therapies at the earliest stages of the disease. “It’s exciting to think of the valuable insights this groundbreaking trial will provide in the prevention of Alzheimer’s dementia,” said Fred Miller, GHR Foundation’s chief operating officer and Alzheimer’s program lead. “We’re pleased to partner boldly on the multiple DIAN-TU trials, all made possible by the strong collaboration between academic researchers, government, industry, philanthropy and the DIAN families themselves.” Both trials are being conducted in association with the Dominantly Inherited Alzheimer Network (DIAN) – an NIH-funded international research network led by Washington University and involving nearly 40 research institutes in North America, Australia, Europe, Asia and South America. The National Institute on Aging has been a major supporter of DIAN and its clinical trials unit since the network was established in 2008. “The Alzheimer’s Association has been a long-term partner with DIAN, and we’re particularly proud of providing the initial funding for the establishment and launch of the Trials Unit in March 2012,” said Maria C. Carrillo, PhD, Alzheimer’s Association chief science officer. “DIAN-TU is a landmark project and has dramatically accelerated the pace of discovery of treatment and prevention strategies for Alzheimer’s disease, and this innovative new prevention study is no exception.” This international effort to find ways to prevent Alzheimer’s disease would not be possible without the support of many partners, as well as the active involvement of DIAN families. “The stakes are high, and studies like this one are expensive to carry out,” McDade said. “We’re thankful for the support from many sources to make this trial possible. We’re also grateful to the families, for their encouragement and willingness to take part in trials like this one.” To read the original article click here.

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Gene Discovery May Hold Key to Better Therapies for OCD

AHA Publisher — Fri, 16 Jul 2021 07:00:18 +0000

Columbia University Irving Medical Center via EurekAlert – NEW YORK, NY (June 28, 2021)–In the first analysis of its kind, researchers at Columbia University Vagelos College of Physicians and Surgeons and several other institutions have linked distinct patterns of genetic mutations with obsessive-compulsive disorder (OCD) in humans. The work, published online June 28 in Nature Neuroscience, confirms the validity of targeting specific genes to develop new OCD treatments and points toward novel avenues for studying this often debilitating condition. OCD, which affects 1% to 2% of the population, often runs in families and genes are known to play a large role in determining who develops the disease. However, the identity of many OCD genes remains unknown. “Many neurological diseases are influenced by strongly acting mutations which can cause disease by themselves,” says David Goldstein, PhD, director of the Institute for Genomic Medicine at Columbia and a senior author on the new paper. “These mutations are individually very rare but important to find because they can provide a starting point for the development of therapeutics that target precise underlying causes of disease.” Although strongly acting mutations have been hypothesized to exist in OCD, statistically reliable evidence has been difficult to obtain. Most previous studies on the genetics of OCD have used a “candidate gene” approach, in which researchers focus on plausible genes that might be involved in pathogenesis and look for genetic signatures of risk. Although that approach has had some successes, it can lead to challenges in statistical interpretation and can miss unexpected genes. As a result, both funding agencies and the pharmaceutical industry increasingly focus on genome-wide analyses that can securely implicate genes in disease risk. “The solution to the problem is to study all the genes in the genome at the same time and ask whether any of them have significant evidence of influencing risk. That had not been done yet at scale in OCD,” says Goldstein. In collaboration with Gerald Nestadt, MBBCh, a psychiatrist at Johns Hopkins University with access to a cohort of OCD patients, Goldstein’s team took this genome wide approach, which uses high-throughput sequencing and computational biology techniques to identify relevant genes anywhere in the genome. The investigators looked at genes that encode protein using whole exome sequencing in more than 1,300 OCD patients and compared them to similarly large control groups. The multi-institution collaboration also included scientists from the University of North Carolina at Chapel Hill, the David Geffen School of Medicine in Los Angeles, Harvard Medical School, and SUNY Downstate Medical Center in Brooklyn. The analysis showed a strong correlation between OCD and rare mutations, particularly in a gene called SLITRK5 that had been previously linked to OCD in candidate-gene studies. Goldstein expects that the new data on SLITRK5 will encourage pharmaceutical companies and translational researchers to develop drugs that target this gene. The study also identified a specific pattern of variation in other genes. “When you look at genes that do not tolerate variation in the human population, those are the genes most likely to cause disease, and with OCD, we see an overall increased burden of damaging mutations in those genes compared to controls,” Goldstein says. “That’s telling us that there are more OCD genes to be found and where to find them.” For patients suffering from OCD and their doctors, new treatments can’t come too soon. OCD causes uncontrollable, recurring thought patterns and behaviors that interfere with patients’ daily lives. “OCD is a disabling disorder that is twice as common as schizophrenia,” says H. Blair Simpson, MD, PhD, professor of psychiatry at Columbia University Vagelos College of Physicians and Surgeons and director of the Center for OCD & Related Disorders at New York State Psychiatric Institute, who was not involved with the new study. Two available treatments, serotonin reuptake inhibiting drugs and cognitive-behavioral therapy, are highly effective, Simpson adds, but only work on about half of patients. “Thus, these genetic findings are very exciting; they indicate that the promise of precision medicine could include OCD, ultimately transforming how we diagnose and treat this disorder.” To read the original article click here.

