N-terminal-targeted anti-amyloid monoclonal antibodies illuminate the therapy for Alzheimer's disease: a systematic review and comprehensive meta-analysis

BackgroundRecent clinical trials of anti-amyloid-beta (A{beta}) monoclonal antibodies (mAbs) have demonstrated that the removal of A{beta} in symptomatic patients can slow down the progression of Alzheimers disease (AD) and reinforce the "amyloid cascade" hypothesis. However, further investigation and analysis of integrated clinical data is needed to interpret the clinical efficacy of these mAbs. In this study, we aimed to estimate the effectiveness of mAbs for AD and firstly assessed the therapeutic efficacy from a perspective of mAbs targeting specific A{beta} domains (N-terminal, C-terminal, central domain, and N-terminal+central domain) in pre-specified subgroups. MethodsIn this systematic review and meta-analysis, we searched on Pubmed, Embase, the Cochrane Library, and ClinicalTrials.gov from their inception until 31 August, 2023, and updated our search on 15 October, 2023, to identify all published randomised controlled trials (RCTs) on various clinical outcomes of anti-A{beta} mAbs in AD. The primary outcomes of interest included Alzheimers Disease Assessment Scale-cognitive subscale (ADAS-cog), Mini Mental State Examination (MMSE), and Clinical Dementia Rating scale-Sum of Boxes (CDR-SB), as well as amyloid positron emission tomography (PET), the main biomarker. Additionally, we collected the data of volumetric Magnetic Resonance Imaging (vMRI), cerebrospinal fluid (CSF), plasma AD biomarkers, and the risks of amyloid-related imaging abnormalities (ARIA). Random-effects models to calculate pooled risk ratios (RRs) and standardized mean differences (SMDs) were employed to analyze the data across multiple studies of all mAbs. Furthermore, we also examined the interrelationships among changes in alterations of cognitive performance, A{beta} deposition, variations in AD biomarkers, and the risks of ARIA both in all mAbs and N-terminal-targeted mAbs by calculating Pearsons correlation coefficients. This study is registered with PROSPERO, No. CRD42023430637. FindingsWe identified a total of 37 eligible studies on quality assessment, of which 34 were included in the meta-analysis. The analysis revealed that eight monoclonal antibodies (aducanumab, lecanemab, donanemab, bapineuzumab, gantenerumab, crenezumab, solanezumab, and ponezumab) demonstrated statistical improvements in cognitive outcomes. Specifically, the ADAS-cog [(total mAbs: SMD: -0.08, 95% CI: -0.11 to -0.04); (N-terminal-targeted mAbs: SMD: -0.08, 95% CI: -0.13 to -0.03)], CDR-SB [(total mAbs: SMD: -0.06, 95% CI: -0.12 to -0.00); (N-terminal-targeted mAbs: SMD: -0.08, 95% CI: -0.16 to -0.01)], and MMSE [(total mAbs: SMD: 0.06, 95% CI: 0.02 to 0.10); (N-terminal-targeted mAbs: SMD: 0.05, 95% CI: -0.00 to 0.10)] demonstrated significant improvement. In addition, the meta-analyses indicated that mAbs also had a statistically significant impact on reducing amyloid PET [(total mAbs: SMD: -1.13, 95% CI: -1.66 to -0.61); (N-terminal-targeted mAbs: SMD: -1.64, 95% CI: -2.27 to -1.02)], accelerating ventricle enlargement [(total mAbs: SMD: 0.22, 95% CI: 0.06 to 0.38); (N-terminal-targeted mAbs: SMD: 0.44, 95% CI: 0.30 to 0.57)], and causing whole-brain atrophy [(total mAbs: SMD: -0.14, 95% CI: -0.26 to -0.03); (N-terminal-targeted mAbs: SMD: -0.24, 95% CI: -0.41 to -0.07)], while increased the risk ARIA-E (total mAbs: RR: 9.79, 95% CI 7.83 to 12.26); (N-terminal-targeted mAbs: RR: 10.79, 95% CI: 8.61 to 13.52)] and ARIA-H [(total mAbs: RR: 1.28, 95% CI 0.98 to 1.67); (N-terminal-targeted mAbs: RR: 1.94, 95% CI: 1.64 to 2.29)]. However, no significant hippocampal volume atrophy was observed [(total mAbs: SMD: 0.00, 95% CI: -0.07 to 0.07); (N-terminal-targeted mAbs: SMD: -0.03, 95% CI: -0.13 to 0.07)]. It should be noted that all above effects were more significant in AD patients treated with N-terminal-targeted mAbs, as observed in subgroup analyses. Additionally, we observed a negative association between ventricular enlargement and A{beta} clearance (Pearsons r: -0.76), especially with the administration of N-terminal-targeted mAbs (Pearsons r: -0.79), indicating a stronger effect on A{beta} clearance. Moreover, there was a strong negative correlation between the improvement in cognitive function and the preservation of hippocampal volume (Pearsons r: -0.70), particularly in the case of N-terminal-targeted