Neuroinflammatory Biomarkers and Related Pharmacological Treatment in Alzheimer's Disease
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摘要: 阿尔茨海默病（Alzheimer's disease，AD）是最常见的慢性神经退行性疾病之一，伴随一系列病理过程，其中神经炎症以神经胶质细胞系统激活为特征，是AD病因学的关键组成部分，及时预防神经炎症或监测炎症可作为AD的前瞻性治疗方法。对神经炎症生物标志物作为早期诊断AD的潜在应用价值及在疾病进展中的临床意义进行综述，总结当前针对AD相关神经炎症药物的治疗研究进展，以期为该领域的后续研究及临床实践提供参考依据。Abstract: Alzheimer's disease （AD） is one of the most common chronic neurodegenerative disorders, characterized by a series of pathological processes. Neuroinflammation, marked by activation of the glial cell system, constitutes a key component of AD pathogenesis. Timely prevention of neuroinflammation or monitoring of inflammatory responses may serve as a prospective therapeutic approach for AD. This article reviews the potential application value of neuroinflammation biomarkers in early diagnosis of AD and their clinical significance in disease progression, and summarizes the current therapeutic research progress on AD-related neuroinflammation drugs, with the aim of providing reference for subsequent research and clinical practice in this field.
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Key words:
- Alzheimer's disease /
- Neuroinflammation /
- Biomarkers /
- Drug therapy
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图 1 AD发病机制及相应生物标志物（用BioRender网站自制）
APP：淀粉样前体蛋白；β-secretase：β-分泌酶；γ-secretase：γ-分泌酶；sAPPβ：可溶性淀粉样前体蛋白β片段；Αβ peptide：Αβ肽；amyloid plaque：淀粉样斑块；BBB:血脑屏障；oxidative stress：氧化应激；ROS：活性氧族；proinflammatory cytokines：促炎细胞因子；IL-1β：白介素-1β；IL-6：白介素-6；TNF-α：肿瘤坏死因子-α；IFN-γ：干扰素-γ；microglial activation：小胶质细胞活化；chemokines：趋化因子；activated cytokines：活化的细胞因子；reactive Astrocyte：反应性星形胶质细胞；GAP-43：神经生长相关蛋白43；SNAP-25：突触体相关蛋白25；neurogranin：神经颗粒素；synaptic dysfunction：突触功能障碍；tau phosphorylation：tau磷酸化；oligomerization：寡聚化；neurofbrillary tangles：神经原纤维缠结。
Figure 1. Pathogenesis of Alzheimer's disease and corresponding biomarkers（Created in BioRender.com）
图 2 根据测试药物作用机制正在进行的AD临床试验
Figure 2. Ongoing AD clinical trials based on the mechanism of action of the in vestigational drug
表 1 认知分期结合生物标志物
Table 1. Cognitive staging combined with biomarkers
生物标志物概况 认知无损害 轻度认知障碍 痴呆症 A-T-（N）- 正常AD生物标志物，认知未受损 MCI的正常AD生物标志物 痴呆症的正常AD生物标志物 A+T-（N）- 阿尔茨海默病的临床前病理变化 MCI的阿尔茨海默病病理变化 伴有痴呆的阿尔茨海默病病理改变 A+T-（N）+ 阿尔茨海默病及伴随的疑似非阿尔茨海默病病理变化，认知未受损 阿尔茨海默病及伴随的疑似非阿尔茨海默病病理变化伴MCI 阿尔茨海默病及伴随的疑似非阿尔茨海默病病理变化伴痴呆 A+T+（N）- 临床前阿尔茨海默病 阿尔茨海默病伴MCI（早期AD） 阿尔茨海默病伴痴呆症 A+T+（N）+ 临床前阿尔茨海默病 阿尔茨海默病伴MCI（早期AD） 阿尔茨海默病伴痴呆症 
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表 2 AD相关抗炎药物（1）
Table 2. Anti-inflammatory drugs associated with AD （2）
