Article(id=1322190401197429213, tenantId=1146029695717560320, journalId=1319373162502258839, issueId=1322190316019499694, articleNumber=null, orderNo=null, doi=10.16016/j.2097-0927.202505045, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1747756800000, receivedDateStr=2025-05-21, revisedDate=1750348800000, revisedDateStr=2025-06-20, acceptedDate=null, acceptedDateStr=null, onlineDate=1793164356755, onlineDateStr=2026-10-28, pubDate=1756483200000, pubDateStr=2025-08-30, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1793164356755, onlineIssueDateStr=2026-10-28, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1793164356755, creator=13701087609, updateTime=1793164356755, updator=13701087609, issue=Issue{id=1322190316019499694, tenantId=1146029695717560320, journalId=1319373162502258839, year='2025', volume='47', issue='16', pageStart='1825', pageEnd='1980', issueExtLink='null', onlineDate='null', pubDate='1756483200000', pubDateStr='2025-08-30', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1793164336447, creator='13701087609', updateTime=1793164553187, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1322191225206198613, tenantId=1146029695717560320, journalId=1319373162502258839, issueId=1322190316019499694, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1322191225206198614, tenantId=1146029695717560320, journalId=1319373162502258839, issueId=1322190316019499694, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=1825, endPage=1837, ext={EN=ArticleExt(id=1322190401428115934, articleId=1322190401197429213, tenantId=1146029695717560320, journalId=1319373162502258839, language=EN, title=Translational opportunities and barriers for blood-based biomarkers in Alzheimer’s disease: from discovery to implementation, columnId=1320434417353470541, journalTitle=Journal of Army Medical University, columnName=Expert Review, runingTitle=null, highlight=null, articleAbstract=

Alzheimer's disease (AD) is the most common type of dementia in the elderly population, imposed a substantial burden on families and society in China. Recent breakthroughs in anti-amyloid beta (Aβ) monoclonal antibody therapies have highlighted the urgent need for early and accurate diagnosis of AD. The advancement of highly sensitive and automated detection platforms for fluid biomarkers has positioned blood biomarkers (BBs) testing as promising tools for early detection, accurate diagnosis, progression monitoring, and therapeutic evaluation in AD. However, their clinical application still faces challenges, including standardization of detection and sample preprocessing, quality control, and confounding factors. Ongoing development of detection technologies and integration of artificial intelligence-driven analytical tools offer promising solutions to these challenges. In the future, efforts should focus on clinical translation pathways, multimodal integration, personalized medicine, and fostering global and national collaborations to accelerate the clinical application of BBs for AD.

, authors=Yanjiang WANG, Shan HUANG, authorsList=Yanjiang WANG, Shan HUANG, authorCompany=null, correspAuthors=Yanjiang WANG, authorNote=null, correspAuthorsNote=null, copyrightStatement=© 2025 Journal of Army Medical University, copyrightOwner=Editorial Office of Journal of Army Medical University, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, fund=null), CN=ArticleExt(id=1322190402023707103, articleId=1322190401197429213, tenantId=1146029695717560320, journalId=1319373162502258839, language=CN, title=阿尔茨海默病血液标志物的突破与挑战:从实验室到临床的转化之路, columnId=1320434417496076879, journalTitle=陆军军医大学学报, columnName=专家述评, runingTitle=null, highlight=null, articleAbstract=

阿尔茨海默病(Alzheimer’s disease,AD)作为老年人群中最常见的神经退行性疾病,其防治已成为全球公共卫生的重要议题。我国AD患病率持续攀升,构成了严峻的社会医疗挑战。随着靶向β淀粉样蛋白(Amyloid-β,Aβ)的单克隆抗体类药物在临床治疗中取得突破性进展,建立早期精准诊断体系的需求日益凸显。在此背景下,基于高灵敏度自动化检测平台的血液生物标志物技术展现出独特优势,为AD的早期筛查、精准分型、病程动态监测及治疗响应评估提供了全新解决方案。然而,该技术的临床转化仍面临诸多挑战,包括检测标准化、样本前处理规范、质量控制体系建立以及复杂系统因素的干扰等。当前,通过持续优化检测技术并结合人工智能辅助分析,有望突破这些技术瓶颈。展望未来,AD血液标志物研究应重点关注以下方向:建立规范的临床转化路径、开发多模态整合诊断模型、挖掘个性化医疗潜力,以及加强全球多中心协作网络建设,从而加速其从实验室到临床的转化进程。

, authors=王延江, 黄珊, authorsList=王延江, 黄珊, authorCompany=null, correspAuthors=王延江, authorNote=null, correspAuthorsNote=
王延江,医学博士,主任医师、教授、博士生导师,陆军军医大学大坪医院神经内科主任。获得国家杰出青年科学基金资助,入选教育部“长江学者”特聘教授、国家“万人计划”领军人才。担任中华医学会神经病学分会常委、中国神经科学学会理事、Vas-Cog Asia(亚洲血管性认知障碍学会)理事。承担国家重点研发计划、国家自然科学基金重点项目等课题,从系统角度探索阿尔茨海默病,提出新理论,发现新药物,建立新技术,开展全国和国际多中心临床试验进行转化研究。以通讯作者在PNAS、Nat Aging、Nat Rev Neurol、Lancet Infect Dis、JAMA Neurol、Sci Adv等杂志发表论文100余篇,获得国家科技进步二等奖、省部级一等奖、第20届Alzheimer Award 。E-mail:
WANG Yanjiang,E-mail:
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Alzheimers Dement,2024,20(8):7698-7714., articleTitle=Plasma miRNAs across the Alzheimer’s disease continuum:Relationship to central biomarkers, refAbstract=null)], funds=null, companyList=[AuthorCompany(id=1322190404154413536, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190401197429213, xref=1, ext=[AuthorCompanyExt(id=1322190404162802145, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190401197429213, companyId=1322190404154413536, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1Department of Neurology,Chongqing Key Laboratory of Aging and Brain Diseases,Army Medical Center of PLA/Daping Hospital of Third Military Medical University,Chongqing,China), AuthorCompanyExt(id=1322190404175385058, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190401197429213, companyId=1322190404154413536, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1陆军特色医学中心(第三军医大学大坪医院)神经内科,衰老与脑疾病重庆市重点实验室,重庆)])], figs=[ArticleFig(id=1322190405635002872, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190401197429213, language=EN, label=Table 1, caption=

