PSEN1

PHOENIX, Nov. 14, 2024. A new Alzheimer's prevention study has received a $74.5 million five-year grant from the National Institute on Aging, part of the National Institutes of Health (NIH). The two-part study will be conducted in members of the world's largest autosomal dominant Alzheimer's disease (ADAD) kindred in Colombia who carry a genetic mutation that makes them all but destined to develop Alzheimer's and become cognitively impaired at an average age of 44. The study is led by Banner Alzheimer's Institute in Phoenix and the Neurosciences Group at the University of Antioquia (GNA) in Medellin, Colombia. It will initially aim to remove amyloid plaques as completely as possible in cognitively impaired and unimpaired carriers of the presenilin 1 (PSEN1) E280A mutation, and then evaluate different ways to stave off the recurrence of plaque deposits and other ensuing elements of the disease. Enrollment is expected to begin in the fall of 2025. The first part of the study will use Eli Lilly and Company's (Lilly) antibody therapy donanemab to remove existing plaques as completely as possible (i.e., to levels consistent with a negative amyloid PET scan). Donanemab has been shown to clear amyloid plaques and slow cognitive decline, and was recently approved by the U.S. Food and Drug Administration for use in patients with mild cognitive impairment and dementia due to Alzheimer's. The study will provide new information about the drug's safety, tolerability, and biological efficacy in the unimpaired and impaired stages of ADAD. The second part of the study will compare the following approaches in the same participants, for safety, tolerability and ability to avert amyloid plaque accumulation and other biological and clinical features of the disease: This study builds on the history, partnership, infrastructure and learnings of the original API ADAD Colombia Trial, which launched a new era in Alzheimer's prevention research when it was announced by NIH in 2012. While the investigational drug in the original trial with crenezumab failed to clear plaques or demonstrate a clinical benefit, the study introduced paradigms to speed up the evaluation of promising prevention therapies, found ways to do so in a vulnerable population in a developing country, and led to a growing number of prevention trials, some of which may find the first effective Alzheimer's prevention therapies within the next few years. Both the original and the new trial tap into GNA's identification of about 6,000 distant relatives from the Colombian PSEN1 E280A kindred, including about 1,200 who carry the ADAD-causing genetic mutation. "We are excited about the chance to advance the fight against Alzheimer's disease in partnership with our outstanding colleagues and these unique families in Colombia," said Robert Alexander, MD, the API's chief scientific officer and one of the prevention trial leaders. "This study will clarify the extent to which the antibody treatment reduces amyloid plaques in the unimpaired and impaired stages of ADAD and test different approaches to maintain low amyloid levels following plaque removal." The new study will enroll 200 cognitively unimpaired and mildly impaired mutation carriers and 40 non-carriers (who will receive placebo) from the Colombian kindred. "This trial is a testament to our dear friend and longstanding partner, Dr. Francisco Lopera, who established GNA, forged a close working relationship with API, and could not have been more committed to these families," said Eric M. Reiman, MD, executive director of Banner Alzheimer's Institute and one of the other API leaders. "He constantly said, 'My families are waiting,' and he played indispensable roles in the effort to find effective prevention therapies." "I am honored to follow in Dr. Lopera's footsteps and continue our work with API," said David Aguillón, MD, GNA's new director and principal investigator of the University of Antioquia study site. "Dr. Lopera and the Antioquia families have inspired all of us to never give up, to maintain our sense of urgency to find effective Alzheimer's prevention therapies, and to do so in ways that will help our Antioquia families." The research study is supported by grant R01AG086363 from the NIH National Institute on Aging, the lead U.S. federal agency supporting and conducting Alzheimer's disease and related dementias research. Lilly and Roche are generously donating the drug supplies that will be evaluated in this study. The study is led by Drs. Robert Alexander, Eric Reiman and Jessica Langbaum from BAI and its API; David Aguillón from the University of Antioquia; and Yakeel Quiroz from the University of Antioquia and Massachusetts General Hospital. API also received a $3 million grant from the Zurich-based NOMIS Foundation to continue to assess about 2,000 mutation carriers and non-carriers from the PSEN1 E280A kindred, provide a shared resource of longitudinal data and blood samples for the field, accelerate enrollment in the new prevention