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Approximately 30% of American’s Can’t Convert This Common B-Vitamin

AHA Publisher — Thu, 03 Dec 2020 08:00:57 +0000

Dr. Don Colbert – Are you one of the 30% of Americans who can’t convert a common B-Vitamin due to a genetic mutation? You may have this gene mutation without even realizing it. It’s called the MTHFR gene mutation. If you’re not familiar, it is crucial to understand how this common mutation affects the metabolism of vitamin B9 in countless Americans. If you are one of the many who has one or two mutations in this gene, you may have accumulated folic acid in your body, leading to low vitamin B9, and you may be suffering from it. MTHFR stands for methylenetetrahydrofolate reduction. When this gene is mutated, unmetabolized vitamin B9 including folate and folic acid can accumulate in the body. The most concerning problem with its accumulation is the potential for high levels of homocysteine. Elevated homocysteine is associated with cardiovascular issues, birth abnormalities, depressed moods, eye conditions, and more. Here’s how to find if you have this mutation, and what you can do to safeguard yourself from unmetabolized folate and folic acid accumulation. The MTHFR Gene Mutation The MTHFR gene is responsible for converting two types of vitamin B9, folate, and folic acid, into their active forms in the body. There are 2 variations of MTHFR gene mutation. The first variation, or a heterozygous variation, is when one piece of this gene is mutated. You can inherit one mutation from either your mom or your dad. The second variation, or a homozygous variation, is having 2 mutations. This means you inherited a mutation from both parents. While having one variation can be only a small problem, having a 2-variation mutation can lead to more serious health issues including the potential for elevated homocysteine. Importance of a Healthy MTHFR Gene The conversion of folate and folic acid into their active states is a vital function in the human body. Inadequate levels of active vitamin B9 are associated with many health issues, including depressed moods, cardiovascular concerns, and birth abnormalities. Both this is a double-sided sword. While inadequate levels are associated with health challenges, the accumulation of inactive vitamin B9 is also damaging. This is why the conversion process is so important if you consume folate or folic acid. Vitamin B9, Folate, and Folic Acid Vitamin B9, folate, and folic acid are often used interchangeably, which can be confusing. Vitamin B9 is typically consumed as folate or folic acid, which are forms of the vitamin. Folate is the naturally-occurring form of B9, and it’s found in many foods including vegetables, fruits, seafood, eggs, dairy, and more (1). Folic Acid, on the other hand, is the synthetic form of Vitamin B9. It is used in supplements, breads, cereals, and other common foods. In fact, the fortification of folic acid in common foods is mandated in the United States (2). As experts became aware of its ability to reduce birth abnormalities, they pushed to include it in foods such as breads, cereals, flour, and more. Sounds great, right? Yes and no. There’s an issue with all this folic acid in our foods and supplements. Both folate and folic acid must be converted into the active form of B9 in order to be used by the body. This conversion can be inefficient and takes many extra steps. In those without the MTHFR mutation, most folate, and some folic acid is readily converted. However, it can still accumulate in the non-active form, especially if it’s consumed daily (3, 4). In those with the gene mutation, much less is converted. And this is a real problem. Accumulated unmetabolized folate and folic acid are associated with health concerns. In some cases, the very issues folic acid supplementation is meant to correct, it promotes. The Vitamin B9 Conversion When folate and folic acid are consumed, the body tries to convert them into 5-methyltetrahydrofolate (5-MTHF) in the digestive system before they enter the bloodstream (5, 6). This conversion requires many steps. They include: Folate or Folic Acid is consumed. They must be converted in the digestive system or liver. Folate or folic acid is changed to dihydrofolate. Dihydrofolate is converted to tetrahydrofolate. Tetrahydrofolate is converted to 5, 10-methylenetetra-hydrofolate 5, 10-methylenetetra-hydrofolate is finally converted to the active form, 5-methyltetrahydrofolate. How can you tell if you’re at risk of unmetabolized vitamin B9? Is your body converting efficiently? Symptoms of MTHFR Mutation While there are no surefire symptoms of this mutation, some conditions have been linked to it. These symptoms are the same as low levels of 5-methyltetrahydrofolate, since folate and folic acid are not efficiently converted. They include: depressed or anxious moods mental health issues cardiovascular and thromboembolic issues whole-body discomfort or pain overactive nerves headaches recurrent pregnancy complications in women of child-bearing age pregnancies with birth abnormalities Testing for MTHFR Mutations If you know you have high levels of homocysteine and/or symptoms of the mutation, such as depressed or anxious moods, you may want to test for it. To do so, you can talk to your doctor and request a test from a lab such as LabCorp. The specific test is called Methylenetetrahydrofolate Reductase (MTHFR) Thermolabile Variant, DNA Analysis. Avoid Folic Acid Accumulation From the Get-Go Whether you have a MTHFR mutation or not, you can choose a better vitamin B9 in your supplements. Take a look at your multivitamin or B-vitamins. Do they include folic acid, or the active form, 5-methyltetrahydrofolate (5-MTHF)? Multivitamins with Optimal Nutrients When looking for a multivitamin, it’s best to find a high-quality one with nutrients that are bioavailable and in the right forms. Specifically, look for those formulated with 5-methyltetrahydrofolate (5-MTHF). Your body will not need to go through the inefficient conversion process, nor will you risk unmetabolized Vitamin B9 accumulation. In fact, 5-MTHF can be found as a prescription. It’s also in some high-quality supplements, including the Divine Health Enhanced Multivitamin. If you have a MTHFR gene mutation, you can rest assured that your body will get the vitamin B9 it needs, in the form it can use. Bottom Line Sometimes, there’s more to a vitamin than meets the eye. Vitamin B9 is a prime example. Since it requires extensive conversion, it’s important to know if you are one of the many with a MTHFR gene mutation, especially if you have symptoms. Always look for high-quality supplements with active forms of nutrients ready to be used in your body. To read the original article click here. For more articles from Dr. Colbert click here.