mAbs. Lastly, a strong correlation was also found between the risk of ARIA and A{beta} reduction in amyloid PET (Pearsons r: -0.60), brain atrophy (Pearsons r: -0.83), and ventricle enlargement (Pearsons r: 0.92). InterpretationThe administration of mAbs that specifically target the N-terminus of A{beta} showed promising results in reducing A{beta} burden and ameliorating cognitive decline. Furthermore, our preliminary findings shed light on the occurrence of brain atrophy, ventricular enlargement, and ARIA, might be attributed to the well clearance of A{beta} deposits caused by mAb administration. In future anti-A{beta} mAb development, our systematic review and meta-analysis indicated that N-terminal-targeted mAbs is an optimizing approach. FundingThis work was supported by National Natural Science Foundation of China (No. 82004430, 82174310). Research in contextO_ST_ABSEvidence before this studyC_ST_ABSThe recent trials of lecanemab and donanemab have provided initial conclusive evidences that removal of A{beta} from symptomatic patients brains can decelerate the progression of Alzheimers disease (AD). These findings offer clinical substantiation for the significance of aberrant A{beta} in AD pathogenesis, thereby reinforcing the validity of the "amyloid cascade" hypothesis. While, the clinical benefit of the monoclonal antibodies (mAbs) is still limited and it is important to note that the treated subjects are still experienced disease progression, albeit at a slower rate. Targeting various forms of A{beta} (monomers, oligomers, fibrils) is considered as the key mechanism of these mAbs efficacy. However, the results indicated that it is not crucial direction to explain the ideal antibody efficacy. In order to discover underlying mechanisms and formulate an enhanced immunotherapeutic regimen, it is essential to further analyze the integrated data of clinical trials. Added value of this studyThis comprehensive systematic review and meta-analysis not only encompassed all reported RCTs investigating the effects of anti-A{beta} mAbs on various clinical outcomes in AD, but also firstly assessed the therapeutic efficacy of targeting specific A{beta} domains (N-terminal, N-terminal+central-domain, central-domain, and C-terminal) by subgroup analyses. Enhanced data syntheses of all included 34 studies demonstrated significant enhancements in cognitive outcomes (ADAS-cog, CDR-SB and MMSE) with the utilization of mAbs. The meta-analysis also revealed that mAbs significantly reduced amyloid burden and certain AD biomarkers, expedited ventricle enlargement and whole-brain atrophy, concurrently increased the risk of ARIA. In addition, a notable efficacy was observed in AD patients by using the mAbs targeting the N-terminus of A{beta}, as evidenced by subgroup analyses by employing different epitopes of A{beta}. Association analysis identified that there was a positive correlation between the extent of reduction in A{beta} deposition after mAbs therapy and the degree of improvement in cognitive function, thereby supporting A{beta} plaques as a pivotal driver of cognitive decline in AD and emphasizing the clinical advantages associated with A{beta} elimination from the brain. Further, we observed a possible association between brain atrophy or ventricular enlargement and A{beta} clearance, especially with the administration of N-terminal-targeted mAbs, which demonstrated a stronger A{beta} clearance. Improvement in cognitive function seemed to be related to both A{beta} clearance and preservation of hippocampal volume. Moreover, the risk of ARIA was strongly correlated with reductions in amyloid PET and brain atrophy, as well as ventricle enlargement. Hence, it is essential for us to recognize that the clinical efficacy of N-terminal-targeted mAbs in clearing A{beta} is crucial. Nevertheless, the exacerbation of cerebral atrophy and the occurrence of ARIA of higher severity are both caused by the great abilities of A{beta} clearance. Implications of all the available evidenceThe findings of this comprehensive meta-analysis provided a strong support for the efficacy of N-terminal-targeted A{beta} antibodies in significantly reducing A{beta} burden and ameliorating cognitive decline in AD patients, which represented a potentially groundbreaking therapeutic strategy. The principle of "structure dictates function" is a guiding tenet that targeting N-terminal region of A{beta} to design superior mAbs is a promising direction for the future.