Investigators & Fellows

Allen Distinguished Investigators Alzheimer's Disease Research

Alzheimer's disease is the sixth leading cause of death in the United States, impacting an estimated 5.3 million Americans. Despite widespread research into treatments for Alzheimer's disease, there is a staggering 99.6% failure rate in clinical trials to bring new treatments to market. 

The Foundation awarded Allen Distinguished Investigator (ADI) grants to five teams of researchers with projects that will open new and innovative avenues of research in Alzheimer's disease by uncovering its elusive biological roots. The projects are funded at a total of $7 million over three years.

In addition to the ADI awards, the Foundation partnered with the Alzheimer's Association to award three grants at the frontier of investigating the role of the immune system in Alzheimer's disease. The awards in this understudied but rich area of research are funded at a total of $500,000. 

About the ADI Alzheimer's Awards

The Allen Distinguished Investigator call for Alzheimer's projects was aimed at providing insights into the basic biological foundations of Alzheimer's, with an emphasis on cell biology. The cohort includes multi-disciplinary teams of research scientists from within the Alzheimer's field paired with scientists who bring new perspectives from outside the field. They will investigate novel and budding areas of research, including the role of gene combinations, white matter damage, pH, and the glymphatic system in disease progression, and development of new methods and tools to study basic processes and identify new treatments.

The 2015 ADI Alzheimer's cohort

Investigator: Ragnhildur Thora Karadottir, University of Cambridge

Ragnhildur Thora Karadottir

Project title: Resolving white matter dysfunction in Alzheimer's disease with novel biosensors

Project team: Dr. Steven F. Lee, Professor Elizabeth (Lisa) Hall, Professor Guy Brown, Professor Carol Brayne, Professor Maria Grazia Spillantini, Professor Michael Coleman

Project description: Half of the human brain is white matter—the tissue that surrounds and insulates neurons—but little is known about how white matter damage occurs in Alzheimer's disease and how it influences the spread of the characteristic protein “tangles” and “plaques” we see in brains of Alzheimer's disease patients. This proposal addresses uncharted territory in Alzheimer's disease research, using a combination of new imaging methods, biosensors and cutting-edge models to enable us to identify the role of white matter in Alzheimer's disease progression for the first time. Importantly, as white matter lesions appear prior to symptom onset and can be monitored noninvasively by new MRI scanners, they may be an ideal biomarker and target for early treatment to block Alzheimer's disease.

Investigator biography: Dr. Ragnhildur Thóra Káradóttir is a Wellcome Trust Career Development Research Fellow at the Wellcome Trust – MRC Stem Cell Institute and Department of Veterinary Medicine at the University of Cambridge. Her research has focused on understanding the function and biology of the CNS white matter, with the particular aim of understanding how neuronal activity regulates oligodendrocyte differentiation and myelination in both health and disease. The main interest of this work is to understand white matter pathology in Alzheimer's disease, with a special focus on myelination. Previously, Dr. Káradóttir held a Royal Society Dorothy Hodgkin research fellowship after her PhD at University College London, prior to moving to University of Cambridge. Dr. Káradóttir has recently been awarded the Lister Institute Research Prize and selected to the FENS-Kavli Network of Excellence. 

Team biographies:

Dr. Steven F. Lee is Royal Society University Research Fellow and Assistant Professor in the Department of Chemistry at Cambridge. His research focuses on building new biophysical tools to study biomolecules primarily using single-molecule fluorescence techniques.

Professor Elizabeth (Lisa) Hall is Professor of Analytical Biotechnology in the Department of Chemical Engineering and Biotechnology at Cambridge. Her research is focused on understanding how biology can be interfaced with electronic, mechanical and optical systems. She was awarded the SAC Gold Medal in Analytical Chemistry by the Royal Society of Chemistry and was recently appointed CBE in the Queen’s 2015 Birthday Honours List for services to Higher Education and Sport.

