The Alzheimer’s Drug Discovery Foundation (ADDF) announces $2.5 million in new funding, which reflects the comprehensive nature of our strategy to prevent and treat Alzheimer’s disease. These 10 new projects encompass clinical trials, innovative drug discovery, prevention research, biomarkers development, and the advancement of the entire field through collaborations and conferences.
Dr. Howard Fillit, Founding Executive Director and Chief Science Officer of the ADDF, noted: “The ADDF understands the enormous effort required to conquer Alzheimer’s disease. We don’t take a 'one-size-fits-all' approach, instead choosing to pursue every avenue necessary to help all patients with Alzheimer’s disease.”
Paul Edison, MD, Imperial College, London
Evaluating the Effects of the Novel GLP-1 Analogue, Liraglutide, in Patients with Alzheimer’s Disease (ELAD Study)
Insulin resistance, a key feature of diabetes, has been identified as a risk factor for Alzheimer’s disease. In addition, insulin receptors have also been shown to be desensitized in Alzheimer’s patients’ brains, providing clues that diabetes drugs could benefit those with Alzheimer’s. Liraglutide is a drug approved for diabetes that can improve insulin signaling, ultimately restoring normal energy utilization in the brain and protecting brain cells from death. This promising clinical trial has been underway for several years and has currently enrolled 103 subjects. This funding will support an “open label” extension of the trial. Patients will be able to continue taking the therapy even after the study has concluded. Their health will continue to be monitored, providing the opportunity to gather additional data on liraglutide’s safety and potential efficacy.
Chris Hulme, PhD, University of Arizona
Optimization of Selective DYRK1A Inhibitors as a Treatment for Alzheimer’s Disease
This program builds upon pivotal data generated by Dr. Chris Hulme and his collaborator, Dr. Travis Dunckley, through support from the ADDF and its partner, the Harrington Discovery Institute. Dr. Dunkley was selected as an ADDF-Harrington Scholar in 2016 to develop drugs that target an overactive enzyme called DYRK1A in Alzheimer’s disease. Inhibiting DYRK1A reduces the accumulation of tau protein, which is a component of tangles and is associated with cognitive decline. With this funding, Dr. Hulme will synthesize and test DYKR1A inhibitors that have optimal drug-like properties to increase the chances for success in human clinical trials. The goal is to support final phases of preclinical testing and, eventually, move into clinical trials.
Michael Parker, D. Phil (Oxon) FAA FAHMS, St. Vincent’s Institute of Medical Research
Activation of Microglial Cells to Promote Clearance of Amyloid-Beta
Dr. Parker and his team recently discovered the structure of a key protein involved in how microglia (i.e., the brain’s immune cells) clear toxic, misfolded proteins such as beta-amyloid from the brain. Importantly, genetic data has linked this immune protein, called CD33, to susceptibility for late-onset Alzheimer’s disease. Dr. Parker used sophisticated computational methods to identify molecules that target CD33. With this funding, he and his team plan to use medicinal chemistry to design and synthesize novel CD33 compounds that stimulate the brain’s immune cells to remove toxic protein aggregates. If successful, Dr. Parker will then develop preclinical drug candidates based on these molecules.
Paolo Pevarello, PhD, Axxam SpA
Exploratory Optimization of New CX3CR1 Modulators for the Treatment of Alzheimer’s Disease
Microglia are the resident immune cells of the brain and are highly involved in neuroinflammation. They can be induced to produce pro- or anti-inflammatory substances, depending on signals they receive from their environment and other cells. There are several signaling molecules on microglia that can influence their activity, one of which is known as the Fractalkine receptor, or CX3CR1. Research has shown that CX3CR1 signaling can beneficially affect the activity of microglia in mice. Axxam has found a set of molecules that can regulate CX3CR1 signaling, which they believe to be the first of their kind. With this round of ADDF funding, Dr. Pevarello and his team will begin developing these molecules into viable drug candidates. These improved compounds will then be used to increase our understanding of the role CX3CR1 plays in Alzheimer’s disease, and may eventually be developed into therapeutics.
