Treatment Effects of Cholinesterase Inhibitors in Alzheimer’s Disease: a Causal Machine Learning Approach
Year: 2026
Type: preprint
Abstract: INTRODUCTION: Treatment response in Alzheimer's 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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.
Source: medRxiv
Authors: Etienne Dedebant, Mathieu Even, Margaux Törnqvist, Fabien Hauw, Tristan Fauvel, Chloé Geoffroy
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Alzheimer's Disease Research Center, 1Florida Alzheimer's Disease Research Center, Vanderbilt Alzheimer's Disease Research Center, Boston University Alzheimer's Disease Research Center, Yale Alzheimer Disease Research Center, UCSD Shiley-Marcos Alzheimer's Disease Research Center P30, Joint Estimate Diffusion Imaging (JEDI) for improved Tissue Characterization and Neural Connectivity in Aging and Alzheimer's Disease, Michigan Alzheimer's Disease Research Center, University of Kansas Alzheimer's Disease Research Center (KU ADRC), Alzheimer Disease Research Center, Alzheimer's Disease Research Center, Oregon Alzheimer's Disease Research Center, Alzheimer's Disease Research Center, UC Davis Alzheimer's Disease Research Center, Johns Hopkins Alzheimer's Disease Research Center, Indiana Alzheimer's Disease Research Center, Cleveland Alzheimers Disease Research Center, New Approaches to Dementia Heterogeneity, Stanford Alzheimer's Disease Research Center, Mount Sinai Alzheimer's Disease Research Center, Mayo Alzheimer's Disease Research Center, University of Washington Alzheimer's Disease Research Center, New Mexico Alzheimer's Disease Research Center, Duke/UNC Alzheimer's Disease Research Center, Wisconsin Alzheimer's Disease Research Center, Alzheimer's Disease Research Centers, UAB Alzheimer's Disease Research Center, National Alzheimer's Coordinating Center, University of Kentucky Alzheimer's Disease Research Center, NORTHWESTERN Alzheimer's Disease Research Center, Penn Alzheimer's Disease Research Center (ADRC), Alzheimer's Disease Research Center, Massachusetts Alzheimer's Disease Research Center (MADRC), South Texas Alzheimer's Disease Center, Goizueta Alzheimer's Disease Research Center, The Alzheimer's Disease Research Center at the University of California, Irvine, Rush Alzheimer's Disease Research Center
OpenAlex ID: W7128722345