Professor Guy Brown is Professor of Cellular Biochemistry at Cambridge. He has published over 150 scientific papers, and several books including: ‘Mitochondria & Cell Death’, ‘The Energy of Life’ and ‘The Living End’. Current research interests include microglia, cell death, mitochondria, nitric oxide, inflammation, and mechanisms of inflammatory neurodegeneration in the brain.

Professor Carol Brayne is a Professor of Public Health Medicine in the Department of Public Health and Primary Care at Cambridge. A main focus of her research has been longitudinal studies of older people following changes over time with a public health perspective and a focus on the brain. She is Director of the Cambridge Institute of Public Health and a Fellow of the Academy of Medical Sciences.

Professor Maria Grazia Spillantini is Professor of Molecular Neurology in the Department of Clinical Neurosciences at Cambridge. Her research is focused on the molecular neuropathology of diseases characterized by tau and alpha-synuclein aggregates. She has received several international prizes including the Potamkin Prize of the American Academy of Neurology. She was elected Fellow of the Academy of Medical Sciences, London in 2010 and Fellow of the Royal Society, London in 2013.

Professor Michael Coleman is a Professor in the Department of Clinical Neurosciences at Cambridge. His research investigates mechanisms of axon degeneration and the roles of axon pathology in a range of neurodegenerative disorders, including Alzheimer’s disease. He has recently been awarded the title of van Geest Professor of Neuroscience at the John van Geest Centre for Brain Repair.

Award amount: $1.32 million

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Investigator: Jeff Iliff and William Rooney, Oregon Health and Science University

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Jeff Iliff  William Rooney

Project title: Mapping glymphatic pathway function in the human brain: Detecting glio-vascular changes that slow amyloid β clearance from the aging brain

Project description: Aging is the strongest risk factor for Alzheimer's disease, yet the age-related changes that render the brain vulnerable to the development of Alzheimer's disease remain unclear. The members of this research team are the pioneers who recently described the “glymphatic system” in animals, which helps to clear plaques and other substances from the brain and is also impaired in the aging brain. This team will use novel methods combined with an established imaging approach to measure the activity of the glymphatic system for the first time in human patients. If successful, this method may be able to provide insight into which patients are vulnerable to the build-up of plaques long before clinical symptoms arise. This could provide a window of treatment opportunities when lifestyle interventions and drug treatments have the greatest opportunity of preventing or delaying Alzheimer's disease.

Investigator biographies:

Dr. Jeff Iliff is an Assistant Professor in the Department of Anesthesiology and Perioperative Medicine and the Knight Cardiovascular Institute at Oregon Health & Science University. While training at the University of Rochester, he was part of the research team that identified a brain cleaning system, termed the ‘glymphatic system' that clears away wastes such as amyloid beta from the brain during sleep. Iliff's recent studies have shown that the glymphatic system may fail in the aging brain and in the young brain after traumatic brain injury. Research in his lab now focuses on identifying the molecular changes that underlie glymphatic system failure with aging and after trauma, extending these studies into human subjects and clinical populations, and discovering ways to co-opt the glymphatic system to improve drug delivery throughout the brain and spinal cord. 

Dr. William Rooney is Senior Scientist and Director of the Advanced Imaging Research Center, and Associate Professor in Behavioral Neuroscience, Biomedical Engineering, and Neurology at Oregon Health & Science University. Dr. Rooney is an imaging scientist and his research focus is on the development of non-invasive biomarkers of normal physiology and pathophysiology with a strong emphasis on vascular and metabolic phenotyping. A primary interest of this work is to understand the fundamental physiology of the glymphatic system in the human brain and generate maps of its function.

Award amount: $1.42 million

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Investigator: Fred “Rusty” Gage, Salk Institute

Fred “Rusty” Gage

Project title: Human age-equivalent directly induced neurons to study functional phenotypes of Alzheimer's disease

Project description: The goal of this research effort is to separate out the role of aging from the role of disease in Alzheimer's disease progression. Dr. Gage will use cutting-edge cell culture methods capable of developing patient-specific neurons, as well as high-throughput RNA sequencing and bioinformatics analysis, to compare changes in gene expression due to age with changes specific to Alzheimer's disease. Since both aging and disease impact neuron function, synapses and network function, this work will provide valuable insights into the role of normal aging in disease progression.

