Hsu, Chih-Wei, Hsu, Tien-Wei ORCID: https://orcid.org/0000-0003-4136-1251, Kao, Yu-Chen, Lin, Yu-Hsuan, Thompson, Trevor ORCID: https://orcid.org/0000-0001-9880-782X, Carvalho, Andre F., Stubbs, Brendon, Tseng, Ping-Tao, Yang, Fu-Chi, Tsai, Chia-Kuang ORCID: https://orcid.org/0000-0001-7693-1408, Yu, Chia-Ling, Tu, Yu-Kang ORCID: https://orcid.org/0000-0002-2461-474X and Liang, Chih-Sung ORCID: https://orcid.org/0000-0003-1138-5586 (2025) 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. The Journal of Prevention of Alzheimer's Disease:100195. ISSN 2426-0266 (Online) (doi:10.1016/j.tjpad.2025.100195)

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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.

Item Type:	Article
Uncontrolled Keywords:	monoclonal antibodies, Alzheimer's disease, Apolipoprotein E4, cholinesterase inhibitors, cognitive function
Subjects:	B Philosophy. Psychology. Religion > BF Psychology 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:	07 May 2025 10:19
URI:	http://gala.gre.ac.uk/id/eprint/50322

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