{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T09:45:24Z","timestamp":1782812724509,"version":"3.54.5"},"reference-count":53,"publisher":"SAGE Publications","issue":"1","license":[{"start":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T00:00:00Z","timestamp":1778457600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Alzheimer\u2019s Disease"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Alzheimer's disease (AD) is the leading cause of dementia worldwide, yet no disease-modifying therapy exists. Systemic inflammation has been proposed as a causal factor, supported by observational studies reporting elevated plasma interleukins in AD, though such studies cannot establish causality. Recent evidence instead highlights local neuroinflammation and microglial dysfunction as key mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This study aimed to determine whether circulating interleukins and their receptors causally influence AD risk.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a two-sample Mendelian randomization (MR) analysis using genetic instruments to test whether genetically predicted levels of eleven circulating interleukins and receptor subunits influence AD risk. Three AD genome-wide association study (GWAS) datasets were analyzed: a primary cohort (n\u2009=\u2009487,511) and two replication cohorts (n\u2009=\u200963,926; n\u2009=\u200955,134). Primary analyses used inverse-variance weighted models, with MR-Egger and weighted median as sensitivity methods. Additional analyses assessed heterogeneity, pleiotropy, directionality, and outlier influence. The study was preregistered and followed STROBE-MR guidelines.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>No consistent evidence supported a causal effect of any circulating interleukin or receptor on AD risk. Nominal associations for IL-1 receptor antagonist (MR-Egger, p\u2009=\u20090.0054) and IL-6 receptor subunit alpha (weighted median, p\u2009=\u20090.014) did not survive false discovery rate correction and failed replication.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings do not support a causal role for circulating interleukins in AD risk. However, TNF-alpha and other non-interleukin mediators were not assessed, and stage-specific effects cannot be excluded due to limitations of summary-level GWAS data. Future studies including broader cytokine panels, disease-stage stratification, and individual-level analyses are warranted.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/13872877261449516","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T05:10:27Z","timestamp":1778562627000},"page":"210-223","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Systemic interleukin signaling and Alzheimer's disease risk: A two-sample cross-replication Mendelian randomization study"],"prefix":"10.1177","volume":"112","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-3591-3684","authenticated-orcid":false,"given":"Hafiz M.","family":"Ahmed","sequence":"first","affiliation":[{"name":"Faisalabad Medical University (FMU)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Ali Siddique","sequence":"additional","affiliation":[{"name":"Faisalabad Medical University (FMU)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Shaheer Ul Islam","sequence":"additional","affiliation":[{"name":"Faisalabad Medical University (FMU)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdul Rafay","family":"Khan Lodhi","sequence":"additional","affiliation":[{"name":"Faisalabad Medical University (FMU)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5639-5682","authenticated-orcid":false,"given":"Muhammad","family":"Owais","sequence":"additional","affiliation":[{"name":"Faisalabad Medical University (FMU)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ubaid Ur","family":"Rehman","sequence":"additional","affiliation":[{"name":"Faisalabad Medical University (FMU)"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,5,11]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)32205-4"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.09.001"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1117172"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11011-025-01538-5"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/imcb.12301"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(15)70016-5"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2990.2012.01307.x"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-023-00627-2"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.796867"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1177\/1533317506289260"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines10061240"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.9b00333"},{"key":"e_1_3_3_14_2","article-title":"Th17 cell-mediated neuroinflammation is involved in neurodegeneration of A\u03b21-42-induced Alzheimer\u2019s disease model rats","volume":"8","author":"Zhang J","year":"2013","unstructured":"Zhang J, Ke K-F, Liu Z, et al. 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