{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T03:30:01Z","timestamp":1793244601635,"version":"4.5.0"},"reference-count":189,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","license":[{"start":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T00:00:00Z","timestamp":1736726400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:p>\n                    Amyloid-beta clearance plays a key role in the pathogenesis of Alzheimer\u2019s disease. However, the variation in functional proteins involved in amyloid-beta clearance and their correlation with amyloid-beta levels remain unclear. In this study, we conducted meta-analyses and a systematic review using studies from the PubMed, Embase, Web of Science, and Cochrane Library databases, including journal articles published from inception to June 30, 2023. The inclusion criteria included studies comparing the levels of functional proteins associated with amyloid-beta clearance in the blood, cerebrospinal fluid, and brain of healthy controls, patients with mild cognitive impairment, and patients with Alzheimer\u2019s disease. Additionally, we analyzed the correlation between these functional proteins and amyloid-beta levels in patients with Alzheimer\u2019s disease. The methodological quality of the studies was assessed via the Newcastle\u2012Ottawa Scale. Owing to heterogeneity, we utilized either a fixed-effect or random-effect model to assess the 95% confidence interval (CI) of the standard mean difference (SMD) among healthy controls, patients with mild cognitive impairment, and patients with Alzheimer\u2019s disease. The findings revealed significant alterations in the levels of insulin-degrading enzymes, neprilysin, matrix metalloproteinase-9, cathepsin D, receptor for advanced glycation end products, and P-glycoprotein in the brains of patients with Alzheimer\u2019s disease, patients with mild cognitive impairment, and healthy controls. In cerebrospinal fluid, the levels of triggering receptor expressed on myeloid cells 2 and ubiquitin C-terminal hydrolase L1 are altered, whereas the levels of TREM2, CD40, CD40L, CD14, CD22, cathepsin D, cystatin C, and \u03b12 M in peripheral blood differ. Notably, TREM2 and cathepsin D showed changes in both brain (SMD = 0.31, 95% CI: 0.16\u20130.47,\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    &lt; 0.001,\n                    <jats:italic toggle=\"yes\">I<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    = 78.4%; SMD = 1.24, 95% CI: 0.01\u20132.48,\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    = 0.048,\n                    <jats:italic toggle=\"yes\">I<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    = 90.1%) and peripheral blood (SMD = 1.01, 95% CI: 0.35\u20131.66,\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    = 0.003,\n                    <jats:italic toggle=\"yes\">I<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    = 96.5%; SMD = 7.55, 95% CI: 3.92\u201311.18,\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    &lt; 0.001,\n                    <jats:italic toggle=\"yes\">I<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    = 98.2%) samples. Furthermore, correlations were observed between amyloid-beta levels and the levels of TREM2 (\n                    <jats:italic toggle=\"yes\">r<\/jats:italic>\n                    = 0.16, 95% CI: 0.04\u20130.28,\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    = 0.009,\n                    <jats:italic toggle=\"yes\">I<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    = 74.7%), neprilysin (\n                    <jats:italic toggle=\"yes\">r<\/jats:italic>\n                    = \u20130.47, 95% CI: \u20130.80\u20130.14,\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    = 0.005,\n                    <jats:italic toggle=\"yes\">I<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    = 76.1%), and P-glycoprotein (\n                    <jats:italic toggle=\"yes\">r<\/jats:italic>\n                    = \u20130.31, 95% CI: \u20130.51\u20130.11,\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    = 0.002,\n                    <jats:italic toggle=\"yes\">I<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    = 0.0%) in patients with Alzheimer\u2019s disease. These findings suggest that triggering receptor expressed on myeloid cells 2 and cathepsin D could serve as potential diagnostic biomarkers for Alzheimer\u2019s disease, whereas triggering receptor expressed on myeloid cells 2, neprilysin, and P-glycoprotein may represent potential therapeutic targets.\n                  <\/jats:p>","DOI":"10.4103\/nrr.nrr-d-24-00865","type":"journal-article","created":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T05:00:17Z","timestamp":1737090017000},"page":"3574-3590","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":14,"title":["Systematic review of amyloid-beta clearance proteins from the brain to the periphery: implications for Alzheimer\u2019s disease diagnosis and therapeutic targets"],"prefix":"10.4103","volume":"20","author":[{"given":"Letian","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyue","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, China Medical University, Shenyang, Liaoning Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ze","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, China Medical University, Shenyang, Liaoning Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, China Medical University, Shenyang, Liaoning Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6206-8404","authenticated-orcid":false,"given":"Jiahe","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Family Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3133-759X","authenticated-orcid":false,"given":"Ke","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, China Medical University, Shenyang, Liaoning Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2025,1,13]]},"reference":[{"key":"R1-20260422","doi-asserted-by":"crossref","first-page":"302","DOI":"10.2174\/1567205019666220511140955","article-title":"Link of BIN1, CLU, and IDE 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