Comparison of core blood biomarkers in AD

, figureFileSmall=null, figureFileBig=null, tableContent=
标志物优点缺点
Aβ42/40AD特异性标志物
疾病上游标志物,早期诊断潜能
比值形式减小个体差异
黏性大,易受样本处理流程影响
血液中变化幅度小
易受外周代谢干扰
pTau217在AD与非AD人群变化幅度大
早期出现血液中可检测的改变
非AD特异性
温度敏感,检测变异较大
修饰态易受样本处理及检测流程影响
pTau181在AD与非AD人群变化幅度较大
早期改变
同pTau217缺点
修饰位点AD特异性较pTau217低
变化幅度低于pTau217
pTau231早期发生可检测的改变
(较其他pTau更早)
具有早期诊断潜能
同pTau217缺点
修饰位点AD特异性较pTau217低
变化幅度低于pTau217
pTau217/Aβ42在AD与非AD人群变化幅度最大
比值具备单一标志物优点
同时较单一标志物更稳定
同单一标志物缺点
检测成本增高
pTau181/Aβ42比值具备单一标志物优点
同时较单一标志物更稳定
同单一标志物缺点
检测成本增高
), ArticleFig(id=1322190405802775033, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190401197429213, language=CN, label=表1, caption=

AD血液核心1标志物对比

, figureFileSmall=null, figureFileBig=null, tableContent=
标志物优点缺点
Aβ42/40AD特异性标志物
疾病上游标志物,早期诊断潜能
比值形式减小个体差异
黏性大,易受样本处理流程影响
血液中变化幅度小
易受外周代谢干扰
pTau217在AD与非AD人群变化幅度大
早期出现血液中可检测的改变
非AD特异性
温度敏感,检测变异较大
修饰态易受样本处理及检测流程影响
pTau181在AD与非AD人群变化幅度较大
早期改变
同pTau217缺点
修饰位点AD特异性较pTau217低
变化幅度低于pTau217
pTau231早期发生可检测的改变
(较其他pTau更早)
具有早期诊断潜能
同pTau217缺点
修饰位点AD特异性较pTau217低
变化幅度低于pTau217
pTau217/Aβ42在AD与非AD人群变化幅度最大
比值具备单一标志物优点
同时较单一标志物更稳定
同单一标志物缺点
检测成本增高
pTau181/Aβ42比值具备单一标志物优点
同时较单一标志物更稳定
同单一标志物缺点
检测成本增高
), ArticleFig(id=1322190405878272506, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190401197429213, language=EN, label=Table 2, caption=

Clinical application scenarios and efficacy of core blood biomarkers in AD

, figureFileSmall=null, figureFileBig=null, tableContent=
血液标志物脑内病理相关性临床应用场景及效能
疾病诊断疾病分期疗效监测
Aβ42/40中中差中
pTau217高高中较高
pTau181较高高中较高
pTau231较高中中中
pTau217/Aβ42高高较高较高
pTau181/Aβ42较高高中较高
), ArticleFig(id=1322190405966352891, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322190401197429213, language=CN, label=表2, caption=

