Precision Medicine for Alzheimer Disease and Related Disorders

Evans Center Affinity Research Collaborative (ARC)

Precision medicine aims to collect, connect, and apply vast amounts of scientific research data and information about our health to understand why individuals respond differently to treatments and therapies, and help guide more precise and predictive medicine worldwide. The ultimate goal of the Precision Medicine for Alzheimer Disease and Related Disorders ARC at Boston University is to initiate a precision medicine program in Alzheimer disease (AD), a clinical area for which there is great need and broad expertise and resources at BU. We hypothesize that the reason current drugs used to treat AD are ineffective and clinical trial studies have largely failed is the assumption that AD is a single disease, when in fact, it has been well documented by clinical, imaging, neuropathological and genetic studies that AD is a heterogeneous disease.

Initially, this ARC seeks to identify subtypes of AD within the Framingham Heart Study (FHS) dataset, validate these subtypes using other available data from the national AD Centers database and other public databases, investigate the biological underpinnings of these subtypes, and identify new therapeutic targets specific for these subtypes. As a first step, we are employing multiple computational strategies including “Big Data” analytics in collaboration with Thomson Reuters for identifying AD subtypes or risk factor profiles that are defined by profiles based on deep phenotyping (e.g., cognitive testing, medical history, brain imaging, biomarker, lifestyle) and ‘Omic (e.g., genetic, genomic, methylomic, proteomic, and metabolomic) data.

Subsequently, ARC investigators will attempt to validate these subtypes in other datasets, derive stratification model(s) for assigning prospectively studied persons along the disease spectrum to disease subtypes for testing drug response and predicting prognosis, and evaluate experimentally the biological underpinnings of one or more subtypes and identify new therapeutic targets.

Research Faculty

Rhoda Au
Professor of Anatomy & Neurobiology, Neurology and Epidemiology at Boston University Schools of Medicine and Public Health

Dr. Au currently serves as Director of Neuropsychology at the Framingham Heart Study, where she has been involved in research related to cognitive aging and preclinical/clinical dementia since 1990. The limits of standard neuropsychological testing led her to apply the Boston Process Approach to increase the sensitivity of these tests. The BPA includes tracking error and extraneous responses and FHS is the first to apply this method to epidemiologic research. Most recently, she has integrated digital technology into the cognitive assessment process while preserving the traditional paper-pencil test experience. Using digital voice and digital pen to capture cognitive performance underlies her current work of determining the potential of digital cognitive biomarkers as surrogate indices to more expensive and invasive fluid and imaging biomarkers. She is also interested in how “big data” analytics can better inform our understanding of disease pathways and treatment. In addition to her work at Framingham, Dr. Au is also currently involved in the School of Public Health led Aging Well Institute that focuses on building multi-sector ecosystems to enable solutions for chronic disease prevention generally and optimizing brain health specifically and to move the primary focus of health technologies from precision medicine to a broader emphasis on precision health.

Alice Cronin-Golomb, Ph.D., Psychological and Brain Sciences
Boston University

I am a professor in the Department of Psychological and Brain Sciences and in the Center for Neuroscience, Boston University. I direct the Center for Clinical Biopsychology and the Vision and Cognition Lab. My departmental affiliations are in the Clinical Program and in the Program in Brain, Behavior and Cognition, reflecting my background and interests in basic research and clinical applications. My main methodology is behavioral and includes psychophysics and neuropsychological assessment of perception and cognition, with collaborators in neuroimaging. We also assess mood, sleep, autonomic function, and gait, and examine interactions between these aspects of function and cognition.

My history of published research on cognition and perception in Alzheimer’s disease (AD) and Parkinson’s disease (PD) extends back over 25 years. Our ARC project builds upon my recent focus on the heterogeneity of clinical and cognitive profiles in PD, with emphasis on subgroup differences. This focus is directly relevant to AD research as we consider heterogeneity in symptoms and underlying pathology. Of further relevance, I am currently collaborating with Dr. Au on a study of cognitive and other biomarkers (affective, inflammatory) in PD, using the data from the Framingham Heart Study (FHS), and I have also directed the neuropsychology research of several graduate and undergraduate students using the FHS database under Dr. Au’s supervision.  Hence, the FHS project and database are well known to me. My experience in the analysis of subgroup data with respect specifically to cognition in neurodegenerative disorders complements the experience of Dr. Au with FHS epidemiological data and Dr. Farrer with -omics data.

