PROJECT SUMMARY/ABSTRACT - Neuropathology Core The overarching goal of the UCD ADRC is to understand the multiple and complex determinants that explain the heterogeneity of cognitive trajectories among diverse older adults. To help achieve this goal, the primary mission of the Neuropathology Core (NPC) is to assess and quantify brain injury in the form of multiple pathologies essential to the most precise and relevant characterization of individual cognitive ability. To provide even deeper pathological phenotypes, the NPC has leveraged and enhanced Core infrastructure by implementing digital pathology and developing machine learning workflows for quantitative regional analysis. These NPC data, when linked with comprehensive cognitive assessment, brain imaging, and other biological markers generated by other ADRC Cores will facilitate new understandings into the protective/risk factors of brain aging and dementia processes. Our NPC is unique in (1) its study subjects have been drawn from a diverse multi-ethnic/racial longitudinal cohort maintained by the Clinical Core (CC) with an emphasis on early disease/early pathology, (2) its collection of tissue samples from cases whose cognitive trajectories have been modified by clinically, imaging proven, and pathologically confirmed cerebrovascular injury and (3) its sizeable number of samples and datasets from minority participants (39 Hispanic/Latino, 18 Asian, and 52 African American) that have resulted in high impact publications. In collaboration with the other ADRC Cores, we have built, maintained, and enhanced our research infrastructure, accumulating unique datasets, high quality samples, and experience in clinic-pathological, translational, and basic research collaborations. New causes and contributing factors of dementia continue to be discovered by studies using post-mortem brain specimens, enriching the pool of biomarkers for risk of dementia. Modern neuropathology techniques (e.g., our machine learning studies) combined with new molecular tools (such as our Quanterix system within the Biomarker core) have the potential to tremendously advance our understanding of disease pathogenesis, thus providing a degree of precision to anchor the clinical and biological heterogeneity commonly observed in dementia. Moreover, neuropathology plays a central role in future interventions, as postmortem diagnosis is the gold standard to establish biomarkers applicability and the efficacy of experimental interventions. Thus, we envision the NPC will continue to be a central player in multi-component research projects in the effort to find new avenues for dementia treatment. As such, the NPC leadership will continue networking with researchers to conduct multidisciplinary research while upgrading the core diagnostic capabilities to enable detection of diverse brain injury pathways using novel methods.