AD血液核心1标志物临床应用场景及效能

, figureFileSmall=null, figureFileBig=null, tableContent=
血液标志物脑内病理相关性临床应用场景及效能
疾病诊断疾病分期疗效监测
Aβ42/40中中差中
pTau217高高中较高
pTau181较高高中较高
pTau231较高中中中
pTau217/Aβ42高高较高较高
pTau181/Aβ42较高高中较高
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阿尔茨海默病血液标志物的突破与挑战:从实验室到临床的转化之路
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王延江 , 黄珊
陆军军医大学学报 | 专家述评 2025,47(16): 1825-1837
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陆军军医大学学报 |专家述评 2025 , 47 (16) : 1825 -1837
阿尔茨海默病血液标志物的突破与挑战:从实验室到临床的转化之路
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王延江 , 黄珊
作者信息
  • 1陆军特色医学中心(第三军医大学大坪医院)神经内科,衰老与脑疾病重庆市重点实验室,重庆
通讯作者:
王延江,医学博士,主任医师、教授、博士生导师,陆军军医大学大坪医院神经内科主任。获得国家杰出青年科学基金资助,入选教育部“长江学者”特聘教授、国家“万人计划”领军人才。担任中华医学会神经病学分会常委、中国神经科学学会理事、Vas-Cog Asia(亚洲血管性认知障碍学会)理事。承担国家重点研发计划、国家自然科学基金重点项目等课题,从系统角度探索阿尔茨海默病,提出新理论,发现新药物,建立新技术,开展全国和国际多中心临床试验进行转化研究。以通讯作者在PNAS、Nat Aging、Nat Rev Neurol、Lancet Infect Dis、JAMA Neurol、Sci Adv等杂志发表论文100余篇,获得国家科技进步二等奖、省部级一等奖、第20届Alzheimer Award 。E-mail:
WANG Yanjiang,E-mail:
Translational opportunities and barriers for blood-based biomarkers in Alzheimer’s disease: from discovery to implementation
Yanjiang WANG , Shan HUANG
Affiliations
  • 1Department of Neurology,Chongqing Key Laboratory of Aging and Brain Diseases,Army Medical Center of PLA/Daping Hospital of Third Military Medical University,Chongqing,China
出版时间: 2025-08-30 doi: 10.16016/j.2097-0927.202505045
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阿尔茨海默病(Alzheimer’s disease,AD)作为老年人群中最常见的神经退行性疾病,其防治已成为全球公共卫生的重要议题。我国AD患病率持续攀升,构成了严峻的社会医疗挑战。随着靶向β淀粉样蛋白(Amyloid-β,Aβ)的单克隆抗体类药物在临床治疗中取得突破性进展,建立早期精准诊断体系的需求日益凸显。在此背景下,基于高灵敏度自动化检测平台的血液生物标志物技术展现出独特优势,为AD的早期筛查、精准分型、病程动态监测及治疗响应评估提供了全新解决方案。然而,该技术的临床转化仍面临诸多挑战,包括检测标准化、样本前处理规范、质量控制体系建立以及复杂系统因素的干扰等。当前,通过持续优化检测技术并结合人工智能辅助分析,有望突破这些技术瓶颈。展望未来,AD血液标志物研究应重点关注以下方向:建立规范的临床转化路径、开发多模态整合诊断模型、挖掘个性化医疗潜力,以及加强全球多中心协作网络建设,从而加速其从实验室到临床的转化进程。

阿尔茨海默病  /  血液标志物  /  早期诊断  /  精准医学  /  转化医学研究

Alzheimer's disease (AD) is the most common type of dementia in the elderly population, imposed a substantial burden on families and society in China. Recent breakthroughs in anti-amyloid beta (Aβ) monoclonal antibody therapies have highlighted the urgent need for early and accurate diagnosis of AD. The advancement of highly sensitive and automated detection platforms for fluid biomarkers has positioned blood biomarkers (BBs) testing as promising tools for early detection, accurate diagnosis, progression monitoring, and therapeutic evaluation in AD. However, their clinical application still faces challenges, including standardization of detection and sample preprocessing, quality control, and confounding factors. Ongoing development of detection technologies and integration of artificial intelligence-driven analytical tools offer promising solutions to these challenges. In the future, efforts should focus on clinical translation pathways, multimodal integration, personalized medicine, and fostering global and national collaborations to accelerate the clinical application of BBs for AD.

