{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T12:08:39Z","timestamp":1785326919589,"version":"3.55.0"},"posted":{"date-parts":[[2026,7,27]]},"group-title":"Epidemiology","reference-count":25,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"funder":[{"name":"NIH NIA","award":["R00AG073454"],"award-info":[{"award-number":["R00AG073454"]}]},{"name":"NIH NIA","award":["R00AG075317"],"award-info":[{"award-number":["R00AG075317"]}]},{"name":"NIH NIA","award":["P01AG082653"],"award-info":[{"award-number":["P01AG082653"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Surrogate endpoints, or measures used in place of the true outcome of interest, have relevance across multiple disease areas. The Prentice Criteria, proposed in 1989, assess surrogacy by evaluating how the treatment\u2019s effect on the true outcome operates through the potential surrogate. Using the A4 Study of solanezumab, we evaluate multiple formulations of the Prentice Criteria using causal mediation. We estimated direct and indirect effects of solanezumab on cognitive decline through cerebral amyloid across different, but reasonable, measures of exposure, mediator, outcome, and covariate adjustment. Unsurprisingly given that solanezumab did not show benefit, estimated indirect effects were close to zero. These results provide little evidence of meaningful mediation for memory and global cognition, but precision varied substantially. Confidence interval widths varied by up to a factor of 17 across specifications. Causal mediation analysis of individual-level randomized trial data may contribute to quantitative surrogate endpoint evaluation, but our findings indicate this is only the case when analytic choices are biologically justified, prespecified, and interpreted with attention to uncertainty.<\/jats:p>","DOI":"10.64898\/2026.07.23.26358810","type":"posted-content","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T17:55:18Z","timestamp":1785174918000},"source":"Crossref","is-referenced-by-count":0,"title":["Surrogate Endpoint Evaluation with Causal Mediation: Lessons from the A4 Trial"],"prefix":"10.64898","author":[{"given":"Evan J.","family":"Hoefen","sequence":"first","affiliation":[{"name":"Department of Epidemiology, Brown University School of Public Health, Providence, Rhode Island, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Flanders","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Brown University School of Public Health, Providence, Rhode Island, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason R.","family":"Gantenberg","sequence":"additional","affiliation":[{"name":"Department of Health Services, Policy and Practice, Brown University School of Public Health, Providence, Rhode Island, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleanor","family":"Hayes-Larson","sequence":"additional","affiliation":[{"name":"Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul K.","family":"Crane","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Washington, Seattle, Washington, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seo-Eun","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Washington, Seattle, Washington, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily H.","family":"Trittschuh","sequence":"additional","affiliation":[{"name":"GRECC, VA Puget Sound Health Care System, Seattle, Washington, United States"},{"name":"Department of Psychiatry, University of Washington, Seattle, Washington, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah F.","family":"Ackley","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Brown University School of Public Health, Providence, Rhode Island, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026072904450686000_2026.07.23.26358810v1.1","doi-asserted-by":"crossref","first-page":"e110201","DOI":"10.1002\/alz70862_110201","article-title":"Reanalysis of the A4 Study to Formally Evaluate Amyloid Removal as a Surrogate for Cognitive Decline","volume":"21","year":"2025","journal-title":"Alzheimer\u2019s & Dementia"},{"issue":"1","key":"2026072904450686000_2026.07.23.26358810v1.2","first-page":"e70205","article-title":"Evaluation of amyloid change as a surrogate for cognitive decline: demonstration in individual-level data from the A4 study of solanezumab","volume":"12","year":"2026","journal-title":"Alzheimer\u2019s & Dementia: Translational Research & Clinical Interventions"},{"issue":"5","key":"2026072904450686000_2026.07.23.26358810v1.3","doi-asserted-by":"crossref","first-page":"glag068","DOI":"10.1093\/gerona\/glag068","article-title":"Substituting