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Using a 10\u2010year observational cohort study coupled with an AI\u2010driven systems pharmacology platform, we identified a natural triterpenoid compound found in colorful fruits and vegetables, \u03b1\u2010Amyrin (\u03b1A), as a therapeutic candidate for Alzheimer's disease (AD). The efficacy of \u03b1A in treating the symptoms of AD, such as Tau tangles, damaged mitochondria, and memory loss, was examined using cross\u2010species models; \u03b1A retained memory in AD\u2010like animal models while also strongly inhibiting Tau pathology, especially p\u2010Tau217, in a cellular \u2018Tau seeding\u2019 system and in Tau[P301S] mice, followed by validation using a human 3D microfluidic system. At molecular level, \u03b1A is a robust mitochondrial regulator, enhancing mitochondrial stress resilience and activation of mitophagy. Mechanistically, \u03b1A inhibits dual leucine zipper kinase (DLK), leading to the inhibition of DLK\u2010Sterile Alpha and TIR Motif Containing 1 (SARM1)\u2010dependent neurodegeneration; this inhibition frees unc\u201051 Like Autophagy Activating Kinase 1 (ULK1)\u00a0from the ULK1\u2010SARM1 complex, allowing it to participate in autophagy\/mitophagy. \u03b1A also shows strong translational potential with a 10.1\u00a0h half\u2010life and the ability to cross the blood\u2010brain barrier. Our results indicate that \u03b1A may act as a mitochondrial guardian against AD via modulating the DLK\u2010SARM1\u2010ULK1\u2010autophagy\/mitophagy axis while further preclinical and clinical studies are warranted.<\/jats:p>","DOI":"10.1002\/advs.202512374","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T05:25:03Z","timestamp":1769145903000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The Mitochondrial Guardian \u03b1\u2010Amyrin Mitigates Alzheimer's Disease Pathology via Modulation of the DLK\u2010SARM1\u2010ULK1 Axis"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4361-8308","authenticated-orcid":false,"given":"Shu\u2010Qin","family":"Cao","sequence":"first","affiliation":[{"name":"Department of Clinical Molecular Biology University of Oslo and Akershus University Hospital  L\u00f8renskog Norway"},{"name":"Department of Clinical Chemistry Faculty of Allied Health Sciences Chulalongkorn University  Pathum Wan Bangkok Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3065-9952","authenticated-orcid":false,"given":"Juan Ignacio","family":"Jim\u00e9nez\u2010Loygorri","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Biology Margarita Salas Center For Biological Research Spanish National Research Council  Madrid Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunguang","family":"Qiu","sequence":"additional","affiliation":[{"name":"Cleveland Clinic Genome Center Cleveland Clinic Research Cleveland Clinic  Cleveland Ohio USA"},{"name":"Department of Genomic Sciences and Systems Biology Cleveland Clinic Research, Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"You Jung","family":"Kang","sequence":"additional","affiliation":[{"name":"Institute of Quantum Biophysics Sungkyunkwan University  Suwon Gyeonggi Republic of Korea"},{"name":"Department of Biophysics Sungkyunkwan University  Suwon Gyeonggi Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khanh Van","family":"Do","sequence":"additional","affiliation":[{"name":"Institute of Quantum Biophysics Sungkyunkwan University  Suwon Gyeonggi Republic of Korea"},{"name":"Department of Intelligent Precision Healthcare Convergence Sungkyunkwan University  Suwon Gyeonggi Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annabel E.","family":"Smith","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute at the University of Cambridge  Cambridge UK"},{"name":"Department of Clinical Neurosciences University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjie","family":"Huang","sequence":"additional","affiliation":[{"name":"MindRank AI Ltd.  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