Alzheimer’s disease  /  blood biomarkers  /  early diagnosis  /  precision medicine  /  translational medical research
王延江, 黄珊. 阿尔茨海默病血液标志物的突破与挑战:从实验室到临床的转化之路. 陆军军医大学学报, 2025 , 47 (16) : 1825 -1837 . DOI: 10.16016/j.2097-0927.202505045
Yanjiang WANG, Shan HUANG. Translational opportunities and barriers for blood-based biomarkers in Alzheimer’s disease: from discovery to implementation[J]. Journal of Army Medical University, 2025 , 47 (16) : 1825 -1837 . DOI: 10.16016/j.2097-0927.202505045
人口老龄化程度在全球范围持续加深,给社会和家庭带来沉重负担。阿尔茨海默病(Alzheimer’s disease,AD)是最常见的神经系统退行性疾病和老龄性痴呆,全球患有AD或其他类型痴呆症的人数已超过5 500万,我国AD患病形势亦愈加严峻[1-2]。近期靶向β淀粉样蛋白(amyloid-beta,Aβ)的单抗药物于国内外相继获批,为AD治疗带来重大突破,同时提出了AD早期、精准诊断的迫切需求[3-4]。
AD的诊断模式经历了从传统临床诊断到基于核心病理蛋白的生物学诊断的重要演变。这种新型生物学诊断模式可将诊断准确率从临床诊断的约75%显著提升至90%以上[5]。目前,AD诊断的金标准仍依赖于脑组织病理学检查,但由于脑活检在临床实践中的可行性限制,这一方法难以广泛应用。在实际临床工作中,基于核心病理标志物Aβ和Tau蛋白(一种微管相关蛋白,负责稳定微管结构,维持细胞骨架功能,其异常磷酸化或聚集可导致神经退行性病变)的正电子发射断层扫描(positron emission tomography,PET)成像技术已成为实际上的诊断“金标准”;而PET检查也存在费用昂贵、普及率低、检测耗时较长,以及单次扫描仅能检测一种生物标志物等不足[6]。除PET检查以外,脑脊液(cerebrospinal fluid,CSF)标志物检测近年也获批应用于临床,然而其有创性操作导致患者接受度普遍较低。
血液标志物(blood biomarkers,BBs)检测具有创伤小、成本低、可重复采样、一次检测多个标志物等优势,相较分子影像学及CSF标志物可及性高,具有广阔的应用前景[7]。然而,BB的临床应用尚存在一系列挑战,包括浓度低导致难以测得、代谢干扰大导致结果不稳定等[8]。随着特异性抗体的研发以及超高灵敏度及全自动化检测平台的逐步应用,精准、稳定地检测血液中低浓度的AD标志物成为可能[9] 。正如阿尔茨海默病协会(Alzheimer’s association)在最新的2024 年AD诊断及分期标准中所述,BB的开发是近年来AD诊断领域最重要的进展,部分BB已显示出等价于CSF标志物(获批于监管部门)的高诊断效能,使得AD的生物学诊断变得更加广泛可及[10-12] 。本文基于AD生物标志物新框架阐述BB领域的问题、进展和前景,旨在推动其临床转化。
AD血液标志物快速发展,展现出诸多优势:能够早于影像学检测到AD相关病理变化,具备早期诊断潜力;较高的特异性有助于区分AD与其他神经退行性疾病;便于重复采样和检测,适用于动态检测病程进展和疗效评估;同时,其创伤小、成本低,易于覆盖更广泛的人群,提升医疗公平性。上述优势使AD血液标志物能够满足抗体治疗时代的临床需求,主要包括早期诊断、鉴别诊断、疾病分期与疗效监测以及医疗公平性提升。
AD病理在症状出现前15~20年就开始启动,当症状出现时提示已发生广泛、不可逆性损伤,此时干预治疗效果有限[13] 。新近靶向Aβ的免疫治疗(如Aducanumab、Lecanemab和Donanemab等抗体药物)可使早期AD患者认知下降延缓,但总体认知获益有限。将干预窗口进一步前移有望获得更佳疗效,表明及早诊断是成功防治AD的关键[3-4] 。体液标志物出现异常通常早于对应的分子影像学,因此BB适合用作早期筛查指标。
AD的临床症状主要包括进行性记忆障碍、执行功能障碍、视空间障碍、行为异常、失语、失用等。上述症状并非AD特有,可能由其他疾病引起,导致AD的临床诊断与病理诊断的符合率仅为75%左右。AD与其他神经退行性疾病(如路易体痴呆、额颞叶痴呆等)的区分是临床日常面临的现实问题。AD特异性的BB可为鉴别诊断提供支持。
动态评估病理进展(如Aβ沉积、Tau磷酸化阶段)是适应抗体靶向治疗时代实现精准医疗、全程管理的前提[14] 。血液样本采集的便捷性使BB更加适用于重复检测、监测病程进展、评估治疗效果[15-17] 。
BB接受度高、检测便捷等优势极大地提高了AD早期诊断、精准分期以及疗效监测的可及性。未配置检测平台的中心也可在符合要求的运输条件下寄送血样至可靠的机构完成检测,弥补了低收入地区分子影像学等高端AD诊断技术不足。
为适应标志物领域新进展,2024年阿尔茨海默病协会将标志物框架更新为由淀粉样斑块(Aβ,A)、神经纤维缠结(Tau,T)、神经变性(neurodegeneration,N)、炎症/免疫机制(Inflammation,I)、血管性损伤(vascular brain injury,V)、突触核蛋白病理(α-synuclein,S)组成的ATNIVS框架,形成围绕AD核心病理标志物-非特异性标志物-共病理标志物的AD诊断、分期标准[5] 。
核心标志物是AD特异性标志物,按照标志物出现异常的阶段分为核心1和核心2两类。
