Core D: Neuropathology Project Summary/Abstract Although there have been significant advances in the identification of biomarkers of Alzheimer's disease (AD), comorbidity is a common finding at autopsy and the neuropathologic assessment at autopsy remains the gold standard for diagnosis. The aims of the Neuropathology Core (Core D) will be: (1) To make neuropathologic diagnoses on all new brain accessions from HASD research participants using standard diagnostic criteria; (2) To perform brain autopsies and to collect, store at -80?C, and distribute formalin-fixed, paraffin-embedded, and frozen brain tissue samples to support HASD Projects and investigators and outside collaborations that enhance HASD research goals; (3) To support Projects 1 and 2 by providing a neuropathologic assessment and quantitative measures of the molecular pathology (beta- amyloidosis, tauopathy, synucleinopathy, and TDP-43 proteinopathy) of cases which come to autopsy. To support the Specific Aims of Project 3 by providing neuropathologic data, quantitative measures of the molecular pathology, and tissue (for mRNA and DNA extraction) relating to cases recruited for the study of genetic variants and their influence on the progression of AD (4) To maintain a computerized neuropathology database (CaTissue) in concert with the Biostatistics Core (Core C) and the Clinical Core (Core B) and the Washington University Neuroscience Blueprint Interdisciplinary Center Core (P30 NS057105). Information stored will include macroscopic images of fresh and fixed brain, demographic data, diagnoses, semi- quantitative morphometric data, neuropathology reports in collaboration with Dr. Perrin, bibliographic information, and data relevant to Core tissue banking activities. If acceptable, neuropathology data also will be transferred, after Biostatistics Core quality control and validation, to the National Alzheimer Coordinating Center (NACC), University of Washington, Seattle, WA (U01 AG016976);(5) To undertake a developmental clinico-biomarker-neuropathologic study of HASD participants to determine the progression of biomarker changes in longitudinally assessed participants who transition from preclinical AD to symptomatic AD and who come to autopsy. Neuropathology will be the benchmark against which biomarker (CSF A?42 and pTau and PET-amyloid imaging) data will be assessed. With the Imaging and Biostatistics Cores and Projects 1 and 2, Core D will explore the contribution of AD biomarker changes with neuropathologic data including measures of A? and pTau burden, synaptic and neuronal loss.