{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T14:20:20Z","timestamp":1790864420175,"version":"4.1.0"},"reference-count":47,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"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":[[2025,9]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Anti-amyloid-\u03b2 (A\u03b2) immunotherapies are emerging as treatments for Alzheimer's disease (AD).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This review examines the structure-activity relationships of anti-A\u03b2 therapeutics tested in phase 3 trials.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed crystallographic data and molecular models to elucidate the A\u03b2 binding mechanisms of donanemab, lecanemab, aducanumab, bapineuzumab, gantenerumab, solanezumab, and crenezumab.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Lecanemab recognizes minimally degraded A\u03b2 missing 1\u20132 residues, avoiding common A\u03b2 in circulation and further degraded material sequestered in plaques. Bapineuzumab buries the N-terminus of A\u03b2 requiring Asp1 and is reactive with benign, common A\u03b2. Donanemab buries the truncated N-Glu3 terminus with strong contacts engaging the cyclized pyro-Glu3 modification. Gantenerumab shows lecanemab-like properties but also binds common A\u03b2. Aducanumab likely needs mAb-mAb cooperation to scavenge a spectrum of A\u03b2 oligomers explaining higher doses. Solanezumab and crenezumab target a pre-amyloid epitope resulting in off-target engagement, including monomers and likely excluding A\u03b2-ApoE complexes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Preventing primary A\u03b2 nucleation failed due to limitations imposed by the blood-brain barrier, intracellular aggregation routes, and the natural abundance of A\u03b2. Anti-A\u03b2 monoclonal antibody therapies in clinical use capture A\u03b2 at various stages of decay where post translational modifications have been used effectively as proxies for time spent in vivo. By targeting a relatively labile epitope of aging A\u03b2, lecanemab selects more biologically active species of A\u03b2 avoiding both benign monomers and old fortified species. This focal point may account for the significant cognitive effects of lecanemab. The structure of aducanumab suggests a broadly neutralizing role has evolved for natural immunity to AD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/13872877251361049","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T07:00:38Z","timestamp":1753858838000},"page":"393-408","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":12,"title":["The structural foundations of anti-amyloid-\u03b2 immunotherapies: Unravelling antibody-antigen interactions in Alzheimer's disease treatment"],"prefix":"10.1177","volume":"107","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2412-3171","authenticated-orcid":false,"given":"Luke A","family":"Miles","sequence":"first","affiliation":[{"name":"The Florey Institute, The University of Melbourne, Parkville, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3072-7940","authenticated-orcid":false,"given":"Colin L","family":"Masters","sequence":"additional","affiliation":[{"name":"The Florey Institute, The University of Melbourne, Parkville, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2025,9]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41594-020-0505-6"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2017.06.2266"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-021-01409-2"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.trci.2018.10.001"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.82.12.4245"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2971"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.14283\/jpad.2022.30"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-24501-0"},{"key":"e_1_3_4_10_2","article-title":"Aducanumab anti-amyloid immunotherapy induces sustained microglial and immune alterations","volume":"221","author":"Cadiz MP","unstructured":"Cadiz MP, Gibson KA, Todd KT, et al. 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