The overarching goal of the ADNI Neuropathology Core (NPC) is to support the discovery and validation of antemortem biomarkers for Alzheimer disease and related dementias (ADRD). To achieve that goal, the NPC performs uniform comprehensive neuropathologic examinations for ADNI participants, allowing clinical diagnoses, fluid biomarker results, and neuroimaging data to be compared to ‘gold-standard’ neuropathologic findings; the NPC also curates ADNI brain tissue specimens to facilitate ADNI and non-ADNI biomarker research. For ADNI4, the NPC will: 1) encourage, collect, process, and store participant brain donations from all ADNI sites for present and future ADRD biomarker studies; 2) provide a uniform neuropathologic assessment of all brain donations; 3) use neuropathologic data from the ADNI cohort to validate clinical diagnoses and AD biomarkers used for enrollment and outcome measures in clinical trials; 4) facilitate the use of ADNI participant brain tissue in biomarker research; 5) develop culturally appropriate strategies to encourage brain donation by all participants, including under-represented groups; and 6) investigate possible neuropathologic disparities in under-represented groups, when suitable cases become available, in support of the ADNI4 diversity initiative. The NPC has very successfully promoted brain donation at ADNI sites in preparation for ADNI4. With support from two NIA administrative supplements, the NPC has: hired a full-time ADNI NPC coordinator; formally surveyed ADNI sites to identify obstacles to brain donation; established an award program to overcome these obstacles; helped 6 sites start new brain donation programs; introduced protocol changes allowing lapsed ADNI2 participants to re-enroll for ‘brain donation only’ and allowing more frequent monitoring of autopsy-consented participants to update donation logistics; and begun to ‘retrieve’ 49 ADNI participant brain donations from ADNI- affiliated ADCs for uniform re-assessment and inclusion in the ADNI NPC Tissue Resource. The ADNI NPC Cohort, now n=133, is expected to grow by approximately 40 per year of ADNI4. Growth of the NPC cohort will be critical for the mission of ADNI4. Clinicopathologic review of the first 84 ADNI brain donations reveals that: only 84% of participants clinically diagnosed with AD dementia (ADD) had sufficient AD neuropathology (ADNC) to account for dementia; only 60% of participants diagnosed with ADD plus another contributing disease showed sufficient ADNC; and 57% of participants who received a non-ADD diagnosis actually harbored ‘low’ or ‘intermediate’ ADNC. Additionally, among participants with sufficient ADNC, 82% also showed neuropathologic co-morbidities with potential to influence cognition and/or biomarker data. These data suggest that: evaluations of biomarkers based on clinical diagnosis may be inaccurate; AD clinical trials relying solely on clinical diagnosis are likely to enroll some patients who do not suffer from AD; ...