核心1生物标志物主要包括A和T1两类,定义了可在活体内检测的AD初始阶段,可用于无症状个体早期诊断AD,以及确认某些认知受损个体的AD潜在病理。A类表示Aβ病理途径直接相关的生物标志物,由淀粉样前体蛋白(amyloid precursor protein,APP)酶解产生,主要包括Aβ38、Aβ40及Aβ42等。体液Aβ42/40浓度降低与脑内淀粉样沉积相关,CSF Aβ42/40已获批用于临床AD诊断,但由于外周代谢干扰等因素,血液Aβ42/40与脑淀粉样斑块沉积水平的相关性不高,与AD病理的关联存在争议[18] 。T1类别代表AD源性分泌型磷酸化Tau,主要包括pTau181、pTau217和pTau231等,这些pTau被认为与Aβ-PET近乎同时出现异常。近年来,血浆pTau检测在临床试验和观察性研究中表现出极佳的诊断性能[19]。与血浆Aβ测定不同,以pTau217为代表的血液pTau呈现偏态分布,在AD与认知正常对照人群中具有明显的浓度差,跨平台测定表现出较强的一致性,具有极高的诊断应用潜能[9]。
核心2标志物主要包括AD病程较后期表现异常的Tau片段(T2),主要反映Tau蛋白缠结的可溶性病理标志物,如其他类型磷酸化Tau蛋白(如pTau205)、微管结合区Tau片段(MTBR-Tau243)以及非磷酸化中段Tau片段。当与核心1标志物结合使用时,核心2标志物可以用于AD分期、分析症状与AD相关性、评估有症状人群进展速度以及无症状人群短期进展风险。核心2 血液标志物在临床应用前尚需更多的研究证据支持。
神经变性(N)标志物表示神经元损伤或神经元功能障碍。虽然神经变性是AD病理过程中的重要环节,但在非AD神经退行性疾病、外伤性脑损伤、缺血性损伤中也常有存在。这一类别的代表性标志物为神经纤维轻链(neurofilament light chain,NfL),神经损伤导致NfL分泌至细胞外并可在血液中被测得。尽管不是特定于AD,血液NfL仍是监测AD进展的优异神经变性标志物[20-21] 。阿尔茨海默病协会AD标志物的2018版框架中另一个代表性神经变性标志物总Tau(tTau),由于新近研究提示其反映神经变性的同时与pTau密切相关,在最新的标志物框架中并未纳入N类别。突触损伤相关的BB还包括神经颗粒素、突触小体相关蛋白25(SNAP25)、突触素1及生长相关蛋白43(GAP43)等,其直接检测以及联合血液神经源性外泌体的应用具有潜在的认知衰退评估及预后判断价值[22-24]。cfDNA是一种在细胞衰老和死亡过程中释放的DNA,通过其甲基化模式分析可识别组织特异性信息,进一步捕捉神经退行性变的总体信号[25-28] 。同样,血液细胞游离信使 RNA(cell-free messenger RNA,cf-mRNA)也具有反映AD 相关的神经退行性改变的潜力[29] 。
免疫炎症(I)相关标志物主要包括星形胶质细胞、小胶质细胞的反应性标志物及系统免疫炎性标志物等。大量证据表明,免疫炎症在AD发生发展过程中发挥重要作用。星形胶质细胞反应性的标志物——胶质纤维酸性蛋白(glial fibrillary acidic protein,GFAP)是最广泛应用的BB之一。虽然GFAP并非AD特异性标志物,但与早期Aβ-PET、较高的痴呆发生风险和更快的认知下降速度相关,血液中GFAP在辅助AD诊断等方面较CSF GFAP具有更好的表现。并且血液GFAP表现较CSF中的GFAP更好[30] 。几丁质酶-3样蛋白1(chitinase-3-like protein 1,CHI3L1/YKL-40) 是一种主要在星形胶质细胞中表达的糖蛋白,与固有免疫系统和神经炎症有关。血浆 YKL-40 水平升高与全脑体积减小、认知能力下降和新发痴呆风险增加相关[31] 。S100B是一种主要存在于星形胶质细胞中的Ca2+结合蛋白,也是反应性星形胶质细胞的标志物,S100B在AD的CSF和血浆中均升高[32] 。骨髓细胞表达的触发受体-2(triggering receptor expressed on myeloid cells-2,TREM2)是小胶质细胞膜上的受体,它直接与Aβ相互作用,这种作用限制了Aβ和Tau的病理增强。可溶性TREM2在AD中增加,并与CSF Aβ阳性患者中的T-Tau和pTau181相关[33] 。可溶性TREM2目前可在血液中进行检测,反映小胶质细胞的相关炎性反应[34] 。此外,系统性免疫伴随AD整个进程,相关BB也可用于反映AD脑内免疫炎性状态。一些非特异性的外周免疫炎症生物标志物,如肿瘤坏死因子、白细胞介素(如IL-6)、免疫球蛋白和补体家族可用于评估AD炎症状态[35]。趋化因子(chemokines)是参与控制免疫细胞迁移和驻留的化学趋化炎症介质,血液趋化因子如趋化因子(C-C基序) 配体1[Chemokine (C-C motif) ligand 1,CCL1]和C-X-C基序趋化因子配体9(C-X-C motif chemokine ligand 9,CXCL9)等可反映神经炎症及与其相关的认知障碍[36] 。此外,APOE基因型作为散发性AD最重要的相关基因,与AD炎症及代谢通路相关,APOE等载脂蛋白也可作为BB反映AD相关免疫炎症及代谢状态[37]。
