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We present the SEA-AD DREAM Challenge, an open, international, model-to-data competition built on the Seattle Alzheimer\u2019s Disease Brain Cell Atlas to predict Alzheimer\u2019s disease neuropathological severity from single-nucleus RNA-sequencing data. Participants developed containerized models to predict categorical neuropathological staging, including overall Alzheimer\u2019s disease neuropathologic change, Braak stage, Thal phase, and CERAD score, as well as quantitative amyloid-\u03b2 and phospho-tau burden measured by 6E10 and AT8 immunohistochemistry. Across 17 eligible teams from 15 countries, the crowdsourcing framework enabled systematic comparison of diverse computational approaches and surfaced a broad landscape of modeling strategies and candidate predictive features. Top-performing methods achieved near-perfect prediction of categorical staging, with the best submission reaching a quadratic weighted kappa of 1.0 for the Overall AD Neuropathological Change score (ADNC), and competitive prediction of quantitative pathological burden in held-out data, with a best concordance correlation coefficient of 0.48. Post hoc perturbation analyses revealed that top categorical-stage predictions relied heavily on donor-level metadata-driven signals rather than transcriptomic features, whereas quantitative pathology prediction was more robust and supported by transcriptomic and cell-type-associated features with potential biological relevance to AD progression. The challenge also introduced the first AI Agent Track in a DREAM Challenge, providing an early benchmark for autonomous and human-guided agentic model development in single-cell neuroscience. This work demonstrates that single-nucleus transcriptomes encode substantial information about Alzheimer\u2019s disease pathology, establishes a reproducible benchmark for molecular neuropathology prediction, and highlights critical principles for designing privacy-preserving, leakage-aware community challenges using deeply phenotyped human brain data.<\/jats:p>","DOI":"10.64898\/2026.07.02.736180","type":"posted-content","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T21:25:21Z","timestamp":1783545921000},"source":"Crossref","is-referenced-by-count":0,"title":["The SEA-AD DREAM Challenge: Community benchmarking human and AI agent solutions for Alzheimer\u2019s disease neuropathology prediction from single-nucleus transcriptomics"],"prefix":"10.64898","author":[{"given":"Hsin-Yu","family":"Lai","sequence":"first","affiliation":[{"name":"Allen Institute, Brain Health, Seattle, WA, 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