Lee, Chuo-Yu, Hsu, Chih-Wei, Tseng, Ping-Tao, Fang, Yi-Ya, Stubbs, Brendon, Thompson, Trevor ORCID: https://orcid.org/0000-0001-9880-782X, Carvalho, Andre F., Lin, Yu-Hsuan, Kao, Yu-Chen, Yang, Fu-Chi, Hsu, Tien-Wei ORCID: https://orcid.org/0000-0003-4136-1251 and Liang, Chih-Sung ORCID: https://orcid.org/0000-0003-1138-5586 (2026) Real-world effectiveness of monoclonal antibody lecanemab versus acetylcholinesterase inhibitors in Alzheimer’s disease: a target trial emulation. Alzheimer's Research & Therapy. ISSN 1758‑9193 (Online) (doi:10.1186/s13195-026-02095-4)

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Abstract

Background: Acetylcholinesterase inhibitors (AChEIs) provide symptomatic relief in Alzheimer’s disease (AD), whereas lecanemab may modify disease progression; however, real-world evidence on its safety and clinical impact remains limited. Therefore, this study aimed to compare the safety and effectiveness of initiating lecanemab versus AChEIs in patients with mild cognitive impairment (MCI) or AD.
Methods: Using the TriNetX US electronic health record network, we conducted a retrospective cohort study including individuals diagnosed with MCI or AD between July 2023 and September 2025. A target trial emulation with 1:1 propensity score matching and Cox models estimated comparative risks.
Results: Lecanemab was associated with a fivefold higher incidence of neuroimaging abnormalities than AChEIs, while 1-year treatment persistence was similar (53.4% vs 52.5%). After matching, 589 patients were included in each cohort. Compared with AChEIs, lecanemab was associated with significantly lower risks of behavioral and psychological symptoms of dementia (BPSD) (HR, 0.52; 95% CI, 0.36–0.77) and emergency visits (HR, 0.66; 95% CI, 0.51–0.85), but a higher risk of hospitalization (HR, 1.31; 95% CI, 1.03–1.67). Lecanemab was also associated with lower use of antipsychotics (HR, 0.47; 95% CI, 0.32–0.70), antidepressants (HR, 0.60; 95% CI, 0.43–0.85), melatonin/orexin antagonists (HR, 0.61; 95% CI, 0.42–0.88), antibiotics (HR, 0.61; 95% CI, 0.44–0.86), and antifungals (HR, 0.57; 95% CI, 0.37–0.88), whereas steroid use was higher among lecanemab users (HR, 2.19; 95% CI, 1.55–3.10).
Conclusions: Compared with an AChEI-based conventional care strategy, lecanemab initiation was associated with comparable treatment persistence and lower observed risks of BPSD, emergency visit as well as reduced use of psychotropic and infection-related medications in exploratory analyses. However, the higher incidence of neuroimaging abnormalities associated with lecanemab, along with increased risks of hospitalization and corticosteroid use, likely reflects proactive clinical monitoring and management of amyloid-related imaging abnormalities (ARIA). While residual confounding cannot be excluded and results warrant cautious interpretation, these exploratory findings warrant further validation in biomarker-confirmed cohorts and head-to-head randomized trials.

Item Type:	Article
Additional Information:	"We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply."
Uncontrolled Keywords:	monoclonal antibodies, lecanemab, acetylcholinesterase inhibitors, Alzheimers, target trial emulation
Subjects:	Q Science > Q Science (General) R Medicine > R Medicine (General) R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Faculty / School / Research Centre / Research Group:	Faculty of Education, Health & Human Sciences Faculty of Education, Health & Human Sciences > Institute for Lifecourse Development Faculty of Education, Health & Human Sciences > Institute for Lifecourse Development > Centre for Chronic Illness and Ageing Faculty of Education, Health & Human Sciences > School of Human Sciences (HUM)
Last Modified:	29 Jun 2026 15:14
URI:	https://gala.gre.ac.uk/id/eprint/53888

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