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

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.

Keywords: Alzheimer's disease; Apolipoprotein E4; Cholinesterase inhibitors; Cognitive function; Monoclonal antibodies.

Fig. 1

Comparisons between mABs and AChEIs on Cognitive Function Abbreviations: AChEI = acetylcholinesterase inhibitor; ADAS-Cog = Alzheimer's Disease Assessment Scale-Cognitive Subscale 14-item; CDR-SOB = Clinical Dementia Rating Scale Sum of Boxes; CrI = credible interval; mAB = anti-amyloid monoclonal antibody; MID = minimally important difference; MMSE = Mini-Mental Status Examination; Pr = posterior probability.

Fig. 2

Comparisons between mABs and AChEIs on adverse events Abbreviations: AChEI = acetylcholinesterase inhibitor; CrI = credible interval; mAB = anti-amyloid monoclonal antibody; MID = minimally important difference; OR = odds ratio; Pr = posterior probability.

Fig. 3

Subgroup analysis of mABs on cognitive function Abbreviations: AChEI = acetylcholinesterase inhibitor; AD = Alzheimer’s disease; ADAS-Cog = Alzheimer's Disease Assessment Scale-Cognitive Subscale 14-item; CDR-SOB = Clinical Dementia Rating Scale Sum of Boxes; INT = interaction effect; mAB = anti-amyloid monoclonal antibody; MCI = mild cognitive impairment; MID = minimally important difference * Values are presented as means with 95 % credible intervals.

Fig. 4

Comparions between individual mABs on ARIA-E and ARIA-H Abbreviations: ARIA-E = Amyloid-related imaging abnormalities-edema; ARIA-H = Amyloid-related imaging abnormalities-hemorrhage; CrI = credible interval; mAB = anti-amyloid monoclonal antibody; MID = minimally important difference; OR = odds ratio; Pr = posterior probability.

Fig. 5

The association between different genotypes and ARIA-E and ARIA-H Abbreviations: ARIA-E = Amyloid-related imaging abnormalities-edema; ARIA-H = Amyloid-related imaging abnormalities-hemorrhage; CrI = credible interval; mAB = anti-amyloid monoclonal antibody; MID = minimally important difference; OR = odds ratio; Pr = posterior probability.

Fig. 6

Summary of spie plots for the overall profile of each active treatment and placebo across the nine outcomes Abbreviations: ADAS-Cog = Alzheimer's Disease Assessment Scale-Cognitive Subscale 14-item; ARIA-E = Amyloid-related imaging abnormalities-edema; ARIA-H = Amyloid-related imaging abnormalities-hemorrhage; CDR-SOB = Clinical Dementia Rating Scale Sum of Boxes; MMSE =Mini-Mental Status Examination; SAE = serious adverse event * Values are presented as surface under the cumulative ranking (SUCRA), with higher SUCRA values indicating more beneficial outcomes.