This study systematically assessed the safety and efficacy of monoclonal antibody therapy for Alzheimer's disease through a meta-analysis, providing insights for clinical and regulatory decisions.

For the past three decades, the amyloid cascade hypothesis has guided therapeutic strategies aimed at mitigating amyloid pathology in Alzheimer's disease. Recently, monoclonal antibodies such as aducanumab, lecanemab, and donanemab have shown potential in clearing amyloid plaques and slowing disease progression. However, uncertainties persist regarding whether these observed improvements are causal or mere associations. Additionally, several trials have reported life-threatening adverse events within the treatment cohorts.

We systematically searched PubMed, Cochrane, and Clinicaltrials.gov databases for randomized controlled trials examining monoclonal antibody safety and efficacy in Alzheimer's. After rigorous screening, eight trials were included for analysis. The primary outcome measure was Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB), supplemented by Alzheimer's Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog13) and Mini-Mental State Examination (MMSE).

The included trials encompassed 5910 patients (2864 in the treatment group and 3046 in the placebo group). We identified a significant advantage of monoclonal antibody therapy for both CDR-SB (WMD:  -0.43; 95% CI: -0.59, -0.28; p < 0.00001, data pooled from eight studies) and ADAS-Cog13 (WMD: -1.14; 95% CI: -1.66, -0.62; p < 0.00001, data pooled from four studies). No significant heterogeneity was noted (I² = 0%). Adverse events, including cerebral edema, effusion, and hemorrhage, were reported. Notably, Donanemab and Lecanemab were linked to brain atrophy, with one study reporting three deaths linked to Donanemab.

This meta-analysis underscores a statistically significant improvement in CDR-SB for monoclonal antibody therapy compared to placebo, but acknowledges associated adverse events, including accelerated brain atrophy and three deaths related to Donanemab treatment. With expedited FDA approval for Alzheimer's monoclonal antibodies on the horizon, a comprehensive evaluation of safety and efficacy is crucial.