AD在发生发展过程中除了以脑组织Aβ沉积及神经纤维缠结为代表的核心病理改变外,同时存在一系列共病理改变,主要包括血管脑损伤(V)和α-突触核蛋白(α-synuclein,S)两类,共病理生物标志物在AD鉴别诊断中具有重要价值。脑血管疾病(V)涵盖不同形式的血管病理或血管性脑损伤,主要经影像学反映。近期研究表明,脑血管相关疾病也可通过BB来得以反映,如血液胎盘生长因子(placental vrowth factor,PIGF)——一种促进新血管生成的分子,可帮助识别血管源性认知障碍[38] 。α-突触核蛋白种子扩增检测(α-synuclein seed amplification assay,αSyn-SAA)对α-突触核蛋白病理变化的识别具有较高敏感性和特异性,皮质α-突触核蛋白病理变化与认知下降相关但与Aβ和Tau病理无明显关联。CSF中的α-突触核蛋白种子扩增检测(αSyn-SAA)在帕金森病和路易体痴呆等神经元突触核蛋白病(neuronal synuclein disease,NSD)中被广泛应用,开发灵敏且准确的血液αSyn-SAA将极大促进该类疾病的诊断,近期研究表明血清和唾液的αSyn-SAA联合使用能够在PD诊断中实现高准确性,其效能不逊于CSF的αSyn-SAA,需要进一步验证[39] 。
近期针对细胞外囊泡及组学检测来源的AD血液标志物也逐渐得到重视,其临床应用价值有待进一步验证。血液脑源性细胞外囊泡(brain-derived extracellular vesicles,BDEVs)及内含物相较于常规BB检测,能够降低外周代谢影响,有望进一步提高AD核心标志物早期诊断的效能。BDEVs的分离是检测过程中的关键步骤,新近技术发展显著提高了BDEVs的分离效率并降低了成本,进一步提升了BDEVs的应用潜力[40] 。相较于当前诊断效能较低的血液Aβ标志物,基于免疫磁性外泌体聚合酶链反应(immunomagnetic exosomal polymerase chain reaction,iMEP)平台检测BDEVs中的Aβ42在区分AD患者与健康个体方面灵敏性和特异性均达95%,准确性高于细胞外囊泡中的pTau181和pTau396[41] 。基于纳米尺度流式细胞术(nanoscale flow cytometry,nFC)的BDEVs检测发现pTau231具有极高的AD诊断效能(AUC=0.96),与pTauS235结合后AUC可进一步提高至0.98[42] 。血液MicroRNA在AD进程中持续失调,具有AD诊断和预后评估潜能[43] 。细胞外基质和细胞信号传导相关的蛋白与Aβ斑块显著相关,包括SPARC相关模块化钙结合蛋白1(SPARC-related modular calcium-binding protein 1,SMOC1)、SPARC相关模块化钙结合蛋白2(SPARC-related modular calcium-binding protein 2,SMOC2)及脊椎蛋白1(spondin 1,SPON1)等,这一结论在不同组织(包括脑组织、CSF及血浆)、不同中心的多个蛋白组学研究中被反复印证,血浆SMOC1 、SMOC2及SPON1在AD早期升高,具有成为早期AD标志物的潜力[44-47] 。翻译后修饰导致的蛋白质结构异常与病理特性紧密相关,Tau蛋白的磷酸化及Aβ蛋白焦谷氨酸化是AD经典的蛋白修饰病理改变,多种新型修饰蛋白具有成为AD血液标志物的潜力[48] 。
ATNIVS标志物框架由2018年阿尔茨海默病协会提出的淀粉样蛋白-神经缠结-神经变性(Amyloid/pTau/neurodegeneration,ATN)框架演变而来,在其基础上提出了BB的应用前景,强调了核心标志物对AD诊断、分期的应用价值,神经变性及免疫炎症标志物对于AD协同诊断、分期及认知评估的应用潜力,以及共病理标志物对AD鉴别诊断的重要意义。由于ATN框架并未涵盖AD病理变化全范围,且随着研究深入新兴标志物层出不穷,研究者提出了开放性的ATX(N)、ATNX等框架,其中X代表与AD病理过程相关的其他生物标志物,包括免疫炎症、氧化应激、营养代谢及微血管病变等类别[49-50]。而2024版框架并未展开描述开放性标志物“X”,具有一定局限性。表1中总结了当前常用的AD血液标志物优缺点。目前AD血液标志物中最具临床应用前景的为核心1标志物,其中Aβ标志物的优势在于其理论核心地位(如经典Aβ级联假说中Aβ占据核心及上游部位),具有早期应用潜力。而由于Aβ自身黏性高的特性,同时外周组织可产生和清除Aβ(如血小板产生Aβ、肝肾对Aβ的清除代谢等),并且血液Aβ在AD和正常人群中变化幅度较小(仅8%~15%),导致血液Aβ临床转化困难。以pTau217为代表的一系列磷酸化Tau蛋白在AD诊断、预测、分期中展现了极高的应用价值,然而,pTau217并非AD特异性,随着研究深入,研究者发现pTau217在等特定研究场景诊断效能降低,在特定人群中难以区分某些疾病状态与AD。pTau231等具有分期潜能的BB仍处于概念性阶段,距离临床应用仍需大量人群研究加以验证。
目前AD血液标志物主要临床应用场景包括诊断与鉴别诊断、疾病分期及疗效监测。最新研究表明,AD血液标志物已初步具备在上述场景的应用能力[5]。为进一步推动其临床转化,仍需在多中心、多种族、大规模人群中开展验证性研究,评估其稳定性和可靠性,加速通过各地区监管机构的审批,实现正式临床应用。
BB诊断应用目前主要依据核心标志物1(结合临床判断),联合非AD共病理标志物等可进一步提高鉴别诊断效能,核心标志物2异常则提示AD是症状的主要贡献者。然而,并非所有可用的核心1血液标志物都具有足够的准确性以满足临床诊断需求。在拟应用人群中识别中度水平老年斑(脑Aβ病理)的准确性应达到90%(或经批准的替代指标,如PET或CSF获批指标)。在诊断方面,BB检测应用于临床应达到经批准的CSF检测的准确性。AD与对照人群CSF Aβ42/40的倍数差异约为50%,而血浆Aβ42/40仅为10%~15%,这种有限的诊断范围也部分解释了血浆Aβ42/40检测的临床稳健性较差的原因[7-8] 。此外,血液Aβ42/40诊断效能低还与Aβ性质不稳定、易黏附、外周代谢影响大有关。Aβ级联假说认为AD病理过程中Aβ占据最为核心及上游的位置,近期研究也发现血浆Aβ42/40异常早于Aβ-PET及CSF中对应标志物的改变,在AD诊断尤其是早期诊断中占有最重要的地位,进一步提示解决上述血液Aβ检测面临的问题是AD 血液标志物需要探索的重点[9] 。