blood-based biomarkers for imaging measures in Alzheimer\u2019s disease studies: implications for sample size and bias","volume":"81","year":"2026","journal-title":"The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences"},{"key":"2026072904450686000_2026.07.23.26358810v1.4","doi-asserted-by":"publisher","DOI":"10.1002\/sim.1780"},{"key":"2026072904450686000_2026.07.23.26358810v1.5","doi-asserted-by":"publisher","DOI":"10.1257\/aer.20131176"},{"key":"2026072904450686000_2026.07.23.26358810v1.6","doi-asserted-by":"crossref","unstructured":"Burzykowski, Tomasz , Geert Molenberghs , and Marc Buyse (2005). The evaluation of surrogate endpoints. Springer Science & Business Media.","DOI":"10.1007\/b138566"},{"key":"2026072904450686000_2026.07.23.26358810v1.7","doi-asserted-by":"publisher","DOI":"10.1177\/009286150003400213"},{"key":"2026072904450686000_2026.07.23.26358810v1.8","doi-asserted-by":"crossref","unstructured":"Ciani, Oriana et al. (2023). \u201cA framework for the definition and interpretation of the use of surrogate endpoints in interventional trials\u201d. In: EClinicalMedicine 65.","DOI":"10.1016\/j.eclinm.2023.102283"},{"key":"2026072904450686000_2026.07.23.26358810v1.9","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199103213241201"},{"key":"2026072904450686000_2026.07.23.26358810v1.10","doi-asserted-by":"publisher","DOI":"10.3945\/ajcn.117.152546"},{"key":"2026072904450686000_2026.07.23.26358810v1.11","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-125-7-199610010-00011"},{"key":"2026072904450686000_2026.07.23.26358810v1.12","doi-asserted-by":"publisher","DOI":"10.1002\/sim.5403"},{"key":"2026072904450686000_2026.07.23.26358810v1.13","doi-asserted-by":"publisher","DOI":"10.1037\/neu0000833"},{"issue":"3","key":"2026072904450686000_2026.07.23.26358810v1.14","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1093\/aje\/kwad197","article-title":"Considerations for use of blood-based biomarkers in epidemiologic dementia research","volume":"193","year":"2024","journal-title":"American journal of epidemiology"},{"key":"2026072904450686000_2026.07.23.26358810v1.15","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdv333"},{"key":"2026072904450686000_2026.07.23.26358810v1.16","doi-asserted-by":"publisher","DOI":"10.1007\/s40266-022-00949-8"},{"key":"2026072904450686000_2026.07.23.26358810v1.17","doi-asserted-by":"publisher","DOI":"10.1037\/neu0000835"},{"key":"2026072904450686000_2026.07.23.26358810v1.18","doi-asserted-by":"crossref","unstructured":"Pease, Alison M et al. (2017). \u201cPostapproval studies of drugs initially approved by the FDA on the basis of limited evidence: systematic review\u201d. In: bmj 357.","DOI":"10.1136\/bmj.j1680"},{"key":"2026072904450686000_2026.07.23.26358810v1.19","doi-asserted-by":"publisher","DOI":"10.1002\/sim.4780080407"},{"issue":"1","key":"2026072904450686000_2026.07.23.26358810v1.20","doi-asserted-by":"crossref","first-page":"e250095","DOI":"10.57264\/cer-2025-0095","article-title":"Evaluating amyloid-beta as a surrogate endpoint in trials of anti-amyloid-beta drugs in Alzheimer\u2019s disease: a Bayesian meta-analysis","volume":"15","year":"2026","journal-title":"Journal of Comparative Effectiveness Research"},{"issue":"6","key":"2026072904450686000_2026.07.23.26358810v1.21","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1080\/10543406.2014.971174","article-title":"Statistical validation of surrogate endpoints: another look at the Prentice Criterion and Other Criteria","volume":"25","year":"2015","journal-title":"Journal of Biopharmaceutical Statistics"},{"key":"2026072904450686000_2026.07.23.26358810v1.22","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2305032"},{"key":"2026072904450686000_2026.07.23.26358810v1.23","doi-asserted-by":"publisher","DOI":"10.18637\/JSS.V059.I09"},{"key":"2026072904450686000_2026.07.23.26358810v1.24","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyw277"},{"key":"2026072904450686000_2026.07.23.26358810v1.25","doi-asserted-by":"publisher","DOI":"10.1097\/EDE.0b013e318258f5e4"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.07.23.26358810","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T11:45:16Z","timestamp":1785325516000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.07.23.26358810"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,27]]},"references-count":25,"URL":"https:\/\/doi.org\/10.64898\/2026.07.23.26358810","relation":{},"subject":[],"published":{"date-parts":[[2026,7,27]]},"subtype":"preprint"}}