Investigator biography: Fred H. Gage, Ph.D., is a Professor in the Laboratory of Genetics at the Salk Institute. Dr. Gage's work concentrates on the adult central nervous system and unexpected plasticity that remains throughout the life of all mammals. In addition, he models human neurological and psychiatric disease using human stem cells. He also studies the genomic mosaicism that exists in the brain as a result of mobile elements that are active in the genome. Dr. Gage a Fellow of the American Association for the Advancement of Science, a Member of the National Academy of Sciences and the Institute of Medicine, and American Philosophical Society, and a Member of the American Academy of Arts and Sciences. Dr. Gage has served as President of the Society for Neuroscience in 2002, and past President for the International Society for Stem Cell Research 2012.

Award amount: $1.51 million

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Investigator: Aimee Kao, University of California, San Francisco
Aimee Kao

Project title: Dysregulation of pH dynamics in Alzheimer's Disease Pathogenesis

Project team: Dr. Diane Barber, Dr. Matt Jacobson, Dr. Torsten Wittmann 

Project description: Alzheimer's disease results in the accumulation of characteristic plaques and tangles: collections of proteins in the brain that cannot be dissolved. It is unknown why neurons fail to clean up these so-called “garbage” proteins, and why this risk of failure increases with age. This research will focus on a “pH hypothesis,” which suggests that impaired regulation of cellular pH promotes neuronal dysfunction and death in Alzheimer's disease by preventing protein clearance and promoting protein aggregation. This understudied area is key to fully understanding the biology of Alzheimer's disease, and may lead to critical and complementary therapeutic strategies aimed at preventing or curing the disease.

Investigator biography: Dr. Aimee Kao is an Assistant Professor in the Department of Neurology at the University of California, San Francisco. Her post-doctoral training includes fellowships with Dr. Bruce Miller on the genotype-phenotype connection in neurodegeneration and Dr. Cynthia Kenyon on the molecular genetics of diseases of aging. Her laboratory focuses on the basic mechanisms of neurodegenerative disorders such as Alzheimer's Disease and frontotemporal lobar degeneration. Her recent work has shed light on how stress, inflammation and cell death mechanisms contribute to impaired proteostasis and neuron loss.

Team biographies:

Dr. Diane Barber is a Professor and Chair in the Department of Cell and Tissue Biology at UCSF. Her research has pioneered new insights on how changes in intracellular pH (pHi) regulate cell processes and behaviors. She recently began investigating how the decreased pHi seen in many neurodegenerative disorders contributes to the pathologies of Alzheimer's disease. Dr. Barber is a recently-elected AAAS Fellow.

Dr. Matt Jacobson is a Professor in the Department of Pharmaceutical Chemistry at UCSF. Dr. Jacobson's research interests are in the area of computational biophysics and computer-aided drug design. He serves on the Scientific Advisory Board of Schrödinger, LLC, and is a founder of Global Blood Therapeutics and Circle Pharma. He has received the NSF CAREER award and an Alfred P. Sloan Fellowship.

Dr. Torsten Wittmann is an Associate Professor in the Department of Cell and Tissue Biology UCSF. His lab is particularly interested in a class of proteins that associate with growing microtubule plus ends. Dr. Wittmann's lab has become interested in ‘opto-cell biology’ approaches to control cell dynamics at high spatial and temporal accuracy to dissect microtubule functions. 

