{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T14:09:49Z","timestamp":1771078189921,"version":"3.50.1"},"posted":{"date-parts":[[2026,2,12]]},"group-title":"Pharmacology and Therapeutics","reference-count":45,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T00:00:00Z","timestamp":1770854400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,12]]},"abstract":"<jats:title>\n                  A\n                  <jats:sc>bstract<\/jats:sc>\n                <\/jats:title>\n                <jats:sec>\n                  <jats:title>INTRODUCTION<\/jats:title>\n                  <jats:p>Treatment response in Alzheimer\u2019s disease (AD) varies substantially across patients, yet no validated frameworks exist to estimate heterogeneous treatment effects (HTE) from observational data while controlling for confounding bias.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>METHODS<\/jats:title>\n                  <jats:p>We developed a causal machine learning framework integrating expert-guided causal graphs, complementary HTE estimators, sensitivity analyses, and policy learning. We applied it to cholinesterase inhibitors (ChEIs) in MCI due to AD to patients from the NACC and ADNI cohorts.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>Analysing 4,049 patients with 12-month and 2,223 with 36-month follow-up, all estimators indicated null or negative long-term ChEI effects on cognitive and functional outcomes, notably on functional measures. ChEIs showed slightly more deleterious effects among men than women.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>DISCUSSION<\/jats:title>\n                  <jats:p>This framework provides a methodology for estimating HTE from observational data. It revealed no beneficial responder subgroups, highlighting the challenge of detecting treatment heterogeneity in moderately sized cohorts. This approach can inform treatment selection for other AD therapies including memantine, anti-amyloid agents, and emerging treatments.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.02.11.26346078","type":"posted-content","created":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T01:20:32Z","timestamp":1770945632000},"source":"Crossref","is-referenced-by-count":0,"title":["Treatment Effects of Cholinesterase Inhibitors in Alzheimer\u2019s Disease: a Causal Machine Learning Approach"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-1712-6355","authenticated-orcid":false,"given":"Etienne","family":"Dedebant","sequence":"first","affiliation":[{"name":"Theremia, Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mathieu","family":"Even","sequence":"additional","affiliation":[{"name":"PreMeDICaL Inria-Inserm, University of Montpellier, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8009-9124","authenticated-orcid":false,"given":"Margaux","family":"T\u00f6rnqvist","sequence":"additional","affiliation":[{"name":"Theremia, Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7052-3873","authenticated-orcid":false,"given":"Fabien","family":"Hauw","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, Center of Cognitive Neurology, Lariboisi\u00e8re Fernand-Widal Hospital, APHP, Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0329-9656","authenticated-orcid":false,"given":"Tristan","family":"Fauvel","sequence":"additional","affiliation":[{"name":"Theremia, Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7004-483X","authenticated-orcid":false,"given":"Chlo\u00e9","family":"Geoffroy","sequence":"additional","affiliation":[{"name":"Theremia, Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"issue":"5","key":"2026021405401398000_2026.02.11.26346078v1.1","first-page":"3708","article-title":"2024 Alzheimer\u2019s disease facts and figures","volume":"20","year":"2024","journal-title":"In: Alzheimer\u2019s & Dementia"},{"issue":"1","key":"2026021405401398000_2026.02.11.26346078v1.2","first-page":"8","article-title":"Heterogeneity in Alzheimer\u2019s Disease Diagnosis and Progression Rates: Implications for Therapeutic Trials","volume":"19","year":"2022","journal-title":"In: Neurotherapeutics"},{"issue":"8","key":"2026021405401398000_2026.02.11.26346078v1.3","first-page":"457","article-title":"Sex differences in Alzheimer disease \u2014 the 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