{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T14:35:14Z","timestamp":1793284514688,"version":"4.5.0"},"reference-count":165,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) represents one of the most prevalent neurodegenerative disorders without approved disease-modifying therapies. A major contributing factor is that, for decades, drug development has focused almost exclusively on repairing or removing lesions within the brain itself. Yet a growing body of work now points to AD as a systemic disorder, rooted in a breakdown of whole-body A\u03b2 homeostasis. Nevertheless cerebral A\u03b2 transport and peripheral A\u03b2 clearance are commonly investigated as independent processes, and the coordinated interplay\u2026 remains insufficiently characterized. This review bridges the current research gap by systematically elaborating the full trafficking cascade of brain-derived A\u03b2 from intracerebral drainage to peripheral elimination. Four major intracranial clearance pathways are comprehensively summarized, including the blood-brain barrier, blood-cerebrospinal fluid barrier, arachnoid granulation venous outflow, and meningeal lymphatic\/glymphatic system. The peripheral clearance processes of circulating A\u03b2 in the blood, liver, kidney, and gastrointestinal tract are further illustrated. A broad spectrum of emerging therapeutic strategies targeting A\u03b2 transport and clearance is also reviewed, including specific pathway modulators, microglia regulators, A\u03b2 aggregation inhibitors, natural multi-target compounds, ultrasound-mediated blood-brain barrier opening, and exosome-based intervention approaches. When we compare the relative contributions of central versus peripheral clearance, Comparative analysis of central and peripheral A\u03b2 clearance indicates that the liver appears to dominate the peripheral elimination of A\u03b2, yet the real driver of cerebral A\u03b2 deposition is not the failure of any single route, but rather the loss of synergy among multiple pathways. This mechanistic framework explains why purely brain-centric therapeutics are unlikely to correct a systemic A\u03b2 imbalance. Instead, future translational efforts should give higher priority to combination regimens that simultaneously facilitate intracerebral drainage and bolster peripheral organ clearance. This review further discusses current hurdles and emerging opportunities in systemic AD drug discovery, with the aim of offering a unified conceptual framework-one that providing a unified conceptual framework for understanding AD pathogenesis and facilitating the exploration of novel therapeutic paradigms.<\/jats:p>","DOI":"10.3389\/fragi.2026.1921485","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:47:24Z","timestamp":1790660844000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["New insight into Alzheimer\u2019s disease: small molecule-A\u03b2 in the brain transport and peripheral organ clearance"],"prefix":"10.3389","volume":"7","author":[{"given":"Tianci","family":"Ma","sequence":"first","affiliation":[{"name":"Clinical Medical College, Hainan Medical University","place":["Haikou, Hainan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongyi","family":"Li","sequence":"additional","affiliation":[{"name":"Clinical Medical College, Hainan Medical University","place":["Haikou, Hainan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Ding","sequence":"additional","affiliation":[{"name":"Clinical Medical College, Hainan Medical University","place":["Haikou, Hainan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shijie","family":"Liu","sequence":"additional","affiliation":[{"name":"Clinical Medical College, Hainan Medical University","place":["Haikou, Hainan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanhao","family":"Gao","sequence":"additional","affiliation":[{"name":"Clinical Medical College, Hainan Medical University","place":["Haikou, Hainan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Li","sequence":"additional","affiliation":[{"name":"Clinical Medical College, Hainan Medical University","place":["Haikou, Hainan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqian","family":"Tong","sequence":"additional","affiliation":[{"name":"Proactive Health and Aging Medicine of Clinical Research and Translational Center, Beijing Geriatric Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Lv","sequence":"additional","affiliation":[{"name":"Neurology Department, Hainan General Hospital, Affiliated Hainan Hospital of Hainan Medical University","place":["Haikou, Hainan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.nbd.2009.07.030","article-title":"Structure and function of the blood-brain barrier","volume":"37","author":"Abbott","year":"2010","journal-title":"Neurobiol. 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