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Experimental Alzheimer’s Drug May Help Kids with Autism

AHA Publisher — Wed, 26 Aug 2020 07:00:20 +0000

Abigail Klein Leichman via Israel21c – An experimental drug called NAP – originally developed for Alzheimer’s disease at Tel Aviv University – could help children with a type of autism caused by ADNP syndrome, a genetic mutation characterized by mental impairment. NAP (also called CP201) was invented by Prof. Illana Gozes of the Department of Human Molecular Genetics and Biochemistry. Twenty years ago, Gozes’ lab discovered the activity-dependent neuroprotective protein (ADNP) gene and its link to autism. Last December, ISRAEL21c reported on Gozes’ groundbreaking discovery that mutations of ADNP accumulate in the brains of Alzheimer’s patients. “NAP is actually a short active fragment of the normal ADNP protein,” said Gozes. When NAP was added to the nerve cells of mice carrying an ADNP mutation, the protein bound to the nerve cell properly and the cells returned to normal function. “The fact that NAP treatment has been successful in restoring the normal function of neuronal-like cell models with impaired ADNP raises hopes that it may be used as a remedy for ADNP syndrome and its severe implications, including autism,” she said. Because other genetic disorders related to autism are characterized by similar pathologies in the brain, “we hope that those suffering from these syndromes will also be able to benefit from NAP treatment in the future.” NAP has been classified as an “orphan drug” by the US Food and Drug Administration. It is in the preparatory stages of a clinical trial in children with ADNP syndrome through the Israeli company Coronis Neurosciences, of which Gozes is chief scientific officer. Treatment with the experimental drug is hoped to aid cognitive improvement in these children and enhance their memory and learning skills. “We hope and believe that we will ultimately reach the goal of developing a drug or drugs that will help children with autism resulting from genetic mutations,” said Gozes. The results of the international study she led showing the deposits of a particular protein in the brain of Alzheimer’s patients and in tissues taken from the postmortem brain of a 7-year-old autistic child in Croatia were published recently in the journal Translational Psychiatry. To read the original article click here. For more articles from Israel21c click here.

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