{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:07:31Z","timestamp":1792789651461,"version":"4.5.0"},"reference-count":91,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:00:00Z","timestamp":1775692800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Key Research and Development Program of China","award":["2025YFA0921900"],"award-info":[{"award-number":["2025YFA0921900"]}]},{"DOI":"10.13039\/501100013314","name":"111 Project","doi-asserted-by":"crossref","award":["B16009"],"award-info":[{"award-number":["B16009"]}],"id":[{"id":"10.13039\/501100013314","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Construction Project of Liaoning Provincial Key Laboratory, China","award":["2022JH13\/10200026"],"award-info":[{"award-number":["2022JH13\/10200026"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease is a devastating progressive neurodegenerative disorder characterized by extracellular amyloid-beta plaques and intracellular tau tangles. Despite recent advancements in amyloid-beta-targeting immunotherapies, achieving safe and definitive disease control remains a profound clinical challenge. The CRISPR\/Cas9 system has emerged as a powerful technology for precision neurogenetics, offering significant potential to address the fundamental questions behind Alzheimer\u2019s disease. This comprehensive review delineates the trajectory of CRISPR applications in Alzheimer\u2019s disease research and therapeutics. First, we explore the integration of CRISPR in engineering high-fidelity in vitro models, such as isogenic induced pluripotent stem cells and three-dimensional cerebral organoids, alongside advanced in vivo mammalian models. Second, we examine how these platforms facilitate unbiased high-throughput genetic screening to uncover molecular underpinnings regulating tau, lipid metabolism, and neuroinflammation. Third, we critically evaluate precision editing strategies targeting core risk genes (APP, MAPT, APOE, and TREM2), explicitly highlighting the severe physiopathological trade-offs between therapeutic efficacy and loss-of-function toxicity. Finally, we address the ultimate translational bottlenecks impeding clinical application. By dissecting the packaging limits of adeno-associated viral vectors and the physical barricade of the blood\u2013brain barrier, we underscore the necessity of transitioning toward next-generation base editors and non-viral lipid nanoparticles to realize safe and efficacious in vivo clinical gene therapies against Alzheimer\u2019s disease.<\/jats:p>","DOI":"10.3390\/ijms27083371","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T09:46:23Z","timestamp":1775727983000},"page":"3371","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["CRISPR Applications in Alzheimer\u2019s Disease: From High-Throughput Genetic Screening to Precision Editing and CNS Delivery"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3325-0730","authenticated-orcid":false,"given":"You","family":"Li","sequence":"first","affiliation":[{"name":"Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University, Shenyang 110819, China"},{"name":"Foshan Graduate School of Innovation, Northeastern University, Foshan 528311, China"},{"name":"National Frontiers Science Center for Industrial Intelligence and Systems Optimization, Northeastern University, Shenyang 110819, China"},{"name":"Key Laboratory of Data Analytics and Optimization for Smart Industry (Northeastern University), Ministry of Education, Shenyang 110819, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7724-3807","authenticated-orcid":false,"given":"Shixin","family":"Ma","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University, Shenyang 110819, China"},{"name":"Foshan Graduate School of Innovation, Northeastern University, Foshan 528311, China"},{"name":"National Frontiers Science Center for Industrial Intelligence and Systems Optimization, Northeastern University, Shenyang 110819, China"},{"name":"Key Laboratory of Data Analytics and Optimization for Smart Industry (Northeastern University), Ministry of Education, Shenyang 110819, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9620-0450","authenticated-orcid":false,"given":"Teng","family":"Fei","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University, Shenyang 110819, China"},{"name":"Foshan Graduate School of Innovation, Northeastern University, Foshan 528311, China"},{"name":"National Frontiers Science Center for Industrial Intelligence and Systems Optimization, Northeastern University, Shenyang 110819, China"},{"name":"Key Laboratory of Data Analytics and Optimization for Smart Industry (Northeastern University), Ministry of Education, Shenyang 110819, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"103652","DOI":"10.1016\/j.drudis.2023.103652","article-title":"CRISPR-Cas9 in Alzheimer\u2019s disease: Therapeutic trends, modalities, and challenges","volume":"28","author":"Chacko","year":"2023","journal-title":"Drug Discov. 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