{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T13:07:49Z","timestamp":1789477669429,"version":"build-2803163510"},"reference-count":91,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:p>Alzheimer\u2019s disease remains a major neurodegenerative disorder for which effective disease-modifying treatments are limited. Adeno-associated virus-mediated gene therapy provides a strategy for sustained modulation of disease-related pathways in the central nervous system. Recent studies have explored this approach for regulating amyloid-\u03b2 (A\u03b2) metabolism, tau pathology, neuroinflammation, genetic risk factors and neurotrophic support. This review summarizes the biological basis for adeno-associated virus delivery in the central nervous system and discusses major therapeutic strategies for Alzheimer\u2019s disease, including approaches targeting A\u03b2 production and clearance, tau expression and degradation, immune microenvironment remodeling, apolipoprotein E modulation and synaptic protection. We further examine key translational barriers, including blood-brain barrier restriction, cross-species differences, immune responses, dose-related toxicity, manufacturing constraints and limited clinical evidence. Finally, we propose that future development should move beyond delivery efficiency alone toward biologically informed vector design, target selection, disease-stage matching and biomarker-guided clinical evaluation.<\/jats:p>","DOI":"10.3389\/fnagi.2026.1901875","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T12:50:27Z","timestamp":1789476627000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["AAV-mediated gene therapy for Alzheimer\u2019s disease: neuroprotective mechanisms and translational challenges"],"prefix":"10.3389","volume":"18","author":[{"given":"Zehua","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Neurology, Gansu Provincial Central Hospital","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Li","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Neurology, Gansu Provincial Central Hospital","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1016\/j.ymthe.2017.10.017","article-title":"Mapping the structural determinants required for aavrh.10 transport across the blood-brain barrier.","volume":"26","author":"Albright","year":"2018","journal-title":"Mol. 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