{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T18:40:10Z","timestamp":1792608010366,"version":"4.5.0"},"reference-count":47,"publisher":"American Society for Clinical Investigation","issue":"20","license":[{"start":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T00:00:00Z","timestamp":1792627200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sponsored by Shanghai Sailing Program","award":["24YF2725800"],"award-info":[{"award-number":["24YF2725800"]}]},{"name":"the China Postdoctoral Science Foundation","award":["2025M772189"],"award-info":[{"award-number":["2025M772189"]}]},{"name":"the National Natural Science Foundation of China","award":["82372073"],"award-info":[{"award-number":["82372073"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,22]]},"abstract":"<jats:p>\n                    Purine metabolism dysregulation has been implicated in Alzheimer\u2019s disease (AD), but its temporal dynamics and mechanistic links to core pathologies remain unclear. This translational study integrated a longitudinal preclinical AD mouse model and clinical cohort investigations to define the role of purine metabolism in AD progression. In APPswe\/PSEN1dE9 (APP\/PS1) mice, serum-untargeted metabolomics identified purine metabolism as the most notably altered pathway, with metabolite levels (e.g., adenine, adenosine) shifting dynamically across disease stages alongside increasing amyloid-\u03b2 (A\u03b2) burden. In the pathology-defined clinical cohort, targeted analysis revealed that serum uric acid and allantoin were specifically depleted in the A\u03b2\n                    <jats:sup>+<\/jats:sup>\n                    cognitively impaired (CI) group and correlated strongly with higher brain A\u03b2 load, increased neuroinflammation, and poorer cognitive scores. Formal mediation analysis elucidated a plausible mechanistic cascade: the association of uric acid\/allantoin with cognitive impairment was primarily mediated by A\u03b2 pathology. Two-year longitudinal data further suggest that changes in specific purine metabolites might predict the rate of cognitive decline. Allantoin supplementation reduced A\u03b2 pathology through promoting microglial phagocytosis of A\u03b2 in APP\/PS1 mice. Our findings identified purine metabolism as a key hub connecting A\u03b2 pathology, neuroinflammation, and clinical progression in AD.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.205511","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T18:00:34Z","timestamp":1792605634000},"source":"Crossref","is-referenced-by-count":0,"title":["Purine metabolism disruption links pathology and cognitive decline in Alzheimer\u2019s disease"],"prefix":"10.1172","volume":"11","author":[{"given":"Xiaohang","family":"Qian","sequence":"first","affiliation":[{"name":"Department of Geriatrics, Medical Center on Aging, Ruijin Hospital,"},{"name":"Department of Neurology and Institute of Neurology, Ruijin Hospital, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongxuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, Medical Center on Aging, Ruijin Hospital,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyue","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, Medical Center on Aging, Ruijin Hospital,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, Medical Center on Aging, Ruijin Hospital,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yawen","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peijing","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, Medical Center on Aging, Ruijin Hospital,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huidong","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, Medical Center on Aging, Ruijin Hospital,"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,10,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2025.102990"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2021.101317"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-025-08186-8"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(25)01329-7"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02505-2"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-025-00912-2"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-025-00997-0"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1002\/alz.70528"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-025-00825-0"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2025.06.005"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnpbp.2025.111491"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2025.105826"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-025-03891-5"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1002\/ana.27227"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3390\/molecules30040839"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1111\/bpa.12592"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2014.08.004"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.602887"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1007\/s40520-020-01541-z"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2024.1511437"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-024-01965-4"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2021.625690"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpba.2014.10.009"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpba.2014.10.010"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0063644"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/nature05292"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1155\/2021\/5525710"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2022.943380"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2020.00160"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3390\/antiox12081569"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2022.113389"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3390\/ijms262411861"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(15)70016-5"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202510270"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.cccn.2003.11.020"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2025.1654152"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2020.02.012"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2013.11.033"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1080\/19490976.2023.2282790"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkp356"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-022-02599-4"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2024.03.031"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1007\/s00259-023-06446-3"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.14283\/jpad.2024.107"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2796.2004.01388.x"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2011.03.005"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1007\/s43657-022-00068-9"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/205511\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T18:00:38Z","timestamp":1792605638000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/205511"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,22]]},"references-count":47,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2026,9,15]]},"published-print":{"date-parts":[[2026,10,22]]}},"alternative-id":["10.1172\/jci.insight.205511"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.205511","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,22]]},"article-number":"e205511"}}