Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, 08017 Barcelona, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28029 Madrid, Spain.
Int J Mol Sci. 2022 Aug 18;23(16):9305. doi: 10.3390/ijms23169305.
Since 1906, when Dr. Alois Alzheimer first described in a patient "a peculiar severe disease process of the cerebral cortex", people suffering from this pathology have been waiting for a breakthrough therapy. Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative brain disorder and the most common form of dementia in the elderly with a long presymptomatic phase. Worldwide, approximately 50 million people are living with dementia, with AD comprising 60-70% of cases. Pathologically, AD is characterized by the deposition of amyloid β-peptide (Aβ) in the neuropil (neuritic plaques) and blood vessels (amyloid angiopathy), and by the accumulation of hyperphosphorylated tau in neurons (neurofibrillary tangles) in the brain, with associated loss of synapses and neurons, together with glial activation, and neuroinflammation, resulting in cognitive deficits and eventually dementia. The current competitive landscape in AD consists of symptomatic treatments, of which there are currently six approved medications: three AChEIs (donepezil, rivastigmine, and galantamine), one NMDA-R antagonist (memantine), one combination therapy (memantine/donepezil), and GV-971 (sodium oligomannate, a mixture of oligosaccharides derived from algae) only approved in China. Improvements to the approved therapies, such as easier routes of administration and reduced dosing frequencies, along with the developments of new strategies and combined treatments are expected to occur within the next decade and will positively impact the way the disease is managed. Recently, Aducanumab, the first disease-modifying therapy (DMT) has been approved for AD, and several DMTs are in advanced stages of clinical development or regulatory review. Small molecules, mAbs, or multimodal strategies showing promise in animal studies have not confirmed that promise in the clinic (where small to moderate changes in clinical efficacy have been observed), and therefore, there is a significant unmet need for a better understanding of the AD pathogenesis and the exploration of alternative etiologies and therapeutic effective disease-modifying therapies strategies for AD. Therefore, a critical review of the disease-modifying therapy pipeline for Alzheimer's disease is needed.
自 1906 年 Alois Alzheimer 博士首次在一名患者中描述“一种独特的严重大脑皮层疾病过程”以来，患有这种疾病的人一直在等待突破性的治疗方法。阿尔茨海默病（AD）是一种不可逆的、进行性的神经退行性脑疾病，是老年人中最常见的痴呆症形式，具有较长的前驱期。全球约有 5000 万人患有痴呆症，其中 AD 占 60-70%。从病理上看，AD 的特征是淀粉样β肽（Aβ）在神经突（神经原纤维缠结）和血管中的沉积（淀粉样血管病），以及磷酸化tau 在神经元中的积累（神经原纤维缠结）大脑，伴有突触和神经元的丢失，以及神经胶质细胞的激活和神经炎症，导致认知障碍，最终导致痴呆。AD 目前的竞争格局包括对症治疗，目前有六种批准的药物：三种乙酰胆碱酯酶抑制剂（多奈哌齐、利斯的明和加兰他敏）、一种 NMDA 受体拮抗剂（美金刚）、一种联合治疗（美金刚/多奈哌齐）和 GV-971（寡甘露糖酸钠，一种来自藻类的寡糖混合物），仅在中国获得批准。预计在未来十年内，将对现有治疗方法进行改进，例如给药途径更简单，给药频率更低，以及开发新的策略和联合治疗，这将对疾病的管理方式产生积极影响。最近，阿杜卡奴单抗（Aducanumab），即第一种疾病修饰疗法（DMT）已被批准用于 AD，几种 DMT 处于临床开发或监管审查的后期阶段。在动物研究中显示出前景的小分子、单抗或多模式策略并未在临床中得到证实（观察到临床疗效的微小到中度变化），因此，需要更好地了解 AD 发病机制，并探索替代病因和治疗方法，以满足 AD 的治疗需求。因此，需要对 AD 的疾病修饰治疗药物管进行深入审查。
