{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T18:48:48Z","timestamp":1782240528007,"version":"3.54.5"},"posted":{"date-parts":[[2026,6,21]]},"group-title":"Neuroscience","reference-count":33,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,21]],"date-time":"2026-06-21T00:00:00Z","timestamp":1782000000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"National Institutes of Health, National Institute on Aging","award":["U54 AG05434503"],"award-info":[{"award-number":["U54 AG05434503"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>INTRODUCTION<\/jats:title>\n                  <jats:p>Improving the predictive validity of preclinical studies for Alzheimer\u2019s disease (AD) requires rigorous evaluation of therapeutic efficacy, safety, and sex-specific responses in translationally relevant models. As amyloid-targeting monoclonal antibodies continue to advance clinically, there is an urgent need to define the molecular milieu that persists after amyloid is reduced and disease progression continues. Leveraging the NIA-funded MODEL-AD Preclinical Testing Core, we investigated the biochemical, functional, and multi-omic signatures associated with chronic administration of murine chimeric aducanumab (chAdu) in 5XFAD mice, including the contribution of IgG-mediated effects.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>METHODS<\/jats:title>\n                  <jats:p>Male and female 5XFAD mice were treated weekly with chAdu beginning at 8 months of age and compared to age-and sex-matched murine IgG2a\u03ba isotype (IgG) and saline controls. Plasma and brain pharmacokinetics, amyloid-beta (A\u03b2), behavioral assessments, and treatment-emergent anti-drug antibodies (ADAs) were quantified. Post-treatment transcriptomic and proteomic analyses were performed to assess molecular pathways associated with chAdu and IgG exposure following 17-week treatment.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>chAdu produced sex-dependent changes in A\u03b2, including increased plasma A\u03b242:40 and reductions in brain A\u03b2 which were associated with mild behavioral impairments in the absence of improvements in cognitive function. IgG control treatment produced similar reductions, indicating biologically active IgG-mediated processes independent of A\u03b2-targeted specificity. Treatment-emergent ADAs occurred in 10% of chAdu-treated mice and were associated with reduced drug exposure and efficacy. Multi-omics analyses confirmed sex-dependent and IgG-mediated effects at both the transcriptomic and proteome level revealing disease-associated genes and proteins not altered despite reductions in amyloid with treatment.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>DISCUSSION<\/jats:title>\n                  <jats:p>These findings demonstrate sex-dependent PK and pharmacodynamic responses to chAdu, identify biologically meaningful IgG-driven effects, and reveal molecular signatures that persist after amyloid reduction. This work provides biological insights into pathways that may remain insufficiently addressed following amyloid lowering; revealing novel targets for future drug discovery to prevent and treat disease.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.16.731973","type":"posted-content","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T04:05:14Z","timestamp":1782101114000},"source":"Crossref","is-referenced-by-count":0,"title":["Molecular mechanisms underlying amyloid lowering by aducanumab: differential and comparative effects of sex and IgG reveal the post-treatment disease brain"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5064-6905","authenticated-orcid":false,"given":"KA","family":"Haynes","sequence":"first","affiliation":[{"name":"Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9567-2851","authenticated-orcid":false,"given":"RS","family":"Pandey","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0049-0073","authenticated-orcid":false,"given":"EH","family":"Doud","sequence":"additional","affiliation":[{"name":"Indiana University School of Medicine, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"ZA","family":"Cope","sequence":"additional","affiliation":[{"name":"Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"GJ","family":"Little","sequence":"additional","affiliation":[{"name":"Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S-P","family":"Williams","sequence":"additional","affiliation":[{"name":"Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"U","family":"Nepali","sequence":"additional","affiliation":[{"name":"Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6554-0695","authenticated-orcid":false,"given":"SK","family":"Quinney","sequence":"additional","affiliation":[{"name":"Indiana University School of Medicine, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Nagar","sequence":"additional","affiliation":[{"name":"Indiana University School of Medicine, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"NB","family":"Charbe","sequence":"additional","affiliation":[{"name":"Indiana University School of Medicine, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L","family":"da Silva","sequence":"additional","affiliation":[{"name":"Indiana University School of Medicine, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2192-1699","authenticated-orcid":false,"given":"JL","family":"Dage","sequence":"additional","affiliation":[{"name":"Indiana University School of Medicine, Indianapolis, Indiana, USA"},{"name":"Stark Neuroscience Research Institute, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"DM","family":"Duong","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Emory University, Atlanta, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4507-624X","authenticated-orcid":false,"given":"NT","family":"Seyfried","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Emory