{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T20:27:57Z","timestamp":1788553677803,"version":"build-2803163510"},"reference-count":105,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Universidad Central de Chile","award":["CIPPTE202505"],"award-info":[{"award-number":["CIPPTE202505"]}]},{"award":["CIPPTE202505"],"award-info":[{"award-number":["CIPPTE202505"]}],"id":[{"id":"https:\/\/ror.org\/0577avk88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Alzheimer\u2019s disease (AD) is a complex neurodegenerative disorder and a major global health challenge. The traditional \u201cone drug\u2013one target\u201d paradigm has shown limitations in addressing its multifactorial nature. Multitarget-directed ligands (MTDLs), designed to modulate multiple pathological pathways, have emerged as a promising therapeutic strategy. Objectives: To examine the structural, thematic, and temporal evolution of multitarget strategies for AD treatment between 2006 and 2025. Methods: A total of 1184 Web of Science-indexed articles were analyzed. Publication growth, h-index, author productivity, institutional and national contributions, and keyword co-occurrence networks were evaluated using VOSviewer. Bibliometric laws (Price, Bradford, Zipf, and Lotka) were applied to characterize productivity patterns and thematic organization. Results: Multitarget research shows exponential growth, suggesting a consolidation of the MTDL paradigm. China, India, the United States, Italy, and Spain were the most productive countries. Early studies focused on cholinesterase inhibition, particularly acetylcholinesterase-based hybrids. The field expanded to include \u03b2-amyloid aggregation, oxidative stress, metal chelation, and blood\u2013brain barrier permeability. Recent trends emphasize integration of computational approaches, including molecular docking, molecular dynamics, virtual screening, and network pharmacology, alongside targets such as BACE1 and GSK-3\u03b2. Conclusions: Multitarget strategies have evolved toward a systems-oriented framework. Despite advances, challenges remain in reducing cholinesterase dependency and improving translational validation. This study provides a framework to interpret therapeutic evolution and guide future network-based drug design.<\/jats:p>","DOI":"10.3390\/ph19071024","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T16:56:55Z","timestamp":1782838615000},"page":"1024","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Evolution of Multitarget Strategies for Alzheimer\u2019s Disease: From Cholinergic Inhibition to Network-Oriented Therapeutic Design (2006\u20132025)"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2434-8461","authenticated-orcid":false,"given":"Jaime","family":"Mella","sequence":"first","affiliation":[{"name":"Instituto de Qu\u00edmica, Facultad de Ciencias, Universidad de Valpara\u00edso, Valpara\u00edso 2360102, Chile"},{"name":"Centro de Investigaci\u00f3n, Desarrollo e Innovaci\u00f3n de Productos Bioactivos (CInBIO), Universidad de Valpara\u00edso, Valpara\u00edso 2360102, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9427-2044","authenticated-orcid":false,"given":"Alejandro","family":"Vega-Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"Laboratorio de Bienestar y Comportamiento Organizacional, Facultad de Medicina y Ciencias de la Salud, Universidad Central de Chile, Santiago 8330507, Chile"},{"name":"Centro de Investigaci\u00f3n en Medicina de Altura, Universidad Arturo Prat, Santiago 8340232, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1864-7561","authenticated-orcid":false,"given":"Mauricio","family":"Soto","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica, Universidad T\u00e9cnica Federico Santa Mar\u00eda, Av. Espa\u00f1a 1680, Valpara\u00edso 2340000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7128-8174","authenticated-orcid":false,"given":"Daniel","family":"Moraga","sequence":"additional","affiliation":[{"name":"Laboratorio de Fisiolog\u00eda, Departamento de Ciencias Biom\u00e9dicas, Facultad de Medicina, Universidad de Tarapac\u00e1, Arica 1000000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7358-409X","authenticated-orcid":false,"given":"Javier","family":"Campanini-Salinas","sequence":"additional","affiliation":[{"name":"Escuela de Qu\u00edmica y Farmacia, Facultad de Ciencias, Universidad San Sebasti\u00e1n, Puerto Montt 5501842, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7471-6536","authenticated-orcid":false,"given":"Eduardo","family":"Sandoval-Obando","sequence":"additional","affiliation":[{"name":"Escuela de Psicolog\u00eda, Facultad de Ciencias Sociales y Humanidades, Universidad Aut\u00f3noma de Chile, Temuco 4800916, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicol\u00e1s","family":"Contreras-Barraza","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias Econ\u00f3micas y Administrativas, Pontificia Universidad Cat\u00f3lica de Valpara\u00edso, Valpara\u00edso 2340025, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4979-6869","authenticated-orcid":false,"given":"Guido","family":"Salazar-Sep\u00falveda","sequence":"additional","affiliation":[{"name":"Facultad de Ingenier\u00eda, Universidad Cat\u00f3lica de la Sant\u00edsima Concepci\u00f3n, Concepci\u00f3n 4090541, Chile"},{"name":"Facultad de Ingenier\u00eda y Negocios, Universidad de Las Am\u00e9ricas, Concepci\u00f3n 4090940, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8815-5979","authenticated-orcid":false,"given":"Natalia","family":"Salas-Guzm\u00e1n","sequence":"additional","affiliation":[{"name":"Facultad de Educaci\u00f3n y Ciencias Sociales, Universidad Finis Terrae, Santiago 7501015, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9592-5203","authenticated-orcid":false,"given":"Remik","family":"Carabantes-Silva","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias Naturales, Matem\u00e1ticas y del Medio Ambiente, Universidad Tecnol\u00f3gica Metropolitana, Santiago 8330383, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9577-5180","authenticated-orcid":false,"given":"Marco","family":"Mellado","sequence":"additional","affiliation":[{"name":"Direcci\u00f3n de Investigaci\u00f3n, Universidad Bernardo O\u2019Higgins, Santiago 8370993, Chile"},{"name":"Laboratorio de Espectroscop\u00eda y Qu\u00edmica Aplicada, Grupo de Investigaci\u00f3n en Ciencias Biom\u00e9dicas Aplicadas, Universidad Central de Chile, Santiago 8330546, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4356386","DOI":"10.1155\/2020\/4356386","article-title":"Oxidative Stress-Mediated Blood-Brain Barrier (BBB) Disruption in Neurological Diseases","volume":"2020","author":"Song","year":"2020","journal-title":"Oxidative Med. 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