类别 药物名称 作用机制 适应证 疗效 不良反应 临床试验阶段 单抗类 Aducanumab 靶向Aβ原纤维和斑块 MCI或轻度痴呆的早期AD患者 在10mg/kg高剂量组中，CDR-SB、MMSE、ADAS-Cog、ADCS-ADL-MCI量表评分分别下降了22%、18%、27%和40%，ENGAGE和EMERGE研究中，大剂量给予Aducanumab可使脑Aβ积累量分别较基线减少59%和71% [74] ARIA、头痛、偶有血管性水肿、荨麻疹、过敏 Aducanumab于2021年6月获FDA批准，成为首个获批的靶向Aβ单克隆抗体药 Lecanemab 靶向可溶性Aβ寡聚物 AD及MCI患者 在3期Clarity AD研究中[75]，Lecanemab在早期AD患者中显示出认知和生活质量的改善及脑淀粉样蛋白的减少，Lecanemab 10mg/kg IV双周被确定为最佳剂量；亚洲地区人群中导致研究药物中断或停药的不良事件发生率及输液相关反应、ARIA-E和ARIA-H等不良事件的发生率低于总体人群，Lecanemab 在亚洲受试者中普遍耐受性良好 ARIA-H、ARIA-E、输液相关反应 于2024年在我国获批上市用于治疗AD Donanemab 靶向Aβ的N端焦谷氨酸，与沉积的Aβ斑块结合启动小胶质细胞清除 AD早期及MCI，中度至重度痴呆患者不适用 2期TRAILBLAZER-ALZ研究表明，与安慰剂相比，AD组认知能力下降减少32%，在ApoE4携带者中更为明显[74] ARIA-E、ARIA-H、超敏反应、输液相关反应、眩晕跌倒 2024年7月获FDA批准 Trontinemab 靶向Aβ斑块及人转铁蛋白受体1（anti-Aβ/TfR1）[76] 早期AD患者 2025年7月阿尔茨海默病协会国际会议，罗氏公布了Trontinemab治疗AD的最新临床数据，相比于1.8mg/kg，3.6mg/kg剂量下的Trontinemab显示出对淀粉样斑块更显著的降低效果，3.6mg/kg剂量的Trontinemab治疗后第196天91%患者的淀粉样蛋白处于阳性阈值以下，1.8mg/kg剂量组在第196天有65%的参与者低于阈值 ARIA-E、ARIA-H、输液反应、贫血，但发生率有所降低 III期临床试验待启动 NSAIDs类 如吲哚美辛、萘普生、阿司匹林等 阻断COX、抑制NF-κB诱导的BACE1转录及激活PPAR-γ降低BACE1启动子活性[48−49] 早期AD患者 流行病学研究显示，NSAIDs显著降低AD风险[53]，但临床试验研究显示其保护作用仅在临床诊断前2年显现，当患者进入典型认知障碍期后，NSAIDs未显示疗效改善[42] 胃肠道出血、消化性溃疡、血小板减少、肝肾功异常、心血管风险等 临床试验
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2 AD相关抗炎药物（1）
2. Anti-inflammatory drugs associated with AD （2）
类别 药物名称 作用机制 适应证 疗效 不良反应 临床试验阶段 小分子
药物甘露特纳 抑制Aβ原纤维及靶向脑肠轴 轻至中度AD患者 抑制苯丙氨酸诱导的Th1细胞增殖进一步降低小胶质细胞活化，与安慰剂组比较，AD组ADAS-cog12、NPI、CIBIC-plus量表评分显著改善[59−60] 心律失常、胃肠反应、眩晕、瘙痒、睡眠障碍等现象 2019年11月在中国首次获批 马赛替尼 靶向c-Kit、Lyn通路，抑制肥大细胞促炎因子释放 轻中度AD患者 改善血脑屏障破坏，减少免疫细胞对中枢神经系统的浸润，抑制炎症细胞因子产生，在24周内作为标准护理附加疗法给药，延缓AD认知能力下降，耐受性可接受[57] 眼睑水肿、胃肠道反应、皮疹、中性粒细胞减少症、肺炎 Ⅲ期试验 NE- 3107 抑制NF-κB炎症通路，可阻断位于Aβ和p-tau上游的EPK以减少炎症[77] 轻中度AD患者 胰岛素增敏及抗炎，在糖耐量受损人群中NE3107降低了参与AD炎症和组织损伤的CRP水平，并增加了抗炎HDL、脂联素水平，抑制胰岛素抵抗、炎症和AD病理[77-78] 暂不清楚 Ⅲ期试验 抗炎中药 茯苓多糖 减少TLR4/NF-κB介导的神经炎症及重塑肠道菌群调控短链脂肪酸缓解AD神经炎症 轻至中度AD患者 抑制TLR4/NF-κB信号通路，降低循环中LPS水平和大脑中IL-6水平[62] 胃肠道不适、过敏、头晕、口干、肝肾功能异常 临床试验 中药复方葛根芩连片 抑制NF-κB/MAPK信号通路减少神经炎症和胶质细胞活化 轻至中度AD患者 GGQLT是临床上常用于治疗炎症性疾病的清热方剂，根据中医理论，清热法与AD的治疗相适应。GGQLT抑制胶质细胞激活，改善胶质细胞形态，降低促炎因子IL-1β和TNF-α的mRNA及蛋白水平，减轻海马神经炎症反应[66] 恶心、过敏、慢性腹泻 临床试验 五味子素B 调节GSK3β/Nrf2/GPX4 信号通路，调控抗氧化和铁死亡通路，实现神经保护作用[67] 轻至中度AD患者 抑制神经元铁死亡过程中TNF-α的释放，阻碍M1促炎型小胶质细胞的激活[67] 动物实验和细胞实验中未观察到明显的毒性或不良反应，其临床应用尚处于研究阶段 动物实验 旋覆花活性成分AB 抑制神经炎症潜在靶标PBK 轻至中度AD患者 抑制炎症和激活自噬，改善脂多糖介导的神经炎症[68] 暂不清楚 动物实验 七福饮 减少NF-κB的核易位，抑制小胶质细胞活化 轻至中度AD患者 补益气血、健脾安神，降低AGER、TLR4及IL-1β和TNF-α的mRNA表达水平[69−70] 消化不良、腹胀、口干、咽痛 临床试验 ARIA：脑部淀粉样蛋白相关影像学异常；ARIA-E：ARIA伴水肿或积液；ARIA-H：ARIA伴脑出血或浅表铁质沉着症
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