The efficacy and safety of anti-amyloid monoclonal antibody versus acetylcholinesterase inhibitor with an in-depth analysis across genotypes and disease stages: a systematic review and meta-analysis - 25/04/25

Doi : 10.1016/j.tjpad.2025.100195

Chih-Wei Hsu ^1,^{^{21
contributed equally to this article as first authors}}, Tien-Wei Hsu ^2,^3,^4,^{^{21
contributed equally to this article as first authors}}, Yu-Chen Kao ^5,⁶, Yu-Hsuan Lin ^7,^8,⁹, Trevor Thompson ¹⁰, Andre F. Carvalho ¹¹, Brendon Stubbs ¹², Ping-Tao Tseng ^13,^14,^15,¹⁶, Fu-Chi Yang ¹⁷, Chia-Kuang Tsai ¹⁷, Chia-Ling Yu ¹⁸, Yu-Kang Tu ^19,^20,^⁎ , Chih-Sung Liang ^5,^6,^⁎
¹ Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
² Department of Psychiatry, E-DA Dachang Hospital, I-Shou University, Kaohsiung, Taiwan
³ Department of Psychiatry, E-DA Hospital, I-Shou University, Kaohsiung, Taiwan
⁴ Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
⁵ Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
⁶ Department of Psychiatry, Beitou Branch, Tri-Service General Hospital, Taipei, Taiwan
⁷ Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan
⁸ Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan
⁹ Department of Psychiatry, College of Medicine, National Taiwan University, Taipei, Taiwan
¹⁰ Centre for Chronic Illness and Ageing, University of Greenwich, London, UK
¹¹ IMPACT (Innovation in Mental and Physical Health and Clinical Treatment) Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, VIC, Australia
¹² Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
¹³ Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
¹⁴ Department of Psychology, College of Medical and Health Science, Asia University, Taichung, Taiwan
¹⁵ Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung, Taiwan
¹⁶ Institute of Precision Medicine, National Sun Yat-sen University, Kaohsiung City, Taiwan
¹⁷ Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
¹⁸ Department of Pharmacy, Chang Gung Memorial Hospital Linkou, Taoyuan, Taiwan
¹⁹ Institute of Epidemiology & Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
²⁰ Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan

^⁎Corresponding authors. Yu-Kang Tu, DDS PhD, Institute of Epidemiology & Preventive Medicine, College of Public Health, National Taiwan University, No. 17, Xuzhou Road, Zhongzheng District, Taipei City 100, Taiwan, Tel: +886-2-33668000Institute of Epidemiology & Preventive MedicineCollege of Public HealthNational Taiwan UniversityNo. 17, Xuzhou Road, Zhongzheng DistrictTaipei City100Taiwan^⁎⁎Chih-Sung Liang, MD, Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Centre, No. 60, Xinmin Road, Beitou District, Taipei, Taiwan 11243, Tel: +886-2-28959808, Fax: +886-2228957633Department of PsychiatryTri-Service General HospitalNational Defense Medical CentreNo. 60, Xinmin Road, Beitou DistrictTaipei11243Taiwan

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Highlight

•	When compared to placebo, only mABs, not AChEIs, were associated with a slower progression of cognitive decline. However, this benefit did not reach the minimally important difference.
•	When compared to ACHEI, mABs were associated with a slower progression of cognitive decline, and did not differ across safety outcomes, including acceptability, tolerability, SAE, and all-cause mortality.
•	The efficacy of mABs did not differ by disease stage, concomitant AD medications, or APOE4 carrier status. However, APOE4 homozygotes carriers were associated with a 5.53-fold increased odds of developing ARIA-E compared to non-carriers.
•	Donanemab and lecanemab seemed to have slightly better efficacy on cognitive function. Lecanemab showed relatively lower risk of ARIA-E among mABs, and aducanumab revealed better acceptability across all active treatments.

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ABSTRACT

BACKGROUND

To date, studies have not compared the efficacy and safety of monoclonal antibodies (mABs) with acetylcholinesterase inhibitors (AChEIs).

METHODS

Five electronic databases were systemic searched from inception to 10 November 2024 for double-blinded randomized controlled trial (RCT) of patients diagnosed with MCI or mild AD treated with mABs or AChEIs for at least 6 months. The primary outcome was change in cognitive function, measured by the Alzheimer's Disease Assessment Scale–cognitive subscale 14-item (ADAS-Cog) and Clinical Dementia Rating Scale–Sum of Boxes (CDR-SOB). The secondary outcomes were acceptability, tolerability, serious adverse events (SAE), and all -cause mortality. For mABs, amyloid-related imaging abnormalities-edema (ARIA-E), and amyloid-related imaging abnormalities-hemorrhage (ARIA-H) were also assessed. Subgroup analyses included (i) MCI versus mild AD; (ii) with versus without concomitant AD medications; and (iii) Apolipoprotein E (ApoE4) carriers versus non-carriers. Data were pooled using a random effects model within a Bayesian framework.

RESULTS

There were 8010 participants (mean age: 71.5 years) across seven mAB trials, and 4993 participants (mean age:70.7 years) in nine AChEI trials. When compared to placebo, only mABs, not AChEIs, were associated with a slower progression of cognitive decline on CDR-SOB (mean difference -0.41 (95% credible interval -0.61 to -0.22); minimally important difference (MID) -1) and ADAS-Cog (-1.35 (-2.36 to -0.36), MID -2); however, these benefits of mABs did not reach MID across the two cognitive measurements. Besides, mABs were associated with a slower progression of cognitive decline on CDR-SOB (-0.30 (-0.60 to -0.001)) than AChEIs, although mABs and AChEIs did not differ across safety outcomes, including acceptability, tolerability, SAE, and all-cause mortality. Further analysis of mABs indicated that their efficacy did not differ by disease stage, concomitant AD medications, or APOE4 carrier status. However, APOE4 homozygotes carriers were associated with a 5.53-fold (2.48 to 13.07) increased odds of developing ARIA-E compared to non-carriers. Finally, lecanemab demonstrated relatively better efficacy and a more favorable profile on ARIA-E compared to aducanumab and donanemab.

CONCLUSIONS

mABs were associated with a slower progression of cognitive decline than AChEIs; however, this effect did not reach the MID. The incidence of ARIA-E with mABs was associated with APOE4 carrier status and was not indicative of treatment efficacy.

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Keyword : Monoclonal antibodies, Alzheimer's disease, Apolipoprotein E4, cholinesterase inhibitors, Cognitive function