pTau217相关检测经过多个临床队列验证被认为已达到诊断及鉴别诊断准确性的要求,其准确性与已批准的CSF对应标志物性能相当,具备足够证据支持其临床应用价值[10-12] 。血液pTau181也具有良好的诊断价值,但其性能稍低于pTau217[51] 。针对pTau217与pTau212双位点的标志物的AD诊断效能较高[52] 。近期,单独的血浆pTau212也被证实在AD诊断及Aβ和Tau病理的检测中表现出与pTau217相似的高诊断效能,且优于pTau181和pTau231[53] 。此外,Aβ与pTau的混合比值(如pTau217/Aβ42)及多标志物联合模型、综合诊断模型(如Aβ42/40+pTau+APOE等)可进一步提高诊断效能[54-57] 。不同认知表型及其他神经系统疾病、系统性疾病共病患病情况可能影响血浆标志物诊断、预测性能,上述标志物在临床应用中仍需注意结合临床信息进行综合判断[58-59] 。
BB实际应用于AD临床诊断尚存在稳定性欠佳、地域及种族差异等问题,如我国人群基线数据尚缺乏,需要借助最新的检测技术基于多中心、大样本量、纵向队列进一步验证[60-61] 。近日,Lumipulse G血浆pTau217/Aβ42成为首个获得美国食品药品监督管理局(Food and Drug Administration,FDA)批准用于辅助AD诊断的血液体外诊断(in vitro diagnosis,IVD)。此前,基于质谱检测Aβ42/40(CN2)也获得了欧洲合格认证标志(conformité Européenne,CE)批准用于AD诊断。我国已有十余家公司围绕AD核心1标志物研发BB检测试剂并获得国内的第二类审批。
2024年最新的AD生物标志物诊断与分期框架中,进一步明确区分了生物学分期和临床分期,此部分主要讨论仅基于BB的分期方案[5]。该方案由AD病程的早期至晚期相应分为“ABCD”四类标志物:初始阶段(Initial-stage biomarkers,A)包括pTau217以及其他准确的血浆检测;早期阶段(Early-stage biomarkers,B)包括pTau205等其他类型的pTau;中期阶段(Intermediate-stage biomarkers,C)包括MTBR-tau243;晚期阶段(Advanced-stage biomarkers,D)包括非磷酸化Tau片段。近期研究证实p-Tau217不仅可用于AD诊断,还具有AD早期诊断的能力,而Aβ和pTau的组合也具有一定指示AD进展的能力,可以有效预测MCI个体的AD进展风险[62-64] 。目前对pTau205、MTBR-tau243和非磷酸化tau片段作为早期、中期和晚期液体标志物的验证仍处于概念阶段,待进一步研究。血浆内源性MTBR-tau243(eMTBR-tau243)与tau-PET及认知相关性强,优于其他血浆tau生物标志物(如%p-tau217和%p-tau205),是极具潜力的评估AD脑内Tau病理负荷的BB[17] 。
BB可作为临床试验入组及疗效监测指标[65] 。前期AD药物开发缓慢部分原因在于缺乏可获得且经济有效的生物标志物,导致临床试验参与者的招募和分层困难。抗Aβ抗体治疗前需明确脑内Aβ沉积。由于Aβ-PET和CSF Aβ42/40评估可及性、接受度较低,BB成为重点探索的替代指标。抗Aβ免疫疗法可以时间和剂量依赖的方式显著减少脑内Aβ斑块水平,使Aβ下游生物标志物(pTau、总Tau和GFAP等)向正常水平变化,因此Aβ及其下游血液生物标志物可用于疗效监测[15-16] 。血浆eMTBR-tau243等可用于监测Tau靶向治疗的疗效[17] 。在对于抗Aβ抗体治疗后个体应谨慎应用前述的血液生物标志物诊断、分期评估方案[4] 。
在AD血液标志物临床转化过程中,仍面临一系列质量控制及技术挑战,主要包括BB检测流程标准化问题、样本预处理规范化以及克服外周代谢干扰因素。构建标准化检测流程及严格的质控体系是BB临床应用的前提。样本预处理流程、检测样本类型以及样本储存条件等对AD血液标志物检测结果具有显著影响。共病等系统性代谢的影响是AD血液标志物临床转化亟待克服的干扰因素。解决上述问题是推动AD血液标志物临床转化的关键,也是未来重点研究方向。
AD 血液标志物检测水平受检测方法、平台、试剂批次、检测环境等多种因素影响,建立标准化分析方法以及严格的质控体系是划定可靠诊断阈值的基础和临床应用的前提。在对BB进行绝对值估计时需基于标准化参考物质,不同种族、地域之间BB可能存在差异,在阈值划定以及结果判读时需综合考虑或予以校正[62] 。
AD血液标志物由于其特性易受生物样本处理流程、储存条件等影响,如Aβ42易黏附,Tau磷酸化修饰对温度敏感。目前各研究中心在样本处理、标志物检测及结果分析等环节存在差异,如血液采集时间及部位、禁食状态、采集-离心间隔时长、环境温湿度以及离心参数等,导致难以获得稳定、统一的AD诊断界值[66] 。阿尔茨海默病协会已将全球CSF标志物标准化联盟质控计划拓展至BB,并提出了检测前血液样本标准化操作流程推荐[66-68] 。2024年的《阿尔茨海默病体液标志物临床应用中国指南》中提出了针对AD血液标志物的样本处理规范,如推荐使用乙二胺四乙酸(Ethylenediaminetetraacetic acid,EDTA)作为抗凝剂的血浆用于检测,血液采集及处理过程中接触的管材推荐使用聚丙烯(polypropylene,PP)材质等[69]。