Lindsay A. Farrer, Ph.D., Chief – Biomedical Genetics
BU Distinguished Professor of Genetics, Boston University School of Medicine

In collaboration with other laboratories worldwide, Dr. Farrer has localized genes causing a variety of rare and common disorders including Alzheimer disease (AD), Wilson disease, Machado-Joseph disease, Waardenburg syndrome, hypertension, sensorineural deafness, and osteoarthritis. Working together with other BU researchers, Dr. Farrer’s lab is leading efforts to identify genes influencing severity and expression of sickle cell anemia and β-thalassemia. His group identified a functional genetic variant in the complement factor H gene which accounts for more than 30% of the attributable risk for age-related macular degeneration (AMD), the leading cause of progressive vision loss and blindness in the elderly.  Dr. Farrer’s major research focus is Alzheimer disease (AD).  Under Dr. Farrer’s leadership, the MIRAGE Study, a multi center study of AD funded since 1991 by the National Institute on Aging, has made several important contributions to our understanding of the interactions between genetic and environmental factors for the disorder. This study has a particular emphasis on the genetics of AD in African Americans and was the first to demonstrate that genetic factors have a major role in the development of AD.  His team has also shown that the ε4 variant of apolipoprotein E (APOE), the strongest AD risk factor identified thus far, is more weakly associated with disease in men and persons older than 75 years. Dr. Farrer co-directed the effort which demonstrated that neuronal sortilin-related receptor SORL1 is genetically and functionally associated with AD, thus establishing intracellular trafficking as an important pathway in AD pathogenesis.  He serves on the Executive Committee of the national AD Genetics Consortium and co-directs the data analysis effort for this large NIH-funded project. These efforts lead to the recent identification of four novel AD susceptibility genes. Currently, his lab is conducting genome wide association studies for AD, AMD and substance dependence.

Ashis Gangopadhyay
Associate Professor and Associate Chair
Boston University

Professor Gangopadhyay been on the faculty at the Department of Mathematics at Boston University since 1989, engaged in teaching and research in theoretical and applied statistics; and is currently Associate Chair of the Department.  Professor Gangopadhyay’s  general areas of research are (i) nonparametric and semiparametric modeling, (ii) modeling of time series and longitudinal data, and (iii) causal inference. Over the years, he has guided eleven Ph.D. students and published many papers in prestigious peer-reviewed journals.  His current research projects include modeling volatility in financial time series and investigation of causal effects in longitudinal data related to public health research.

Dr. Kolachalama’s laboratory leverages advanced machine learning, image processing and biophysical modeling tools to understand pathophysiological mechanisms that would pave way towards developing biomarkers and biomedical technologies that are of prognostic relevance. Their laboratory’s focus for over a decade has been within the cardiovascular domain, and specifically on endovascular device-based therapies. They are currently exploring other areas including chronic kidney disease, colorectal cancer, ophthalmology and Alzheimer’s disease.

Kathleen G Morgan, PhD
Professor, Health Sciences

My research group works at the intersection of neuroscience and the cardiovascular system.  We are especially interested in developing novel possible therapeutic approaches to prevent or reverse vascular dementia subsequent to aging-induced increases in aortic stiffness. Increased aortic stiffness is known to lead to subsequent microbleeds and white matter lesions of brain tissue. With our collaborators, we are currently using a microbubble-targeted cell permeant decoy peptide approach to decrease the stiffness of the aortic vascular smooth muscle cytoskeleton in an effort to decrease the onset of Alzheimer’s Disease-Related Dementias in a mouse model of aging.

Benjamin Wolozin, M.D., Ph.D.
Professor of Pharacology, Neurology and the Program in Neuroscience
Boston University School of Medicine

Dr. Wolozin’s research investigates the pathophysiology of neurodegenerative diseases. His research investigates the mechanisms by which genes cause dementia (Alzheimer’s disease and Frontotemporal Dementia) and movement disorders (Parkinson’s disease and Amyotrophic Lateral Sclerosis). Dr. Wolozin’s research on the role of stress granules in neurodegenerative diseases is a major focus of his laboratory. A growing body of evidence, including work from the Wolozin laboratory, increasingly highlights the important contributions of RNA binding proteins (RBPs) translational regulation in the pathophysiology of neurodegenerative disease. The work of the Wolozin lab addresses the roles of “regulated protein aggregation and membraneless organelles” on proteostasis, RNA metabolism, neuronal function and neurodegeneration. Investigating the biology of RNA granules (with a particular focus on stress granules), provides a theoretical framework for understanding the biology of neurodegenerative disease, as well as new directions for therapeutic intervention for tauopathies and other neurodegenerative diseases. Dr. Wolozin has developed methods to analyze the pathological RNA granules and stress granules that accumulate in brain diseases.

Dr. Wolozin graduated magna cum laude from Wesleyan University in Middletown, CT. He earned his M.D. and Ph.D. degrees from Albert Einstein College of Medicine, and did his postdoctoral fellowships at the National Institute of Mental Health. He joined Loyola University Medical Center in 1996, and moved to Boston University in 2004. Dr. Wolozin is a fellow of the AAAS and has received numerous awards for his research. These awards includes the Donald B. Lindsley Prize, Society for Neuroscience, the A. E. Bennett Award from the Society for Biological Psychiatry, the Zenith Award from the Alzheimer Association, the Graduate Faculty of the Year from Boston University Evans Center and the Boston University Spivack award for distinguished research in neuroscience. He has served on numerous editorial boards, chaired NIH study sections. and is a member of the Public Education and Communication Committee for the Society for Neuroscience. Dr. Wolozin has published over 150 papers or book chapters, and been awarded 4 patents.

Dr. Wolozin is also co-founder and Chief Scientific Officer of the biotechnology company, Aquinnah Pharmaceuticals, Inc., which is using the biology of RNA binding proteins to develop new therapies for amyotropic lateral sclerosis and Alzheimer’s disease.