Brent Stockwell, PhD, The Trustees of Columbia University
Evaluation and Development of Optimized PDI Modulators for Alzheimer’s Disease
Dr. Stockwell and his team are pursuing a novel strategy to reduce the level of oxidative stress in brain cells, which contributes to the development and progression of Alzheimer’s disease. He is targeting a specific protein known to be a large source of oxidative stress, called PDI. PDI levels increase in the presence of large amounts of misfolded proteins, a hallmark of Alzheimer’s and other neurodegenerative diseases. Dr. Stockwell and his team have engineered the drug LOC14 to target PDI. In preclinical experiments, LOC14 protects brain cells from several neurodegenerative diseases, including Huntington’s. With this funding, the team will create and test improved versions of LOC14 and develop biomarkers that can be used in eventual clinical trials. Dr. Stockwell hopes to develop LOC14 into a first-in-class therapy for Alzheimer’s.
Joe Menetski, PhD, Foundation for the National Institutes of Health
The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a landmark study currently being conducted at 59 clinical sites in the United States and Canada. It is the NIH's largest public-private partnership on brain research. ADNI is designed to facilitate the use and evaluation of biomarkers in clinical trials for Alzheimer’s. ADNI3 began in 2016 and will continue through 2021. It seeks to identify the earliest changes in brain structure and function as people transition from normal cognitive aging to mild cognitive impairment and early Alzheimer’s disease. In addition to continuing to follow approximately 697 subjects from the first and second phases annually, ADNI3 will enroll approximately 371 new subjects, while collecting clinical, cognitive, MRI, amyloid PET, FDG PET, cerebrospinal fluid, and genetic and autopsy data. This funding supports those efforts as well as new measurements of brain tau PET on all subjects over the course of a few years. ADNI3 will also enhance its current clinical tests by adding computerized cognitive testing and a performance-based functional assessment and updating its genetics methodology.
Meredith Upton, MLIS, Foundation for the National Institutes of Health
Inflammatory Markers for Early Detection and Subtyping of Neurodegenerative and Mood Disorders
Few biomarkers exist for diagnosing and subtyping patients with neurodegenerative diseases and psychiatric disorders. Prior research has shown that biological markers of abnormal inflammation levels are found in patients with these disorders. The goal of this two-year Biomarkers Consortium project is to identify and validate inflammatory biomarkers in cerebral spinal fluid (CSF) and/or blood. This will aid in the diagnosis and categorization of patients with neurodegenerative diseases and mood disorders. And the information generated from these efforts will facilitate clinical trials of therapies targeting inflammation.
George Vradenburg, UsAgainstAlzheimer’s
Building a Brain Healthy Ecosystem: Improving Detection and Diagnosis through Healthcare System Change and Consumer Engagement
Recruiting patients for Alzheimer’s clinical trials is slow and can delay the advancement of new medicines for patients. With is funding, UsAgainstAlzheimer’s will build the Brain Healthy Ecosystem. This program will increase rates of early dementia detection and diagnosis and patient participation in Alzheimer’s and brain health clinical trials. They will accomplish these goals by convening Healthcare System Alzheimer’s Readiness Roundtables, building Healthy Brain Working Groups, developing a messaging framework, building a content library for brain health, and distributing the brain health content through UsAgainstAlzheimer’s wide-reaching networks. Benefits of implementing the Brain Healthy Ecosystem include: 1) earlier detection of cognitive impairment, 2) introduction to evidence-based lifestyle interventions or co-morbidity management to slow cognitive decline, and 3) introduction to clinical studies and trials for individuals with or at risk of Alzheimer’s disease.
Kristine Yaffe, MD, University of California, San Francisco
Connection Between Depressive Symptoms and Dementia: When Best to Intervene
Many studies have reported that depression is linked to cognitive decline and dementia. However, it is currently unknown whether the timing of depression (e.g., early adulthood, midlife, or later-life) or the timing of treatment affects dementia risk. And there is evidence that antidepressants may reduce markers of Alzheimer’s disease, but it is not clear whether they lower dementia risk. With this funding, Dr. Yaffe will pool data from 4 cohorts of people ages 18 to 90+ in order to understand the relationships between depression, depressive symptoms, and the effects of antidepressants on cognitive decline and dementia risk. She will examine several classes of antidepressants including selective serotonin reuptake inhibitors (SSRIs). Findings from this study will identify which antidepressant treatment, if any, are useful in lowering dementia risk.
Alison Drone, Foundation for the National Institutes of Health
Alzheimer’s Disease Research Summit 2018 Sponsorship
The ADDF is a proud sponsor of the 2018 Alzheimer’s Disease Summit. It is organized by the National Institutes of Health (NIH) with the goal to continue the development of a multi-disciplinary research agenda to accelerate the discovery and delivery of effective treatments for Alzheimer’s patients. More than 500 leaders from academia, industry, nonprofit organizations, and the federal government attend.