Our patients, and the needs of the science, demand that we try to answer the difficult question, “what will happen to me?”. In this renewal application of MADRC, an interdisciplinary Center for the study of Alzheimer’s and related dementias at Massachusetts General Hospital, Harvard Medical School, we will build on promising scientific advances to contribute to answering this question. We propose 7 Cores (Administrative, Clinical, Biomarker, Imaging, Neuropathology, Data, and Outreach) and a Research Education Component (REC). Each Core has two major strategic goals: 1) to bring to bear each Core’s unique expertise to understand the drivers of clinical progression in “normal” aging, Alzheimer’s Disease (AD), Lewy Body Disease (LBD), and Frontotemporal Dementia (FTLD), and 2) to develop strategies and technologies to improve precision of measuring pace of progression of both clinical symptoms and underlying disease processes. Our Research Cohort, which has been rebuilt with a renewed commitment to priority populations, is a state-of-the-art clinical phenotyping laboratory that will allow us to measure multiple aspects of pace of clinical progression across a spectrum from normal cognition to mild dementia. We will, for example, develop digital phenotyping and explore strategies to “take the research to the participant” to break down barriers and improve measurements. The Biomarker Core uses single molecule detection (simoa) and other technologies focused on analytes present in plasma that reflect brain pathologies, including tau, amyloid β, inflammation markers, and, in work we are very excited about, synaptic loss. Our Imaging Core will, for the first time, be resourced to perform longitudinal MRI and PET scans on the Research Cohort and will explore the use of novel MRI techniques that promise additional precision. The Neuropath Core is building a set of matched brain/iPS cell pairs from individuals with different (often mixed) etiologies of dementia and provided them to NCRAD to facilitate studies of how disease related phenotypes measured in iPS cells relate to neuropathological changes in the brain, and to clinical change. The Data Core has led major new “Big Data” initiatives and is the analytical engine of the Center. The ORE Core brings to bear modern behavioral and community engaged research to our group. It takes the lead in recruitment of a diverse cohort for MADRC studies, clinical trials, and other affiliated programs, and in building effective networks of communication with the community and with health care professionals in our eco-system. As a team, we will be able to explore potential drivers of clinical progression comparing with markers of disease progression (eg amyloid and tau), neuroinflammation, vascular lesions and neurodegeneration, appreciating that most of our participants will have multiple drivers of cognitive change, and aware that these relationships may differ in different populations. Finally, education and trainin...