Award amount: $1.32 million

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Investigator: Michael Keiser, Martin Kampmann and David Kokel, University of California, San Francisco

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Michael Keiser Martin Kampmann David Kokel

Project title: Systematic elucidation of cellular networks controlling proteinopathy in Alzheimer's disease

Project description: The goal of this research project is to combine three powerful and innovative technologies to the study of gene combinations and drugs that control the formation of plaques and tangles in Alzheimer's disease, with the long-term goal of understanding the network of genes controlling all aspects of Alzheimer's disease. The project will take a big data approach to the problem, and use techniques including: 1) computational analysis of an unprecedented “big data” set of 500,000 triple-screened drug compounds, 2) the massively parallel functional interrogation of all human genes and hundreds of thousands of gene combinations, and 3) high throughput behavioral analysis of gene and drug effects in a novel zebrafish model of Alzheimer's disease.

Investigator biographies:

Dr. Michael Keiser is an Assistant Professor in the Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Diseases at the University of California San Francisco, with a joint appointment in the Department of Bioengineering & Therapeutic Sciences. He led development of a new systems pharmacology platform to predict unexpected drug activities and side effects, the Similarity Ensemble Approach. His lab investigates how small molecules strike “chords” of multiple targets at once to perturb cellular and disease networks. A major focus of this work is on the discovery of chords for neurodegenerative diseases, where therapeutics acting through polypharmacology may enable entirely novel treatment routes. Previously, Dr. Keiser co-founded a start-up company, after training at UCSF and Stanford University. Dr. Keiser has recently been selected for a Glenn Award for Research in the Biological Mechanisms of Aging.

Dr. Martin Kampmann is an Assistant Professor in the Department of Biochemistry & Biophysics and the Institute for Neurodegenerative Diseases at the University of California, San Francisco. He spearheaded the development of a functional genomics platform that makes it possible to robustly identify human genes relevant to a cellular process of interest, and to elucidate cellular pathways and networks using systematic genetic interaction maps. The focus of Dr. Kampmann's research is the network maintaining the functional state of cellular proteins, termed the proteostasis network. Dr. Kampmann aims to elucidate how the proteostasis network is challenged and rewired in diseases, especially cancer and neurodegenerative diseases. Identification of proteostasis factors that control formation, spread, and clearance of protein aggregates associated with neurodegenerative diseases will shed light on the disease mechanisms and reveal potential therapeutic targets. Dr. Kampmann has recently been awarded a Pathway to Independence Award by the National Institutes of Health.

Dr. David Kokel is an Assistant Professor in the Department of Physiology and the Institute of Neurodegenerative Diseases at the University of California San Francisco. He developed a platform for combining high throughput behavioral phenotyping with large-scale chemical screening in zebrafish. A major goal of Dr. Kokel's research is to discover novel neuroactive compounds and understand their effects on the brain and behavior. Before joining UCSF, Dr. Kokel was an assistant Professor at Harvard Medical School.

Award amount: $1.42 million


Investigator: Sally Ann Frautschy, University of California, Los Angeles

Project title: Tau accumulation and removal: Role of glia and mediators of inflammation

Project description: Inflammation in the brain has a significant impact on the development of the characteristic tangles of tau protein in brains of Alzheimer's disease patients. This project will use a mouse model to examine the role of inflammation in the proliferation of tau proteins in the brain. This research will, for the first time, uncover the role of the immune inflammatory response on tau development and determine whether processes involved in normal synapse elimination are also implicated in the spread of tau across synapses.

Investigator biography: Dr. Sally Frautschy is a Professor in the Department of Neurology at the University of California, Los Angeles. A primary focus of her work is to understand neuroinflammatory mechanisms contributing to Alzheimer's dementia and develop models that recapitulate key features of the disease. She has used these models to identify safe pleiotropic compounds that correct multiple aspects of the disease and have been translated to the clinic. Previously, Dr. Frautschy original focus was on neuroendocrinology of chronic stress and brain trauma, both risk factors for Alzheimer's, and in 1988 she began studying Alzheimer's. In addition to pioneering some of the initial non-transgenic models of Alzheimer's, she was the first to demonstrate phagocytic clearance and removal of plaques, now known to play a role in efficacy of the amyloid vaccine, and her recent focus has been on downstream mechanisms contributing to memory loss, related to tau. Dr. Frautschy has recently been awarded a grant entitled “Exploring the differential roles of astrocyte and microglia in the phagocytosis of extrasynaptic tau and neurodegeneration” to understand neuroinflammatory mechanisms in health and disease in controlling tau spreading, which has relevance to disease progression in Alzheimer's, brain trauma and other tauopathies.

