{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T04:44:43Z","timestamp":1779165883926,"version":"3.51.4"},"reference-count":37,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T00:00:00Z","timestamp":1771027200000},"content-version":"vor","delay-in-days":44,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000957","name":"Alzheimer's Association","doi-asserted-by":"publisher","award":["AARFD\u201024\u2010130878"],"award-info":[{"award-number":["AARFD\u201024\u2010130878"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R00AG073454"],"award-info":[{"award-number":["R00AG073454"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["P01AG082653"],"award-info":[{"award-number":["P01AG082653"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["K00AG06843"],"award-info":[{"award-number":["K00AG06843"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["F99AG083306"],"award-info":[{"award-number":["F99AG083306"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["K00AG083306"],"award-info":[{"award-number":["K00AG083306"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["A&amp;amp;D Transl Res &amp;amp; Clin Interv"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Differential amyloid change has served as a surrogate outcome in Alzheimer's disease trials, allowing accelerated approval of aducanumab and lecanemab. Individual\u2010level data from the A4 study support the demonstration of novel methods to evaluate amyloid's validity as a surrogate for cognitive decline.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In 812 participants, cognitive change was measured using the Clinical Dementia Rating Sum of Boxes (CDR\u2010SB) score. Instrumental\u2010variable analysis estimated the effect of amyloid change; mediation analysis quantified proportion of cognitive effects mediated by amyloid change.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Each 10\u2010Centiloid reduction in amyloid due to randomization to treatment was associated with a 0.026 higher CDR\u2010SB score (95% confidence interval [CI]: \u22120.013, 0.065). Amyloid reduction mediated 14.6% of solanezumab's effect on cognition (95% CI: \u2212122%, 208%).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Near\u2010zero effect estimates for amyloid change on cognitive decline in the A4 study suggest minimal impact of limited amyloid change reduction in populations with little disease progression. The broader question of validity of amyloid as a surrogate outcome cannot be conclusively answered in data from the A4 study due to study\u2010intrinsic limitations. Replication in anti\u2010amyloid trials with larger treatment effects will evaluate whether amyloid is an appropriate surrogate outcome.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>This study evaluated amyloid change's validity as a surrogate for cognitive and functional decline in AD drug trials.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Newly available individual\u2010level trial data from the A4 study enabled the application of epidemiologic and econometric methods to assess amyloid's impact on cognition.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>IV and causal mediation analyses estimated the effect of amyloid change on cognitive outcomes.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Amyloid change mediated 15% of solanezumab's cognitive effect, though estimates were imprecise due to limited disease progression in the sample and solanezumab's minimal amyloid removal.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Applying the same methods to data from trials of more effective anti\u2010amyloid drugs could validate amyloid as a surrogate outcome, guide related regulatory decisions, and influence treatment strategy.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/trc2.70205","type":"journal-article","created":{"date-parts":[[2026,2,15]],"date-time":"2026-02-15T02:20:12Z","timestamp":1771122012000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Evaluation of amyloid change as a surrogate for cognitive decline: demonstration in individual\u2010level data from the A4 study of solanezumab"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0181-6063","authenticated-orcid":false,"given":"Sarah F.","family":"Ackley","sequence":"first","affiliation":[{"name":"Department of Epidemiology Brown University  Providence Rhode Island USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael D.","family":"Flanders","sequence":"additional","affiliation":[{"name":"Department of Epidemiology Brown University  Providence Rhode Island USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Audrey","family":"Murchland","sequence":"additional","affiliation":[{"name":"Department of Epidemiology Boston University  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruijia","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Epidemiology Boston University  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingxuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Epidemiology &amp; Biostatistics UCSF  San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sachin J.","family":"Shah","sequence":"additional","affiliation":[{"name":"Division of General Internal Medicine and Center for Aging and Serious Illness Massachusetts General Hospital  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward D.","family":"Huey","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Human Behavior Alpert Medical School of Brown University  Providence Rhode Island USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. Maria","family":"Glymour","sequence":"additional","affiliation":[{"name":"Department of Epidemiology Boston University  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,2,14]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMp2110468"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000207438"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tjpad.2025.100102"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.14342"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abi6401"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.70068"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abl8366"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.n156"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13470"},{"key":"e_1_2_9_11_1","article-title":"Effect of reduction in brain amyloid levels on change in cognitive and functional decline in randomized clinical trials: an instrumental variable meta\u2010analysis","author":"Pang M","year":"2022","journal-title":"Alzheimers Dement"},{"key":"e_1_2_9_12_1","article-title":"Evaluating amyloid\u2010beta as a surrogate endpoint in trials of anti\u2010amyloid drugs in Alzheimer's disease: a Bayesian meta\u2010analysis [Internet]","author":"Ren S","year":"2025","journal-title":"arXiv"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13735"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.14283\/jpad.2024.126"},{"key":"e_1_2_9_15_1","article-title":"Comment on \u201cEffect of reduction in brain amyloid levels on change in cognitive and functional decline in randomized clinical trials: an updated instrumental variable meta\u2010analysis\u201d","author":"Ackley SF","journal-title":"Alzheimer's Dement"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.n346"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-publhealth-032315-021402"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-statistics-032921-035359"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.7561"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2023.111242"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.13239"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3007941"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2305032"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.51048"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000200046"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.14283\/jpad.2024.125"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.14283\/jpad.2020.38"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwi187"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1037\/a0020761"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1097\/EDE.0b013e31828d0590"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4419-1764-5_8"},{"key":"e_1_2_9_32_1","article-title":"Semi\u2010parametric model approach to causal mediation analysis for longitudinal data","author":"Li Y","year":"2025","journal-title":"Statist Model"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2212948"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.14336"},{"key":"e_1_2_9_35_1","unstructured":"Could Benefit of Plaque Removal Grow in Time? | ALZFORUM [Internet]. 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