trial, and provide education and social support for the families irrespective of their participation in the study. About Banner Alzheimer's Institute Since its inception in 2006, Banner Alzheimer's Institute has sought to find effective Alzheimer's disease prevention therapies within twenty years, establish a new model of care for cognitively impaired patients and family caregivers, and forge new models of collaboration in biomedical research. It has made groundbreaking contributions to the unusually early detection, tracking, diagnosis, study and prevention of Alzheimer's disease. It includes the pioneering Alzheimer's Prevention Initiative, an extensive profile of research studies and clinical trials, comprehensive clinical, family and community service programs, leading brain imaging and blood-based biomarker research programs, and strategic partnerships with public and private research organizations around the world. About the Alzheimer's Prevention Initiative The Alzheimer's Prevention Initiative (API) is an international collaborative formed in 2009 to launch a new era of Alzheimer's prevention research. Led by Banner Alzheimer's Institute, the API conducts prevention trials in cognitively healthy people at increased risk for Alzheimer's disease. API continues to establish brain imaging, fluid biomarker and cognitive endpoints needed to rapidly test promising prevention therapies. It also leads participant recruitment registries to accelerate enrollment into Alzheimer's-focused studies. API is intended to provide the scientific means, accelerated approval pathway and enrollment resources needed to evaluate the range of promising Alzheimer's prevention therapies and find ones that work without losing another generation. For more information, go to alzheimerspreventioninitiative.com. About Grupo de Neurociencias de Antioquia Grupo de Neurociencias de Antioquia (GNA), at the University of Antioquia in Medellín, is ranked as one of the best research organizations in Colombia. For more than three decades, GNA has characterized what is now considered the world's largest population with early-onset familial Alzheimer's disease, and it continues to play pioneering roles in the effort to find effective Alzheimer's prevention therapies. GNA has also characterized large and paradigmatic populations with other forms of dementia and other neurogenetic disorders. SOURCE Banner Alzheimer's Institute Whatever your topic of interest, subscribe to our newsletters to get the best of Drugs.com in your inbox.

A class of proteins that regulates cell repair and enhances cell growth-signaling systems could be a promising new target for the treatment of Alzheimer's and other neurodegenerative diseases, according to a new study. They found that disrupting necessary sugar modifications of these proteins promotes cell repair and reverses cellular abnormalities that occur in neurodegenerative diseases. A class of proteins that regulates cell repair and enhances cell growth-signaling systems could be a promising new target for the treatment of Alzheimer's and other neurodegenerative diseases, according to a new study led by researchers at Penn State. They found that disrupting necessary sugar modifications of these proteins promotes cell repair and reverses cellular abnormalities that occur in neurodegenerative diseases. The study appeared today (July 2) in the journal iScience, and the researchers have a patent related to this work. "Strategies to treat Alzheimer's disease to date have largely focused on pathological changes prominent in the late stages of the disease," said Scott Selleck, professor of biochemistry and molecular biology in the Penn State Eberly College of Science and leader of the research team. "Although recently [U.S. Food and Drug Administration]-approved drugs have shown the ability to modestly slow the disease by targeting one of these changes, amyloid accumulation, drugs that affect the earliest cellular deficits might provide important tools to stop or reverse the disease process. We are interested in understanding the earliest cellular changes that are found not only in Alzheimer's, but shared across other neurodegenerative diseases, including Parkinson's and amyotrophic lateral sclerosis (ALS)." Roughly 6.9 million Americans over the age of 65 are estimated to be living with Alzheimer's disease, according to the Alzheimer's Association. Despite its widespread impact, there is no agreed upon biological cause or mechanism for the disease. Cell-signaling molecules called heparan sulfate-modified proteins have been implicated in the development of Alzheimer's, but their specific role has remained unclear, Selleck said. In this study, the research team first performed a series of analyses in human cell lines and mouse brain cells that express aspects of Alzheimer's, showing that these proteins regulate cellular processes known to be affected in several neurodegenerative diseases. Heparan sulfate-modified proteins are found both on the