{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T20:40:49Z","timestamp":1768077649142,"version":"3.49.0"},"reference-count":19,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,11,3]],"date-time":"2022-11-03T00:00:00Z","timestamp":1667433600000},"content-version":"vor","delay-in-days":306,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alz &amp; Dem Diag Ass &amp; Dis Mo"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>While the Dominantly Inherited Alzheimer Network Trials Unit (DIAN\u2010TU) was ongoing, external data suggested higher doses were needed to achieve targeted effects; therefore, doses of gantenerumab were increased 5\u2010fold, and solanezumab was increased 4\u2010fold. We evaluated to what extent mid\u2010trial dose increases produced a dose\u2010dependent treatment effect.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Using generalized linear mixed effects (LME) models, we estimated the annual low\u2010 and high\u2010dose treatment effects in clinical, cognitive, and biomarker outcomes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Both gantenerumab and solanezumab demonstrated dose\u2010dependent treatment effects (significant for gantenerumab, non\u2010significant for solanezumab) in their respective target amyloid biomarkers (Pittsburgh compound B positron emission tomography standardized uptake value ratio and cerebrospinal fluid amyloid beta 42), with gantenerumab demonstrating additional treatment effects in some downstream biomarkers. No dose\u2010dependent treatment effects were observed in clinical or cognitive outcomes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Mid\u2010trial dose escalation can be implemented as a remedy for an insufficient initial dose and can be more cost effective and less burdensome to participants than starting a new trial with higher doses, especially in rare diseases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>We evaluated the dose\u2010dependent treatment effect of two different amyloid\u2010specific immunotherapies.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Dose\u2010dependent treatment effects were observed in some biomarkers.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>No dose\u2010dependent treatment effects were observed in clinical\/cognitive outcomes, potentially due to the fact that the modified study may not have been powered to detect such treatment effects in symptomatic subjects at a mild stage of disease exposed to high (or maximal) doses of medication for prolonged durations.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/dad2.12367","type":"journal-article","created":{"date-parts":[[2022,11,3]],"date-time":"2022-11-03T13:33:27Z","timestamp":1667482407000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Evaluation of dose\u2010dependent treatment effects after mid\u2010trial dose escalation in biomarker, clinical, and cognitive outcomes for gantenerumab or solanezumab in dominantly inherited Alzheimer's disease"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6808-8737","authenticated-orcid":false,"given":"Guoqiao","family":"Wang","sequence":"first","affiliation":[{"name":"Washington University St Louis School of Medicine  St. Louis Missouri 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