ANNUAL REPORT July 1, 2016 to June 30, 2017 Table of Contents Introduction. .Page 3 Annual Scientific Conference Agenda. Page 9 Institutional Information. Page 37 - Research Summaries - Key Personnel Project Progress Reports . .Page 69 - Project Progress Reports by Institution 2016-2017 Publications, Manuscripts, & Grants - Publications and Manuscripts. Page 221 - Current and Pending Grants. Page 246 Poster Abstracts. Page 278 Institutional Budgets and Justifications . See companion report 2 Introduction to the Annual Report Background The Arizona Alzheimer’s Consortium is the nation’s leading model of statewide collaboration in Alzheimer’s disease (AD) research. It includes more than 150 researchers and staff from seven principal organizations, including Arizona State University, Banner Alzheimer’s Institute, Banner Sun Health Research Institute, Barrow Neurological Institute, Mayo Clinic Arizona, the Translational Genomics Research Institute, and the University of Arizona, and from three affiliated organizations, including the Critical Path Institute, Midwestern University, and the University of Arizona College of Medicine, Phoenix. Established in 1998, the Consortium is intended to make a transformational difference in the scientific fight against AD, to engage Arizona’s underserved and understudied Native American and Latino communities, to help address the unmet needs of patients and family caregivers, and to advance the understanding and promotion of healthy cognitive aging. The Consortium’s major themes are the early detection and prevention of AD. Its primary goal is to find effective AD prevention therapies as soon as possible. The Consortium is widely recognized as a model of multi-institutional collaboration in biomedical research. It capitalizes on complementary resources and expertise from different disciplines and organizations to address scientific problems in the most impactful way. Its researchers receive critical support from the state of Arizona (through the Arizona Department of Health Services [ADHS] and its Arizona Biomedical Research Commission [ABRC]), the participating organizations, a competitive Arizona AD Center (ADCC) grant from the National Institute on Aging (NIA), and numerous other grants and contracts. Eric Reiman, MD, is the Director of the Consortium and the NIA-sponsored ADCC, Richard Caselli, MD, is the ADCC’s Associate Director, and Carol Barnes, PhD, chairs the Consortium’s 26-member Internal Scientific Advisory Committee. Mr. David Jerman is Administrative Director of the Consortium’s state- and organizational-supported research program, Mrs. Andrea Schmitt is Administrative Director of its ADCC grant, and Executives from each of the seven principal organizations serve on the Consortium’s Board of Directors. The Consortium’s external advisors include Drs. Marilyn Albert, Zaven Khachaturian, Bruce Miller, and Thomas Montine, who are internationally recognized for their contributions and leadership roles in the study of AD and/or related disorders. They conduct annual site visits, review the progress and productivity of the Consortium and ADCC, and provide formal feedback and recommendations to the researchers, NIA, and state. The Arizona Alzheimer’s Consortium capitalizes on the state’s strengths in brain imaging, genomics, the computational, mathematical and statistical analysis of complex data sets, the basic, cognitive and behavioral neurosciences, clinical and experimental therapeutics, and neuropathology research. It has made pioneering contributions to the scientific understanding, unusually early detection and tracking of AD, the accelerated evaluation of putative AD 3 prevention therapies, and the scientific understanding of the aging mind and brain. It has introduced new ways for different stakeholders to work together, it has provided data, biological samples and interested research participants for researchers inside the state and around the world, and it has introduced promising new care models for patients and family caregivers. It continues to attract new researchers and clinicians, and support other biomedical research developments in the state. Indeed, it has helped to make Arizona a destination center for the advancement of AD research and care. State and organizational matching funds continue to provide the “glue” for this geographically distributed research program, the “fuel” needed to launch new research initiatives, and the framework needed to reach the Consortium’s over-arching goals. Funds are used to support dozens of research projects each year, almost all of which involve researchers from different scientific disciplines, and about half of which include researchers from different organizations. As one of our advisors observed, Arizona has become known around the world for its courage, groundbreaking organizational and scientific paradigms, and ability to make things happen in the fight against AD. The Arizona ADCC has received continuous competitive NIA grant funding since 2001. The ADCC’s Administrative, Clinical, Data Management and Statistics, Neuropathology, and Education and Information Cores and its competitive Pilot Project Program have supported researchers and projects inside and outside of the state. In place of its previous Education and Information Core, the ADCC’s most recent renewal grant includes an Outreach and Recruitment Core and Research Education Component (REC). ADCC’s most recent competitive renewal grant application to NIA received an Outstanding Impact Score and highly favorable reviewer comments. The Summary Statement noted our statewide programs’ “exceptional” track record, productivity and impact, its “outstanding scientific contributions, regional, national, and international initiatives, and impact,” its “effective” leadership and collaborative model, “impressive” commitments from the state and each of our participating organizations, and its leadership roles in the fight against AD. In July 2016, the ADCC received its fourth consecutive five-year renewal grant. Productivity and Impact The Arizona Alzheimer’s Consortium is not only the leading statewide AD Center in the nation, but one of the most productive AD research programs in the world. Since its inception in 1998, its researchers have generated more than 4,000 publications, 1,000 research grants and contracts, and $1.5 billion in new investments, including more than half of those investments in the last 5 years. Consortium researchers have made pioneering contributions to the study of AD, related disorders, and the aging mind and brain: • They have helped clarify genetic and non-genetic risk factors and disease mechanisms, offered targets at which to aim new AD treatments, provided new insights about the pathological changes associated with AD and related disorders, and introduced promising ways to treat and prevent AD. They have also provided invaluable public resources of genetic, neuronal gene expression, longitudinal and neuropathological data and high-quality brain tissue, and introduced new endophenotypic approaches, and data-sharing and collaborative paradigms to assist researchers around the world in these endeavors. 4 • They have played leadership roles in the early detection and tracking of AD, including the detection and tracking of progressive brain imaging, other biomarkers, and cognitive changes—as well as the detection of neurodevelopmental changes—in cognitively unimpaired persons at genetic risk, and they have provided invaluable resources of data and volunteers from persons at three levels of genetic risk for AD in the Arizona APOE4 Gene Dose Cohort and in Colombian early-onset AD-causing mutation carriers from the world’s largest autosomal dominant AD kindred. They have introduced new experimental paradigms, image-analysis techniques and composite cognitive tests to help in this endeavor. Their work anticipated and helped to advance the conceptualization of preclinical AD, has informed the design of prevention trials in persons at increased genetic and/or biomarker risk, and helped to launch a new era in AD prevention research. • They continue to clarify how different molecular processes and brain cells, regions, networks, and mental operations orchestrate memory and other thinking abilities, and how they are affected by AD and aging. They have developed, tested and used groundbreaking neuroscientific, experimental and behavioral paradigms to help in these endeavors; and they have played leading roles in the international study of the aging mind and brain. • They have played leadership roles in the use of brain imaging in the detection, tracking, and scientific study of AD, and they have introduced methods to do so with improved power. They have played leadership roles in the effort to validate amyloid and emerging PET methods in persons at the end of life who subsequently donate their brains, supporting their current or future FDA approval for use in the clinical setting. • They continue to provide a world-leading resource of longitudinal and neuropathological data, brain and body tissues for the study of AD, Parkinson’s disease, and related disorders in its Brain and Body Donation Program. • With >$500M in philanthropic, NIA and industry funding, they established the Alzheimer’s Prevention Initiative (API) to launch a new era in AD prevention research, establish the shared sense of urgency, scientific means, accelerated approval pathway, enrollment resources, public-private partnerships, and vetting mechanisms needed to rapidly test promising prevention