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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Computational models of Alzheimer\u2019s disease (AD) rarely connect cellular heterogeneity, spatial tissue organization, pathology cascades, and pharmacological intervention within one auditable workflow. We present CellSwarm-AD, a four-layer framework comprising five cell agent classes, a spatial A\u03b2 diffusion environment, an A\u03b2\u2013Ca2+\u2013tau\u2013NF-\u03baB\u2013viability cascade with repository PK\/PD models, and an optional experiment orchestration interface. Layer 3 was demonstrated with reproducible prompt templates and deterministic mock outputs; no live large language model was used to generate or modify the quantitative simulation outputs or statistical results. In a prespecified 78-week virtual trial (n = 200 per arm), patient-level repeated measurements were analyzed with Gaussian generalized estimating equations. Week-78 mean (SEM) MMSE-like changes were \u22121.747 (0.071) for the placebo, \u22121.368 (0.076) for lecanemab, \u22121.428 (0.067) for donepezil, and \u22121.369 (0.065) for independently simulated donepezil plus memantine. The corresponding single-trial Cohen\u2019s d values versus the placebo were 0.395, 0.354, and 0.426. Across 20 independent n = 200-per-arm trials, the mean d values were 0.337, 0.359, and 0.326, respectively; replicates were not pooled. Ablation removed most of the treatment contrast when PK\/PD was disabled, and fixed-domain grid testing showed decreasing relative L2 error from 6.20% (100 \u00d7 100) to 1.49% (200 \u00d7 200) against a 400 \u00d7 400 reference. These results establish a reproducible proof-of-concept while identifying calibration dependence, weak cross-layer coupling, and the absence of individual-level external validation as current limitations.<\/jats:p>","DOI":"10.3390\/ijms27156915","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T12:57:56Z","timestamp":1785761876000},"page":"6915","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CellSwarm-AD: A Multi-Scale Agent-Based Framework for Virtual Alzheimer\u2019s Disease Trials"],"prefix":"10.3390","volume":"27","author":[{"given":"Chun-Lin","family":"Tan","sequence":"first","affiliation":[{"name":"State Key Laboratory of Southwestern Chinese Medicine Resources, Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang-Mei","family":"Zheng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Southwestern Chinese Medicine Resources, Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-Fei","family":"Zhu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Southwestern Chinese Medicine Resources, Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quan-Quan","family":"Xiong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Southwestern Chinese Medicine Resources, Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Southwestern Chinese Medicine Resources, Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9968-2069","authenticated-orcid":false,"given":"Xuan-Lin","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Naval Medical University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,1]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2023). 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