surface of animal cells and in the matrix between cells. This class of proteins are named for a sugar polymer that bears many sulfate groups, called heparan sulfate. Heparan sulfate chains are attached to specific proteins, and this modification allows these proteins to assemble signaling complexes that affect cell growth and influence how the cell interacts with its environment. These signaling pathways also regulate autophagy, a process of cell repair that clears out damaged or dysfunctional components in the cell. "In the early stages of several neurodegenerative diseases, autophagy is compromised, which means cells have a reduced repair capacity," Selleck said. "In this study, we determined that heparan sulfate-modified proteins suppress autophagy-dependent cell repair. What's more, we show that by compromising the structure and function of the sugar modifications of these proteins, the levels of autophagy increase so cells can take care of damage." The researchers found that, in human and mouse cells, reducing the function of heparan sulfate-modified proteins also rescued other pathologies that arise early in neurodegenerative diseases, improving the function of mitochondria -- which are responsible for energy production in the cell -- and reducing build-up of lipids, or fatty compounds, inside cells. The researchers then evaluated the role of heparan sulfate-modified proteins in an animal model of Alzheimer's, a fruit fly with deficits in a presenilin protein. Presenilin mutations cause early onset disease in humans and likewise in fruit flies; defective presenilin causes cell death and brain degeneration. In flies with deficits in presenilin, reducing the function of heparan sulfate chains suppressed the death of neurons and corrected other cell defects as well. These results are directly relevant to recent human genetics research, the researchers said. "Individuals with mutations in a presenilin gene, PSEN1, develop Alzheimer's in their mid-40s. But if they also inherit a rare genetic change in a specific protein called APOE, the disease is delayed, sometimes by decades," Selleck said, explaining that APOE plays an important role in lipid transport and binds to heparan sulfate. "This change in APOE -- which has been in the news lately -- greatly reduces APOE binding to heparan sulfate. Our work builds on and extends these findings, directly implicating heparan sulfate in Alzheimer's pathology involving both PSEN1 and APOE. Targeting the enzymes that make heparan sulfate could provide a means of blocking neurodegeneration in humans." Collectively, these results show that disrupting the structure of heparan sulfate modifications, blocks or reverses early cellular problems in these models of Alzheimer's. "We save the animal from neuron cell loss, mitochondrial defects and rescue behavior deficits that serve as a measure of nervous system function," Selleck said. "These findings suggest a promising target for future treatments that could rescue the earliest abnormalities that occur in many neurodegenerative diseases." The researchers also explored how gene expression changed when they eliminated the capacity of human cells to make heparan sulfate chains. They found that expression levels of more than 50% of approximately 70 genes known to be associated with late-onset Alzheimer's disease were modulated, including APOE, suggesting a link between heparan sulfate-modified proteins and the more common and late onset forms of Alzheimer's disease. "There is a critical need to focus on cellular changes that occur at the earliest times in disease progression and develop treatments that block or reverse them," Selleck said. "We demonstrate that reduced autophagy, mitochondrial defects and lipid build-up -- all common changes in neurodegenerative disease -- can be blocked by altering one class of proteins, those with heparan sulfate modifications. We think these molecules are promising targets for drug development." The researchers suspect that disrupting this pathway to promote cell repair systems could be important for a wide variety of other diseases where autophagy defects occur. "The applications of manipulating this pathway may be broadly useful across a number of human medical conditions," Selleck said. The research team at Penn State also includes co-authors Nicholas Schultheis, doctoral student in the Biochemistry, Microbiology and Molecular Biology program; Alyssa Connell, research assistant; and Richard Mueller, Alexander Kapral, Robert Becker, Shalini Shah, Mackenzie O'Donnell, Matthew Roseman, Lindsey Swanson and Sophia DeGuara, all undergraduate students. Contributions were also made by researcher Weihua Wang and Associate Professor of Pharmacology Fei Yin at the University of Arizona and graduate student Tripti Saini and Assistant Professor of Biochemistry and Molecular Biology Ryan Weiss at the University of Georgia. Funding from the National Institutes of Health and the Penn State Eberly College of Science supported this research.

