Monoclonal antibodies (mAbs) have made significant progress in the treatment of Alzheimer''s disease (AD). However, mAbs are associated with adverse effects, including Amyloid-Related Imaging Abnormality (ARIA...Monoclonal antibodies (mAbs) have made significant progress in the treatment of Alzheimer''s disease (AD). However, mAbs are associated with adverse effects, including Amyloid-Related Imaging Abnormality (ARIA), which manifests as edema or effusion (ARIA-E) and hemorrhage (ARIA-H). The mechanisms behind these effects are not yet fully understood. Moreover, spontaneous ARIA has been insufficiently explored, and mAb therapies, particularly lecanemab, have mainly focused on patients with theAPOE-ε4 allele carrier. This review aims to address this gap by examining the mechanisms of spontaneous ARIA, ARIA induced by mAbs, and the influence of genetic variants on ARIA development. The autoantibody-Aβ-mediated immune response targets excessive Aβ deposits, increasing immune activity through microglial reactivity. The heightened immune response, driven by Aβ accumulation in blood vessels, promotes angiopathy and inflammation, potentially contributing to spontaneous ARIA. TheAPOE-ε4 allele carrier is more strongly associated with ARIA-E because it redistributes Aβ deposition from the brain to blood vessels, influencing microglial reactivity. The redistribution enhances vascular integrity and reduces the risk of ARIA-H. However, it also increases the likelihood of ARIA-E due to Aβ accumulation in the vasculature, triggering inflammation. In contrast, the development of ARIA-H is linked to increasedTREM2 expression and microglial reactivity, leading to impaired vascular integrity and disrupted matrix remodeling, which worsens the condition. Additionally, the adverse effects of mAbs may extend beyond theAPOE-ε4 allele, possibly impacting other genetic variants involved in microglial reactivity, Aβ redistribution, and vascular integrity.展开更多
Alzheimer’s disease(AD)is the most common type of dementia.Monoclonal antibodies(MABs)serve as a promising therapeutic approach for AD by selectively targeting key pathogenic factors,such as amyloid-β(Aβ)peptide,ta...Alzheimer’s disease(AD)is the most common type of dementia.Monoclonal antibodies(MABs)serve as a promising therapeutic approach for AD by selectively targeting key pathogenic factors,such as amyloid-β(Aβ)peptide,tau protein,and neuroinflammation.Specifically,based on their efficacy in removing Aβplaques from the brains of patients with AD,the U.S.Food and Drug Administration has approved three anti-amyloid MABs,aducanumab(AduhelmR),lecanemab(LeqembiR),and donanemab(Kisunla™).Notably,lecanemab received traditional approval after demonstrating clinical benefit,supporting the Aβcascade hypothesis.These MABs targeting Aβare categorized based on their affinity to diverse conformational features of Aβ,including monomer,fibril,protofibril,and plaque forms of Aβas well as pyroglutamate Aβ.First-generation MABs targeting the non-toxic monomeric Aβ,such as solanezumab,bapineuzumab,and crenezumab,failed to demonstrate clinical benefit for AD in clinical trials.In contrast,secondgeneration MABs,including aducanumab,lecanemab,donanemab,and gantenerumab directed against pathogenic Aβspecies and aggregates have shown that reducing Aβdeposition can be an effective strategy to slow cognitive impairment in AD.In this review,we provide a comprehensive overview of the current status,mechanisms,outcomes,and limitations of second-generation MABs for the clinical treatment of AD.Moreover,we discuss the perspectives and future directions of anti-amyloid MABs in the treatment of AD.展开更多
文摘Monoclonal antibodies (mAbs) have made significant progress in the treatment of Alzheimer''s disease (AD). However, mAbs are associated with adverse effects, including Amyloid-Related Imaging Abnormality (ARIA), which manifests as edema or effusion (ARIA-E) and hemorrhage (ARIA-H). The mechanisms behind these effects are not yet fully understood. Moreover, spontaneous ARIA has been insufficiently explored, and mAb therapies, particularly lecanemab, have mainly focused on patients with theAPOE-ε4 allele carrier. This review aims to address this gap by examining the mechanisms of spontaneous ARIA, ARIA induced by mAbs, and the influence of genetic variants on ARIA development. The autoantibody-Aβ-mediated immune response targets excessive Aβ deposits, increasing immune activity through microglial reactivity. The heightened immune response, driven by Aβ accumulation in blood vessels, promotes angiopathy and inflammation, potentially contributing to spontaneous ARIA. TheAPOE-ε4 allele carrier is more strongly associated with ARIA-E because it redistributes Aβ deposition from the brain to blood vessels, influencing microglial reactivity. The redistribution enhances vascular integrity and reduces the risk of ARIA-H. However, it also increases the likelihood of ARIA-E due to Aβ accumulation in the vasculature, triggering inflammation. In contrast, the development of ARIA-H is linked to increasedTREM2 expression and microglial reactivity, leading to impaired vascular integrity and disrupted matrix remodeling, which worsens the condition. Additionally, the adverse effects of mAbs may extend beyond theAPOE-ε4 allele, possibly impacting other genetic variants involved in microglial reactivity, Aβ redistribution, and vascular integrity.
基金funded by Basic Science Research Program of the National Research Foundation of Korea(NRF)which is funded by the Ministry of Science,ICT&Future Planning(RS-2023–00240010 to M.M.,NRF-2022R1A6A3A13053190 and RS-2024–00450135 to Y.N.,RS-2023–00212388 to S.K.,and RS-2023–00273557 to Y.H.P.)a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute(KHIDI),funded by the Ministry of Health&Welfare,Republic of Korea(RS-2023-KH138733 to M.M.).
文摘Alzheimer’s disease(AD)is the most common type of dementia.Monoclonal antibodies(MABs)serve as a promising therapeutic approach for AD by selectively targeting key pathogenic factors,such as amyloid-β(Aβ)peptide,tau protein,and neuroinflammation.Specifically,based on their efficacy in removing Aβplaques from the brains of patients with AD,the U.S.Food and Drug Administration has approved three anti-amyloid MABs,aducanumab(AduhelmR),lecanemab(LeqembiR),and donanemab(Kisunla™).Notably,lecanemab received traditional approval after demonstrating clinical benefit,supporting the Aβcascade hypothesis.These MABs targeting Aβare categorized based on their affinity to diverse conformational features of Aβ,including monomer,fibril,protofibril,and plaque forms of Aβas well as pyroglutamate Aβ.First-generation MABs targeting the non-toxic monomeric Aβ,such as solanezumab,bapineuzumab,and crenezumab,failed to demonstrate clinical benefit for AD in clinical trials.In contrast,secondgeneration MABs,including aducanumab,lecanemab,donanemab,and gantenerumab directed against pathogenic Aβspecies and aggregates have shown that reducing Aβdeposition can be an effective strategy to slow cognitive impairment in AD.In this review,we provide a comprehensive overview of the current status,mechanisms,outcomes,and limitations of second-generation MABs for the clinical treatment of AD.Moreover,we discuss the perspectives and future directions of anti-amyloid MABs in the treatment of AD.
