Critical assessment of anti-amyloid-β monoclonal antibodies effects in Alzheimer's disease: a systematic review and meta-analysis highlighting target engagement and clinical meaningfulness

Abstract

Despite most monoclonal antibodies against Aβ in Alzheimer's failed to demonstrate efficacy, the newest antibodies showed statistically significant clinical effects. We conducted a systematic review and meta-analysis to assess the efficacy, target engagement, and safety of anti-Aβ antibodies in sporadic AD including phase III RCTs published up to November 28, 2023. Antibodies as a drug class, attenuated worsening on the clinical scales CDR-SB and ADAS-Cog by very small effect sizes and reduced amyloid on PET by a very large effect size. Reduction of amyloid on PET was moderately correlated with CDR-SB and ADAS-Cog reductions. However, antibodies increased risk of ARIA-E and ARIA-H by a very large and moderate effect size, respectively. In subgroup analyses by individual drug, Donanemab and Lecanemab induced the largest benefits. In subgroup analyses by binding affinity, antibodies without binding to monomers were associated with the most favorable effects. Despite statistical significance for improvement on clinical measures, antibody effects were below the threshold of clinically meaningful change during the period they were studied. However, the newest antibodies demonstrably interfere with the underlying ΑD pathophysiology and therefore their benefit could be cumulative over time leading to larger clinical effects in subsequent years. PROSPERO registration no. CRD42022381334.

Fig. 1

Flow diagram of study selection.

Fig. 2

Forest plots of (a) Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) and (b) Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) meta-analyses with subgroup analyses by individual drug.

Fig. 3

(a) Forest plot of amyloid PET with subgroup analysis by individual drug. (b) Correlation graph between effect sizes of amyloid PET and CDR-SB. (c) Correlation between amyloid PET and CDR-SB with subgroups based on binding affinity for Aβ monomers. (d) Correlation graph between effect sizes of amyloid PET and ADAS-Cog. (e) Correlation between amyloid PET and ADAS-Cog with subgroups based on binding affinity for Aβ monomers.

Fig. 4

Forest plots of (a) Amyloid-Related Imaging Abnormalities with edema/effusion (ARIA-E) and (b) ARIA with microhemorrhages or superficial siderosis (ARIA-H) with subgroup analyses by individual drug.