Longitudinal Multi-Domain Cognitive Assessment of Anti-Amyloid Monoclonal Antibodies Versus Acetylcholinesterase Inhibitors in Early Alzheimer's Disease: A Systematic Review and Meta-Analysis.

AIM: To compare the longitudinal cognitive changes of AChEIs and mAbs separately across three different cognitive measurements.

METHODS

We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) in individuals with mild cognitive impairment (MCI) or mild Alzheimer's disease (AD). Major databases (PubMed, Embase, CENTRAL, PsycINFO, and ClinicalTrials.gov) were searched from inception to April 6, 2025. The primary outcomes were changes in the Alzheimer's Disease Assessment Scale-Cognitive Subscale-14 Items (ADAS-Cog), Mini-Mental State Examination (MMSE), and Clinical Dementia Rating-Sum of Boxes (CDR-SB).

RESULTS

Overall, monoclonal antibodies (7 trials, n = 8010) exhibited comparatively homogeneous and an increasing separation from placebo over time within trials, whereas acetylcholinesterase inhibitors (9 trials, n = 4993) showed greater heterogeneity and an apparent attenuation of effect with longer follow-up. On ADAS-Cog, acetylcholinesterase inhibitors demonstrated a nonsignificant pooled effect with substantial heterogeneity (MD = -0.24, 95% CI -1.22 to 0.73; I2 = 76%), whereas monoclonal antibodies were associated with a statistically significant and relatively consistent improvements within trials (MD = -1.27, 95% CI -1.69 to -0.84; I2 = 0%). On MMSE and CDR-SB, acetylcholinesterase inhibitors yielded modest and borderline effects, respectively (MMSE MD = 0.10, 95% CI 0.07 to 0.13; CDR-SB MD = -0.11, 95% CI -0.22 to 0), whereas monoclonal antibodies showed statistically significant benefits (MMSE MD = 0.42, 95% CI 0.07 to 0.77; CDR-SB MD = -0.41, 95% CI -0.62 to -0.20). For CDR-SB, AChEIs showed minimal statistical heterogeneity (I2 = 0%) despite variable individual trajectories, whereas mAbs showed moderate heterogeneity (I2 = 56%).

CONCLUSIONS

In patients with MCI or mild AD, mAbs showed consistent efficacy on MMSE and ADAS-Cog but demonstrated heterogeneous effects on CDR-SB. In contrast, AChEIs showed heterogeneous and modest efficacy across all three measurements. These findings should be interpreted with caution due to the study's limitations.