University, Atlanta, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6612-6111","authenticated-orcid":false,"given":"M","family":"Sasner","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, Maine USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8507-2561","authenticated-orcid":false,"given":"BT","family":"Lamb","sequence":"additional","affiliation":[{"name":"Indiana University School of Medicine, Indianapolis, Indiana, USA"},{"name":"Stark Neuroscience Research Institute, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1210-8791","authenticated-orcid":false,"given":"AL","family":"Oblak","sequence":"additional","affiliation":[{"name":"Indiana University School of Medicine, Indianapolis, Indiana, USA"},{"name":"Stark Neuroscience Research Institute, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"PR","family":"Territo","sequence":"additional","affiliation":[{"name":"Indiana University School of Medicine, Indianapolis, Indiana, USA"},{"name":"Stark Neuroscience Research Institute, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"GW","family":"Carter","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA"},{"name":"The Jackson Laboratory, Bar Harbor, Maine USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1460-8127","authenticated-orcid":false,"given":"SJ","family":"Sukoff Rizzo","sequence":"additional","affiliation":[{"name":"Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026062311051934000_2026.06.16.731973v1.1","doi-asserted-by":"publisher","DOI":"10.1002\/trc2.12038"},{"key":"2026062311051934000_2026.06.16.731973v1.2","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-215699"},{"key":"2026062311051934000_2026.06.16.731973v1.3","doi-asserted-by":"publisher","DOI":"10.7705\/BIOMEDICA.6967"},{"key":"2026062311051934000_2026.06.16.731973v1.4","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-051022-043645"},{"key":"2026062311051934000_2026.06.16.731973v1.5","doi-asserted-by":"publisher","DOI":"10.14283\/jpad.2022.30"},{"key":"2026062311051934000_2026.06.16.731973v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/nature19323"},{"key":"2026062311051934000_2026.06.16.731973v1.7","doi-asserted-by":"publisher","DOI":"10.1080\/14737175.2024.2402058"},{"key":"2026062311051934000_2026.06.16.731973v1.8","doi-asserted-by":"publisher","DOI":"10.1002\/alz.70293"},{"key":"2026062311051934000_2026.06.16.731973v1.9","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines12112636"},{"key":"2026062311051934000_2026.06.16.731973v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(24)01883-X"},{"key":"2026062311051934000_2026.06.16.731973v1.11","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1004568"},{"key":"2026062311051934000_2026.06.16.731973v1.12","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-231198"},{"key":"2026062311051934000_2026.06.16.731973v1.13","doi-asserted-by":"publisher","DOI":"10.1002\/alz.14467"},{"key":"2026062311051934000_2026.06.16.731973v1.14","doi-asserted-by":"publisher","DOI":"10.1002\/TRC2.12110"},{"key":"2026062311051934000_2026.06.16.731973v1.15","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2021.713726"},{"key":"2026062311051934000_2026.06.16.731973v1.16","doi-asserted-by":"publisher","DOI":"10.1002\/trc2.12317"},{"key":"2026062311051934000_2026.06.16.731973v1.17","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000410"},{"key":"2026062311051934000_2026.06.16.731973v1.18","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2025.2537118"},{"key":"2026062311051934000_2026.06.16.731973v1.19","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M113.036095"},{"key":"2026062311051934000_2026.06.16.731973v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.jim.2016.02.008"},{"key":"2026062311051934000_2026.06.16.731973v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.trci.2016.06.002"},{"key":"2026062311051934000_2026.06.16.731973v1.22","doi-asserted-by":"publisher","DOI":"10.21769\/bioprotoc.1787"},{"key":"2026062311051934000_2026.06.16.731973v1.23","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12862"},{"key":"2026062311051934000_2026.06.16.731973v1.24","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2022.3392"},{"key":"2026062311051934000_2026.06.16.731973v1.25","doi-asserted-by":"publisher","DOI":"10.3233\/ADR-230025"},{"key":"2026062311051934000_2026.06.16.731973v1.26","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24065549"},{"key":"2026062311051934000_2026.06.16.731973v1.27","doi-asserted-by":"publisher","DOI":"10.1177\/1533317519899800"},{"key":"2026062311051934000_2026.06.16.731973v1.28","doi-asserted-by":"publisher","DOI":"10.1002\/alz.095657"},{"key":"2026062311051934000_2026.06.16.731973v1.29","doi-asserted-by":"publisher","DOI":"10.1177\/13872877251375985"},{"key":"2026062311051934000_2026.06.16.731973v1.30","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01484-7"},{"key":"2026062311051934000_2026.06.16.731973v1.31","doi-asserted-by":"publisher","DOI":"10.1002\/trc2.70149"},{"key":"2026062311051934000_2026.06.16.731973v1.32","doi-asserted-by":"publisher","DOI":"10.1002\/alz.71142"},{"key":"2026062311051934000_2026.06.16.731973v1.33","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-022-00547-7"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.06.16.731973","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T18:05:27Z","timestamp":1782237927000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.06.16.731973"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,21]]},"references-count":33,"URL":"https:\/\/doi.org\/10.64898\/2026.06.16.731973","relation":{},"subject":[],"published":{"date-parts":[[2026,6,21]]},"subtype":"preprint"}}