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Although multiple A\u03b2 clearance pathways have been reported, the fibrinolytic system remains the only enzymatically validated degradation route. Notably, a striking paradox is emerging: fibrinolytic agents exhibit both neuroprotective and AD-promoting effects in clinical observations. This duality necessitates urgent investigation into the fibrinolytic system\u2019s double-edged sword mechanism in AD pathogenesis. This review provides the first comprehensive analysis of the fibrinolytic system\u2019s dichotomous regulatory functions in AD progression, summarizes current advancements in the pathogenesis and therapeutic interventions, and proposes novel research directions. By resolving this molecular paradox, we aim to accelerate transformative breakthroughs in AD prevention and precision medicine strategies. Fibrinolytic System: Neuroprotection vs. Pathogenesis. The fibrinolytic system alleviates AD by directly degrading A\u03b2 and indirectly improving the microenvironment of the central nervous system and cerebrovascular system. Meanwhile, this system also accelerates AD by promoting neuroinflammation and tau hyperphosphorylation.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s10571-026-01699-6","type":"journal-article","created":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T03:54:41Z","timestamp":1772164481000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Double-Edged Sword Effect of the Fibrinolytic System in Alzheimer\u2019s Disease"],"prefix":"10.1007","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-1917-1069","authenticated-orcid":false,"given":"Mingqing","family":"Tang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8757-8196","authenticated-orcid":false,"given":"Meimei","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1333-8046","authenticated-orcid":false,"given":"Xianying","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9196-3308","authenticated-orcid":false,"given":"Chunzhan","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lichao","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,27]]},"reference":[{"issue":"2","key":"1699_CR1","doi-asserted-by":"publisher","first-page":"447","DOI":"10.3233\/jad-180241","volume":"64","author":"H Akhter","year":"2018","unstructured":"Akhter H, Huang WT, van Groen T, Kuo HC, Miyata T, Liu RM (2018) A small molecule inhibitor of plasminogen activator inhibitor-1 reduces brain amyloid-\u03b2 load and improves memory in an animal model of Alzheimer\u2019s disease. 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