Abstract - Precision Neuropathology Core The Precision Neuropathology (NP) Core has been a valuable and frequently utilized resource for UW ADRC in support of its vision of characterizing and understanding heterogeneity of Alzheimer's disease and related dementias (ADRD). The NP Core has fostered development of innovative approaches to assess neuropathology of ADRD, which are essential to more precisely measure neuropathologic change. We build on this tradition of innovation in this proposal by applying novel, highly quantitative multiplexed immunoassays developed in the NP Core to measure neuropathology that, combined with better methods of collecting and storing tissue for state-of-the-art applications including single cell molecular profiling, expanded pathological sampling informed by structural and functional imaging, ex vivo MRI-guided pathologic sampling in every brain, and 3D image reconstruction, and quantitative analysis in both gross and microscopic samples, enable us to deeply characterize the structural substrate for ADRD heterogeneity. We combine this comprehensive analysis of human brains with a cell types and stem cell component composed of experts in their respective fields who are committed to providing support for ADRD-related mechanistic studies, all while supporting every core of the ADRC and local and national research. Thus, our Aims reflect our commitment to integrate traditional diagnostic excellence and extensive tissue and data sharing with radiographically informed extensive sampling and a battery of highly quantitative, molecularly specific tissue and in silico approaches to precisely measure ADRD neuropathology. Our specific aims are to (i) build a highly accessible repository of brain tissue and fluid, (ii) provide diagnostic expertise according to the latest guidelines, (iii) develop innovative approaches, (iv) provide cell types and stem cell support for ADRD research, and (v) promote durable ADRD research through support of ADRC Cores, development projects, and local and national research. All of our research activities are focused on enhancing the research value of tissue and body fluid donations from cognitively healthy individuals and those along the ADRD spectrum while ensuring proper safeguards.