Aims

To investigate the efficacy of monoclonal antibodies against Amyloid-beta (Aβ) in Alzheimer’s disease (AD).

Methods

Pubmed, Web of Science and ClinicalTrials.gov were searched for phase III randomized controlled trials (RCTs) and random-effects meta-analyses were performed.

Results

Seventeen RCTs (12,585 patients) were included. Monoclonal antibodies improved the cognitive outcomes ADAS-Cog {SMD = -0.06 [95% CI (-0.10; -0.02), I²= 0%]} and MMSE {SMD = 0.05 [95% CI (0.01; 0.09), I²= 0%]}, but did not improve the cognitive/functional measure CDR-SOB.

Antibodies decreased PET amyloid {SMD = -1.02 [95% CI (-1.70; -0.34), I²= 95%]} and CSF p181-tau {SMD = -0.87 [95% CI (-1.32; -0.43), I² = 89%]}, but increased ARIA risk {RR = 4.30 [95% CI (2.39; 7.77), I²= 86%]}. Antibody effects on reducing PET amyloid SUVR were correlated with their effects on decreasing (improving) ADAS-Cog (r = 0.66, p = 0.02)

In subgroup analysis by drug, Aducanumab improved ADAS-Cog, CDR-SOB, ADCS-ADL, and decreased amyloid PET SUVR and CSF p181-tau. Solanezumab improved ADAS-Cog and MMSE, and increased (improved) CSF Aβ_1-40. Bapineuzumab, Gantenerumab and Crenezumab did not improve any clinical outcomes, but Bapineuzumab and Gantenerumab decreased CSF p181-tau. All drugs except Solanezumab increased ARIA risk.

Conclusions

The increased power of this meta-analysis allowed us to detect small clinical and large biomarker improvements induced by anti-Aβ monoclonal antibodies. These findings support the view that Aβ remains a rational target for AD drug development and provide moderate support for the continuous development of anti-Aβ monoclonal antibodies as a treatment for AD.