Pharmacological and Clinical Heterogeneity of Anti-Amyloid Monoclonal Antibodies in Early Alzheimer’s Disease: A Systematic Review and Meta-Analysis of Randomized Trials

Background: Anti-amyloid monoclonal antibodies represent the first disease-modifying therapeutic strategy targeting amyloid-β pathology in early Alzheimer’s disease (AD). Although several agents have demonstrated the ability to reduce cerebral amyloid burden, their clinical efficacy and safety remain subjects of substantial scientific and regulatory debate. This study aimed to synthesize randomized evidence evaluating the benefit–risk profile of anti-amyloid monoclonal antibodies in biomarker-confirmed early AD. Methods: A systematic review and classical pairwise meta-analysis of randomized controlled trials (RCTs) was conducted following the PRISMA 2020 guidelines. PubMed/MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched for phase III placebo-controlled trials evaluating lecanemab, donanemab, aducanumab, and gantenerumab in patients with mild cognitive impairment due to AD or mild AD dementia with biomarker confirmation of amyloid pathology. The primary outcome was change from baseline in the Clinical Dementia Rating–Sum of Boxes (CDR-SB) at the longest available follow-up. Safety outcomes included amyloid-related imaging abnormalities with edema or effusion (ARIA-E), amyloid-related imaging abnormalities with hemorrhage (ARIA-H), serious adverse events, and treatment discontinuation. Random-effects meta-analyses were performed. Results: Six randomized comparisons derived from four phase III trials involving 7695 participants met the eligibility criteria. Anti-amyloid monoclonal antibodies were associated with a statistically significant slowing of clinical progression compared with placebo (pooled mean difference in CDR-SB: −0.42 points; 95% CI −0.59 to −0.25; I2 = 78%). The observed effect was primarily driven by trials of lecanemab and donanemab, whereas aducanumab demonstrated discordant results across trials and gantenerumab showed no clinically meaningful benefit. Despite statistical significance, the magnitude of the pooled effect approached the lower boundary of the minimal clinically important difference reported for CDR-SB in early AD. Treatment was associated with a markedly increased risk of ARIA-E (pooled risk ratio 10.1; 95% CI 7.8–13.0), with moderate heterogeneity across studies. Most ARIA-E events were asymptomatic and detected through protocol-mandated MRI monitoring. Conclusions: In biomarker-confirmed early Alzheimer’s disease, anti-amyloid monoclonal antibodies produce a statistically significant but modest slowing of clinical decline accompanied by a substantially increased risk of ARIA. The benefit–risk profile appears heterogeneous across individual antibodies and may reflect pharmacological differences in amyloid targeting and clearance mechanisms. These findings support cautious, individualized use of anti-amyloid therapies and highlight the need for longer-term studies to determine whether short-term slowing of decline translates into clinically meaningful disease modification.