Neuropathology Core (Core D) – Project Summary The Neuropathology Core will provide state-of-the-art collection, storage, and distribution of brain and other biospecimens, establish neuropathological diagnoses of decedent Clinical Core participants, and provide resources and expertise for nonhuman primate (NHP) models for pivotal mechanistic and therapeutic AD research. The Core will oversee repositories derived from longitudinal collection of biospecimens obtained from adults at high risk for AD due to genetic and metabolic risk factors, as well as low-risk adults, and adults with MCI and AD, and from analogous studies in NHPs. These repositories will provide unique opportunities to identify novel biomarkers, neurodegenerative antecedents, and therapeutic targets, and will be made available to NCRAD and to ADC investigators. The Core utilizes an innovative inter-institutional leadership model in which a team of neuropathologists from Wake Forest and the University of Washington will employ state-of- the-art virtual microscopy, webconferencing, and biospecimen sharing to accelerate the development of Neuropathology operations at the newly established Wake Forest ADCC. Interinstitutional publication has already resulted, and an NHP study of age-associated AD-like neuropathology completed which provide proof of concept for this approach. Thus, we will accomplish the following Specific Aims: 1) To oversee a repository of brain tissue, CSF, DNA, and blood from participants enrolled in the Clinical and MESA Cores of the Wake Forest ADCC, using state-of-the-art methods for specimen collection, processing, storage, and distribution; 2) To facilitate distribution of data and specimens in the repository to Wake ADCC and ADC network investigators, as well as to NCRAD and AD researchers world-wide; 3) To conduct rigorous neuropathological diagnostic evaluations and clinical-pathological investigations of decedent Clinical and MESA Core participants, using an innovative inter-institutional model that incorporates the latest technology in virtual microscopy and web conferencing; 4) To facilitate the measurement of key biomarkers of AD pathology and innovative markers of metabolic/vascular function; and 5): To establish preclinical models of AD and pathological brain aging in NHPs using procedures analogous to human protocols, and in doing so (a) create a repository of brain tissue, CSF, DNA, biospecimens, and neuroimaging data, and (b) NHP cohorts and rodent models, that can be used for pivotal mechanistic and therapeutic studies.