{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T05:47:24Z","timestamp":1785822444206,"version":"3.56.0"},"reference-count":202,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"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>\n                    Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss, affecting millions worldwide. Despite extensive research, effective treatments remain limited. Polysaccharides, abundant biological macromolecules derived from natural resources have emerged as promising therapeutic candidates due to their antioxidant, anti-inflammatory, and neuroprotective properties. This narrative review summarizes recent preclinical and limited clinical evidence on natural polysaccharides and their structure\u2013activity relationships (SAR) in AD. We focus on their ability to mitigate amyloid-beta (A\u03b2) aggregation, reduce tau hyperphosphorylation, modulate neuroinflammation, and enhance cognitive function. We emphasize novel mechanistic insights and highlight how fungal, algal, plant, and bacterial polysaccharides exert broad multi-targeted effects. Importantly, this is the first review to integrate SAR with challenges of bioavailability and blood\u2013brain barrier (BBB) penetration, offering a framework for optimizing therapeutic design. Novel insights into the molecular mechanisms, such as activation of Nrf2 and autophagy pathways, are discussed. We also underscore the translational value of polysaccharides, noting that strategies such as structural modification, nanoparticle conjugation, and pharmacokinetic profiling could accelerate their progression toward clinical application. However, most evidence is limited to\n                    <jats:italic>in vitro<\/jats:italic>\n                    and animal models, with critical challenges including poor bioavailability, limited blood-brain barrier penetration, and a lack of standardized clinical data. We conclude that natural polysaccharides are promising, low-toxicity therapeutic agents for AD management. But for complete validation of their therapeutic potential, standardized pharmacokinetic profiling, rigorous safety assessment, and well-designed clinical trials are urgently required.\n                  <\/jats:p>","DOI":"10.3389\/fnagi.2026.1877358","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T05:38:13Z","timestamp":1785821893000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Emerging neuroprotective mechanisms and therapeutic potential of natural polysaccharides in Alzheimer's disease"],"prefix":"10.3389","volume":"18","author":[{"given":"Noor","family":"Muhammad","sequence":"first","affiliation":[{"name":"College of Biology and Food Engineering, Anyang Institute of Technology","place":["Anyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Ai","sequence":"additional","affiliation":[{"name":"College of Biology and Food Engineering, Anyang Institute of Technology","place":["Anyang, China"]},{"name":"College of Life Sciences, Jinggangshan University","place":["Ji'an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Limin","family":"Yang","sequence":"additional","affiliation":[{"name":"Biomedical Sciences, Radiation Therapy Department, Anyang District Hospital","place":["Puyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuelong","family":"Cui","sequence":"additional","affiliation":[{"name":"Biomedical Sciences, Radiation Therapy Department, Anyang District Hospital","place":["Puyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqiang","family":"Wang","sequence":"additional","affiliation":[{"name":"Biomedical Sciences, Radiation Therapy Department, Anyang District Hospital","place":["Puyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoting","family":"Weng","sequence":"additional","affiliation":[{"name":"College of Biology and Food Engineering, Anyang Institute of Technology","place":["Anyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Biology and Food Engineering, Anyang Institute of Technology","place":["Anyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohib Ullah","family":"Kakar","sequence":"additional","affiliation":[{"name":"Faculty of Marine Sciences, Lasbela University of Agriculture Water and Marine Sciences (LUAWMS), Uthal","place":["Balochistan, Pakistan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suliman","family":"Khan","sequence":"additional","affiliation":[{"name":"Faculty of Veterinary and Animal Sciences, Lasbela University of Agriculture, Water and Marine Science, Uthal","place":["Baluchistan, Pakistan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sajjad","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Faculty of Veterinary and Animal Sciences, Lasbela University of Agriculture, Water and Marine Science, Uthal","place":["Baluchistan, Pakistan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imran","family":"Iqbal","sequence":"additional","affiliation":[{"name":"Department of Pathology, NYU Grossman School of Medicine, New York University Langone Health, New York","place":["NY, United States"]},{"name":"Department of Surgery - Otolaryngology, School of Medicine, Yale University, New Haven","place":["CT, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"27515","DOI":"10.1038\/s41598-024-78036-8","article-title":"Protective effects of Marinobacter nauticus strain GH3 exopolysaccharide on the Oreochromis niloticus model for Alzheimer's disease","volume":"14","author":"Abdel-Razik","year":"2024","journal-title":"Sci. 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