New research finds one copy of a protective genetic variant, APOE3 Christchurch, delayed onset of Alzheimer's disease for 27 members of a ~6,000-person family in Colombia at high risk for early-onset Alzheimer's in their 40s due to carrying the 'Paisa' (Presenilin-1 E280A) mutation. This work builds on a 2019 case report of a woman in this family who had two copies of the Christchurch variant and delayed Alzheimer's into her 70s. The new findings are the first to show that one copy of the variant confers some level of protection and increases the researchers' confidence that this genetic pathway should be targeted for therapeutics. A scientific story that began with a discovery in just one extraordinary patient is now panning out. In 2019, an international team that included researchers from two Mass General Brigham hospitals -- Mass Eye and Ear and Massachusetts General Hospital (MGH) -- reported on the case of a patient who did not develop cognitive impairment until her late 70s, despite being part of a family at extremely high genetic risk for developing early-onset Alzheimer's disease. In addition to having the genetic variant that causes an autosomal dominant form of Alzheimer's disease, the woman had two copies of a rare variant of the APOE3 gene, called Christchurch (APOE3Ch). Now, the research team reports on an additional 27 members of the family who carry just one copy of the variant and experienced delayed disease onset. The study, published in The New England Journal of Medicine, represents the first evidence that having one copy of the Christchurch variant may confer some level of protection against autosomal dominant Alzheimer's disease, even if less pronounced compared to when two copies are present. The findings have important implications for drug development, suggesting the potential effects of targeting this genetic pathway. "As a clinician, I am highly encouraged by our findings, as they suggest the potential for delaying cognitive decline and dementia in older individuals. Now we must leverage this new knowledge to develop effective treatments for dementia prevention," said co-first author Yakeel T. Quiroz, PhD, clinical neuropsychologist and neuroimaging researcher and director of the Familial Dementia Neuroimaging Lab in the Departments of Psychiatry and Neurology at Massachusetts General Hospital." As a neuroscientist, I'm thrilled by our findings because they underscore the complex relationship between APOE and a deterministic mutation for Alzheimer's disease, potentially paving the way for innovative treatment approaches for Alzheimer's disease, including targeting APOE-related pathways." Quiroz and her team at MGH and co-senior study author Joseph Arboleda-Velasquez, MD, PhD, of Mass Eye and Ear, have been working with their colleagues in Colombia as part of the MGH Colombia-Boston (COLBOS) biomarker study to examine family members of the world's largest-known kindred with a genetic variant called the "Paisa" mutation (Presenilin-1 E280A). The Paisa mutation is an autosomal dominant variant, meaning that inheriting just one copy of the mutated gene from a parent is enough to cause a genetic condition. The family consists of about 6,000 blood relatives, and about 1,200 carry the variant. Carriers of this Paisa variant are destined to develop Alzheimer's disease; most develop mild cognitive impairment in their 40s, dementia in their 50s, and die from complications of dementia in their 60s. Francisco Lopera, MD, director of the Grupo de Neurociencias de Antioquia in Medellín, Colombia, and co-senior author of the NEJM paper, is the neurologist who discovered this family and has been following them for the last 40 years. In addition to the 2019 case report about a family member with two copies of the Christchurch variant, molecular studies have added further biological evidence that the variant could be playing a protective role. In 2023, the research team identified another "resiliency gene variant" called Reelin-COLBOS that appeared to delay the onset of symptoms in other family members. The new study in NEJM reports on a larger group of individuals from this family who carry a copy of the Christchurch variant. "Our original study told us that protection was possible, and that was an important insight. But if a person needs two copies of a rare genetic variant, it just comes down to luck," said co-senior author Joseph F. Arboleda-Velasquez, MD, PhD, an associate scientist at Mass Eye and Ear. "Our new study is significant because it increases our confidence that this target is not only protective, but druggable. We think that therapeutics inspired by protected humans are much more likely to work and to be safer." The research team assessed 1,077 descendants of the Colombian family. They identified 27 family members who carried both Paisa mutation and one copy of the Christchurch variant. On average, these family members began showing signs of cognitive impairment at age 52, compared to a matched group of family members who did not have the variant, who began showing signs at age 47. The family members also showed signs of dementia four years later than those who did not carry the variant. Two of these individuals had functional brain imaging performed. Scans showed lower levels of tau and preserved metabolic activity in areas typically involved in Alzheimer's disease, even in the presence of amyloid plaques -- proteins considered a hallmark of Alzheimer's disease. The team also analyzed autopsy samples from four deceased individuals that showed less pathology in blood vessels, a characteristic that appears important for the protective effects of APOE3 Christchurch. The authors note that their study was limited to a relatively small number of people carrying both the Paisa and Christchurch variants, and to a single, extended family. They write that further studies involving larger and more ethnically diverse samples of Alzheimer's disease may shed further light on the protective effect of the Christchurch variant and help determine if findings from the family in Colombia could translate into discoveries relevant for treating sporadic forms of Alzheimer's disease. "As a next step, we are currently focused on improving our understanding of the brain resilience among the remaining family members who carry one copy of the Christchurch variant. This involves conducting structural and functional MRI scans and cognitive evaluations, as well as analyzing blood samples to assess their protein and biomarker pro " said Quiroz. "The unwavering commitment to research shown by our Colombian patients with autosomal dominant Alzheimer's and their families has been indispensable in making this study possible and allowing us to continue to work toward interventions for this devastating disease."