Biological heterogeneity in ADRD

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Abstract The UW ADRC's driving scientific focus is investigating the biological heterogeneity of ADRD – the mechanistic and biological underpinnings of the pathophysiology of disease as well as the factors countering degeneration and dementia. Our Center was one of the first to recognize etiologic heterogeneity in Alzheimer's disease2 and this focus is still urgently needed. New technologies and paradigms have emerged to analyze biological mechanisms of ADRD, and require well characterized human subjects and well-curated biospecimens. The proposed organizing framework for our core research resources is multi-disciplinary ADRD phenotyping. The four key disciplines to integrate are genetic, cognitive, topographic/anatomic, and neuropathologic. In this framework, the brain space is the point of integration of the other biomarkers of AD, as the magnitude and location of the different pathologies are the most tangible and objective manifestation of the outcome of different pathophysiological pathways. Thus a key aspect of our work will include integrating biomarkers extended over the cerebral cortex, as derived from imaging and neuropathology, with fluid biomarkers, cognitive and genetic information. An important goal is to support better stratification of AD phenotypes to advance investigation of candidate AD mechanisms. The UW ADRC is uniquely poised to undertake this work, which incorporates the historical strengths of the Center and research resources of the UW, leverages the collective expertise of the Core Leads and the Director, and benefits from new technical abilities that enable us to implement this program. New components are being proposed to bring expertise dedicated to bridging disciplines by innovations in techniques, methods, and informatics. These include Stem Cell and Precision -omics components in the Precision Neuropathology Core, Psychometrics component in the Clinical Core, Informatics expertise in the new Imaging and Biomarker Core and an Open Neuroscience workshop in the Research Education Component. Our Center's philosophy is to view ADRD not only through the lens of what is lost, but also through what is spared, and the associated retained strengths. This perspective permeates our Center, from motivating our interest in the biological and mechanistic basis of resilience and anatomic sparing, to the outreach efforts of the ADRC and its associated Memory and Brain Wellness Center. Another important theme of our Center is ADRD in American Indians and Alaska Natives. Building on our successful efforts in the last 5 years, we plan to extend our outreach efforts to Native tribes and organizations in Washington State, to improve their readiness for ADRD research, and to make a focused effort to understand and develop models to overcome the barriers to biospecimen collection and data sharing in this population.