阿尔茨海默病治疗药物的突破

Recent advances in the therapeutic development for Alzheimer’s disease

阿尔茨海默病(Alzheimer’s disease,AD)是发病率最高的神经退行性疾病,主要表现为记忆力下降,认知功能缺陷,目前尚无有效的治疗手段.随着人口老龄化加剧,AD发病率逐年上升,找到有效的AD药物刻不容缓.对AD发病机理的研究中,Aβ假说是普遍接受的致病机制:淀粉样蛋白(amyloid-β,Aβ)沉积产生神经毒性,导致神经元死亡.针对该致病机理设计的Aβ单抗药物的研发却很曲折,在2023年7月,美国食品药品监督管理局(U.S.Food and Drug Administration,FDA)批准上市抗Aβ的单克隆抗体Lecanemab,在经过18个月的药物注射后,与安慰剂组相比,治疗组患者大脑中Aβ沉积发生明显减少,减缓疾病的进程.与此同时,另一个Aβ单抗Donanemab药物也表现出相似的治疗效果.这不仅证明Aβ假说的正确性,为大量的AD患者带来治疗的希望和曙光.因此,这两种药物被Science评为2023十大科学突破之一.但是,这两种药物仅对AD早期的病人有较好的治疗效果,且药物的使用可能会带来脑出血(amyloid-related imaging abnormalities-hemorrhage,ARIA-H)、脑水肿(amyloid-related imaging abnormalitiesedema or effusions,ARIA-E)等副作用,这些副作用在APOEε4纯和患者出现的比例更高.因此,寻求更安全有效的治疗药物仍需更进一步研究.

Alzheimer’s disease(AD)is the most common neurodegenerative disorder that mainly affects elderly people.AD is a progressive disease beginning with mild learning and memory impairment and gradually evolving to severe dementia,which is accompanied by impairments in complex attention,language function,behavior,and social ability.Two primary neuropathological hallmarks in the brain of AD patients have been recognized and studied extensively,including the accumulation of extracellular plaques primarily comprising aggregated amyloid-β(Aβ)and intracellular neurofibrillary tangles(NFTs)constituted of hyperphosphorylated Tau protein.As the population aging intensifies,the incidence of AD increases accordingly.Thus,there is an urgent need to develop effective therapies to prevent or slow down the progression of AD.Although many drugs have been designed to target AD pathology,only a few have entered the clinical trials,mainly monoclonal antibodies targeting Aβ.The goal of many anti-Aβantibodies is to lower the levels of parenchymal Aβas well as Aβdeposition in the AD brain.The amyloid cascade hypothesis suggests that Aβaccumulation triggers disease pathogenesis,so therapies that lower parenchymal Aβmight be expected to slow AD progression.Recently,the U.S.Food and Drug Administration(FDA)has approved Lecanemab and Donanemab,both are anti-Aβmonoclonal antibodies that target and remove Aβfrom the brain,for the treatment of AD.Among AD patients with the early symptom,Lecanemab and Donanemab could effectively reduce Aβdeposition and are proven to be clinically meaningful benefits based on clinical rating scales such as CDR-SB and iADRS.These findings support that Aβindeed is an effective therapeutic target.Besides having serious adverse events,such as microhemorrhage,superficial siderosis(ARIA-H),and amyloid-related imaging abnormalities(ARIA)with edema or effusions(ARIA-E),these antibody-based regimes appear to be effective only for AD patients in the early stages.In addition to Aβ,therapies targeting other molecules have also been developed,including monoclonal antibodies targeting N-Tau(N-terminal Tau)and P-Tau(phosphorylated Tau).The stage of tau pathology has well correlation with the progression of cognitive impairment.Thus,many antibodies are designed to lower the level of parenchymal tau aggregation or to inhibit abnormal hyperphosphorylation of tau.Unfortunately,N-tau-directed monoclonal antibodies have failed in phase II clinical trials,and the antibodies targeting P-tau are still in phase II clinical trials.Owing to apolipoprotein E(APOE)especially APOE4 being the strongest genetic risk gene in LOAD(late-onset AD),many therapies are designed to modulate the expression or function of APOE.Despite numerous preclinical studies in animal models have investigated APOE-directed therapies that may eventually translate clinically,so far,no therapies targeting APOE have completed phase II clinical trials.Multiple studies suggest that chronic using of anti-inflammation drugs may lower the incidence of AD,but many anti-inflammation drug treatments failed in clinical trials.Up to now,only Trem2 activating and CD33 blocking monoclonal antibody have entered phase I trials.Due to the diversity and complexity of AD pathology,further research efforts are definitely needed to discover more safe and effective therapeutic drugs.