NEUROPATHOLOGY CORE SUMMARY The importance of human brain tissue in ADRD research cannot be overstated, both as a resource to explore and define novel molecular pathways, as well as a critical resource for animal researchers who wish to validate their findings in human tissue. The AMP-AD initiative recently launched by NIA is further validation of the importance of human brain tissue in defining disease-relevant pathways and has resulted in numerous publications that have added to our evolving understanding of AD pathogenesis. The Columbia University ADRC Neuropathology (NP) Core has a long history of serving the wider ADRD research community’s need for well characterized human brain tissue, and we will continue this mission under this P30 renewal. The chief function of the NP Core is to provide state-of-the-art diagnostic services, and to collect, maintain, and distribute optimally prepared brain samples to researchers at Columbia and throughout the world. We will also facilitate research within our core with procured tissue samples, with a focus on our two pathways of interest (i.e. the ‘immune response’ and the ‘endosomal trafficking’ pathways). The NP Core also has a responsibility to train and educate the next generation of neurodegenerative disease researchers and brain bankers. Finally, we will use the resources of the NP Core to promote research into ADRD at risk populations. With regards to tissue banking and distribution, the NP Core has a well-established procedure for receiving and banking brains, and we will continue this protocol for this P30 renewal. Upon death of a donor, one half brain is immersed in formalin and kept for thorough neuropathological evaluation, and the contralateral half is extensively dissected at the fresh state and processed to yield up to 150 blocks and pulverized aliquots of parenchyma. Our samples are barcoded and electronically tracked, which aids in organizing the samples, maintaining them safely, and ultimately speeds the selection of samples for research. With regards to education, the NP Core has a longstanding tradition of educating the next generation of neuroscientists and brain bankers, through weekly brain cutting, monthly clinicopathological conferences, and periodic hosting of visiting neuroscientists throughout the world. Finally, we will use the resources of the NP Core to promote research into at risk ADRD populations through continued collaboration with researchers studying the development of ADRD pathology, and we will facilitate clinical trials through post-mortem assessment of how well disease modifying therapies have engaged target proteins and pathways.