Award amount: $300,000

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Investigator: Claudia Balducci, Pharmacological research Institute Mario Negri

Project title: Can mesenchymal stem cell secretome repair Alzheimer's disease brains?

Project description: A subset of stem cells called mesenchymal stem cells have anti-inflammatory effects on disease in cell culture, but this has yet to be demonstrated in Alzheimer's disease outside of a dish. This research will use a transgenic mouse model to investigate whether material from mesenchymal stem cells could be used as a therapy for Alzheimer's when administered intravenously. Research will focus on the ability of this kind of treatment administration to affect the brain, with specific attention on the role of microglia—the resident immune cell of the brain. This research may lead to the development of potential therapies for Alzheimer's disease.

Investigator biography: Dr. Claudia Balducci is a tenured senior scientist in the Department of Neuroscience at the IRCCS Mario Negri Institute for Pharmacological Research in Milan (Italy) where she arrived in 1998. She has been a project leader at that institute since she obtained her PhD in November 2009. She is an independent scientist with her own research space and group with PhD students, technicians and post-doctoral fellows, with high-level responsibilities. Her research is devoted to Alzheimer's disease (AD) with a primary focus on devising new therapeutic approaches able to counteract the neuropathological process at multiple levels, and identifying those pathological mechanisms leading to synaptic and cognitive dysfunction in association to neuroinflammatory process. She has long-term experience in animal cognitive behavior and animal models of AD at neuropathological and therapeutic levels, and she has exploited this expertise to identify early neuropathological changes preceding plaque deposition and promote new therapeutic approaches. She recently developed a new acute AD mouse model used to specifically decipher the mechanism of action of beta amyloid oligomers, nowadays recognized as the main pathogenic factors of AD. Previously (1995-1997), Dr. Balducci worked in the USA, where she was involved in drug addiction studies at the Scripps Research Institute in San Diego (CA) and subsequently as a consultant for the setting up of drug self-administration in rats at the Psychiatric institute in Chicago (IL).

Award amount: $100,000

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Investigator: Jonas J. Neher, Hertie Institute for Clinical Brain Research

Project title: Effect of transient peripheral immune stimulation in AD pathology

Project description: It remains unknown whether inflammatory events during normal adulthood can have an effect on the brain's immune response. Additionally, recent data show that infections outside the brain can contribute to the onset of Alzheimer's disease, indicating that inflammatory events throughout life could affect Alzheimer's disease pathology. This research will focus on the suppression of pro-inflammatory responses as well as the induction of anti-inflammatory responses that may be beneficial in blocking Alzheimer's disease.

Investigator biography: Dr. Jonas Neher is a Junior Group Leader (Asst Professor) at the Hertie Institute for Clinical Brain Research, University of Tuebingen (Germany). His research is focused on the role of the brain's resident immune cells, the microglia, in neuropathology and particularly Alzheimer's disease. He is especially interested in innate immune memory in these cells, i.e. whether they show long-term changes following stimulation, as this may represent a novel non-genetic risk factor for neurological conditions. Previously, Dr. Neher received a Gates Cambridge Scholarship to carry out his Ph.D. work at the University of Cambridge (2005–2009), UK, where he also stayed for his first postdoctoral position. He then received a Roman Herzog Research Fellowship from the Charitable Hertie Foundation to perform research in the Department of Cellular Neurology at the Hertie Institute for Clinical Brain Research in Tuebingen, Germany (2011–2013).

Award amount: $100,000