{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T05:12:56Z","timestamp":1788671576186,"version":"build-2803163510"},"reference-count":28,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"vor","delay-in-days":25,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100004191","name":"Novo Nordisk","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004191","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp; Dementia"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>In clinical studies, it is scientifically important, and a regulatory expectation, that objectives be translated into key clinical questions by specifically defining treatment effects to be estimated. Estimands are part of a structured framework, as presented in International Council for Harmonisation (ICH) E9(R1), by which study objectives are linked to a suitable study design and tools for estimation. Estimands are constructed using five attributes: treatment, population, variable (or endpoint), population\u2010level summary for the variable, and intercurrent events (ICEs). ICEs occur after treatment initiation and can affect the existence or interpretation of the measurements. In Alzheimer's disease (AD), potential ICEs include additional AD medication use, discontinuation of treatment, and death. We describe estimands in recent clinical studies of anti\u2010amyloid therapies, including gantenerumab, lecanemab, and donanemab, in AD and use the evoke and evoke+ studies of semaglutide in early\u2010stage symptomatic AD as examples of estimand application in AD trials.<\/jats:p>","DOI":"10.1002\/alz.71676","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T11:18:53Z","timestamp":1787743133000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Estimating treatment effects in clinical studies of Alzheimer's disease: What are estimands and why do we need them?"],"prefix":"10.1002","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2374-7727","authenticated-orcid":false,"given":"Suzanne","family":"Hendrix","sequence":"first","affiliation":[{"name":"Pentara Corporation  Millcreek Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig","family":"Mallinckrodt","sequence":"additional","affiliation":[{"name":"Pentara Corporation  Millcreek Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rikke Mortensen","family":"Abschneider","sequence":"additional","affiliation":[{"name":"Novo Nordisk A\/S  S\u00f8borg Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alireza","family":"Atri","sequence":"additional","affiliation":[{"name":"Banner Sun Health Research Institute  Sun City Arizona USA"},{"name":"Banner Alzheimer's Institute  Phoenix Arizona USA"},{"name":"Brigham and Women's Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mette Dahl","family":"Bendtsen","sequence":"additional","affiliation":[{"name":"Novo Nordisk A\/S  S\u00f8borg Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa Leon","family":"Colombo","sequence":"additional","affiliation":[{"name":"Novo Nordisk A\/S  S\u00f8borg Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard H.","family":"Feldman","sequence":"additional","affiliation":[{"name":"Alzheimer's Disease Cooperative Study, Department of Neurosciences University of California San Diego, La Jolla  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Johannsen","sequence":"additional","affiliation":[{"name":"Novo Nordisk A\/S  S\u00f8borg Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Cummings","sequence":"additional","affiliation":[{"name":"Chambers\u2010Grundy Center for Transformative Neuroscience Department of Brain Health Kirk Kerkorian School of Medicine University of Nevada  Las Vegas Nevada USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"key":"e_1_2_8_2_1","unstructured":"Accessed September 2025.International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use.ICH harmonised guideline: addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical principles for clinical trials E9(R1).2019.https:\/\/database.ich.org\/sites\/default\/files\/E9\u2010R1_Step4_Guideline_2019_1203.pdf"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/pst.1765"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s43441\u2010019\u201000061\u2010x"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.16347"},{"key":"e_1_2_8_6_1","unstructured":"Accessed September 2025.European Medicines Agency.ICH E9(R1) addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical principles for clinical trials. Step 5.2020.https:\/\/www.ema.europa.eu\/en\/documents\/scientific\u2010guideline\/ich\u2010e9\u2010r1\u2010addendum\u2010estimands\u2010and\u2010sensitivity\u2010analysis\u2010clinical\u2010trials\u2010guideline\u2010statistical\u2010principles\u2010clinical\u2010trials\u2010step\u20105_en.pdf"},{"key":"e_1_2_8_7_1","unstructured":"Accessed May 2025.Food and Drug Administration.E9(R1) statistical principles for clinical trials: addendum: estimands and sensitivity analysis in clinical trials.2021.https:\/\/www.fda.gov\/media\/148473\/download"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2025.4347"},{"key":"e_1_2_8_9_1","unstructured":"Accessed May 2025.European Medicines Agency.Guideline on the clinical investigation of medicines for the treatment of Alzheimer's disease.2018.https:\/\/www.ema.europa.eu\/en\/documents\/scientific\u2010guideline\/guideline\u2010clinical\u2010investigation\u2010medicines\u2010treatment\u2010alzheimers\u2010disease\u2010revision\u20102_en.pdf"},{"key":"e_1_2_8_10_1","unstructured":"Accessed September 2025.European Medicines Agency.Concept paper on the need for revision of the guideline on the clinical investigation of medicines for the treatment of Alzheimer's disease.2025.https:\/\/www.ema.europa.eu\/en\/documents\/scientific\u2010guideline\/concept\u2010paper\u2010need\u2010revision\u2010guideline\u2010clinical\u2010investigation\u2010medicines\u2010treatment\u2010alzheimers\u2010disease_en.pdf"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195\u2010024\u201001666\u20107"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/trc2.70200"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(26)00459\u20109"},{"key":"e_1_2_8_14_1","unstructured":"Accessed October 2025.International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. ICH E9(R1) estimands and sensitivity analysis in clinical trials. 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