AD 血液标志物水平受多方面影响,主要包括大脑产生和清除、外周产生和清除、大脑和外周血液间的交换能力。外周脏器组织对Aβ和Tau等AD 血液标志物存在显著影响,进而影响脑内病理水平[8,70] 。近期两项来自梅奥诊所老龄化研究(Mayo clinic study of aging,MCSA)发现,在异质性大、共病率高的人群中,系统代谢因素显著影响AD血液标志物,其中慢性肾病、心肌梗死和脑卒中影响最大。这些系统因素甚至不亚于脑内Aβ病理状态对BB的影响,干扰BB阈值划定和AD诊断应用[71-72]。此外,一些生物因素也可影响BB的水平,如年龄、体重指数、生物节律、睡眠、服用药物、生活方式等[8,70] 。因此,克服系统代谢的影响是AD血液标志物临床转化中亟待解决的重要问题。
AD血液标志物领域的迅速进展得益于检测技术的进步。新兴技术有效克服了传统检测的局限性,显著推动了AD血液标志物的临床应用:超高灵敏性检测方法弥补BB因浓度低而难以测得的缺陷;自动化检测平台显著降低了操作者、检测环境等差异导致的偏倚;特异性抗体研发进一步提高了BB的诊断、预测等效能,使其满足临床应用标准(等效于已获批的CSF标志物)。当前的研发方向集中于高灵敏度检测技术的进一步优化、微创/无创技术的开发以及人工智能(Artificial intelligence,AI)在辅助分析中的应用,进一步推动AD血液标志物的临床转化。
AD 血液标志物领域取得的显著进展得益于技术的进步,如特异性抗体以及超高灵敏度、全自动化检测平台的研发[73-79] 。传统的ELISA技术难以检测到低浓度BB,新近的单分子阵列(Single molecule array,Simoa)、微尺度多因子免疫检测平台(Meso scale discovery,MSD)、免疫磁性还原(Immunomagnetic Reduction,IMR)和核酸连接免疫夹心测定(Nucleic acid linked immuno-sandwich assay,NULISA)等技术检测阈广、检测下限低,可满足AD血液标志物检测,且检测所需体积小、可进行多重标志物检测,如NULISA仅需15 µL样本即可测量上百种分析物[62,80] 。基于质谱技术的C2N Diagnostics Precivity AD平台血液Aβ42/40 已获得CE批准用于临床。基于化学发光免疫测定的Fujirebio Lumipulse G平台的CSF Aβ42/40和基于电化学发光的Roche Elecsys Cobas平台的CSF pTau181/Aβ42和tTau/Aβ42已相继获得FDA及CE批准用于临床。上述平台血液pTau217及pTau217/Aβ42等AD诊断效能不逊于CSF标志物,有望近期获批用于临床[79] 。
一系列基于血液的新兴微创或无创技术逐步开发并用于AD 血液标志物检测。衰减全反射傅里叶变换红外光谱(Attenuated total reflection Fourier transform infrared spectroscopy,ATR-FTIR) 是一种非破坏性、快速、高灵敏度的分子分析技术,通过将样品与高折射率晶体接触,利用红外光与样品的相互作用,获得样品的分子振动信息和化学组成,已应用于AD血液检测[81] 。动态光散射(dynamic light scattering,DLS)技术用于测量蛋白质的布朗运动,提供有关粒子大小和浓度的信息,可用于AD诊断以及早期诊断研究[82] 。上述2种检测方法可基于血液样本的总体特性进行分析,具有无创性在体检测的潜力及临床推广应用价值。金属同位素DNA步行器是一种基于DNA纳米技术的创新工具,结合DNA酶和金属同位素的特性实现生物分子信号的自主放大与检测,适合血液低浓度多重生物标志物的筛查,目前已用于与AD相关BB检测[83] 。免疫磁性外泌体聚合酶链反应(iMEP)平台利用DNA结合抗体快速检测临床血液外泌体中的内含物,为血液外泌体中的AD生物标志物提供了一种有效的检测技术,具有极高的灵敏度和特异性,能够在临床实践中优化AD的早期诊断和监测[41]。多分析物自动微流控免疫测定(Simple PlexTM)的新型平台Ella现已进入AD生物标志物领域,可用于血浆NfL等检测[84]。新技术还包括Nano Mosaic和针对Aβ短片段(Aβ1-16、Aβ4-16、Aβ4-9、Aβ5-16、Aβ5-12、Aβ5-9、Aβ12-16等)的特殊检测等[80,85-86] 。
AD 血液标志物的AI辅助分析及基于机器学习的模型构建,是当前AD研究领域的前沿热点之一。利用AI技术及机器学习方法整合多种组学数据(如基因组学、转录组学、蛋白组学、蛋白修饰组学和代谢组学),可提高AD诊断、分期、预测及治疗效果评估的准确性。基于英国生物银行(UK Biobank)的基因组学、蛋白质组学、代谢组学以及用药数据训练的综合模型可有效预测AD发病年龄[87] 。AD 血液标志物结合影像学及临床信息构建模型可有效估算Tau缠结负荷和分布[88]。基于血液转录组学的机器学习建模能够识别出易进展为AD的轻度认知损害(mild cognitive impairment,MCI)患者[89]。基于机器学习结合血浆微小核糖核酸与AD核心BB建模可将区分能力提高多达9%[90]。需注意的是模型构建需要基于大样本量临床队列研究,尤其是高复杂度模型构建对样本量要求更为严格,且需要在人群中验证其稳健性。
随着检测技术的不断进展,AD 血液标志物在临床诊疗中的应用潜力逐步凸显。然而,AD 血液标志物从科研到临床的转化仍面临诸多挑战。未来应着眼于临床转化路径、多模态整合、个性化医疗潜力及全球和全国协作需求等方向进一步推动AD血液标志物临床转化。
短期内为应对AD靶向治疗时代的迫切需求,应尽快推动标准化BB检测平台落地。然而,AD 血液标志物从科研水平到初级医疗机构落地的临床转化路径尚存一系列挑战。目前基于部分高灵敏、全自动化检测平台的pTau217等BB已达到临床应用标准,但其稳定性仍需进一步验证。同时,检测平台仪器引入、维护成本高,同时由于血液受外周代谢等干扰,其临床应用需采取复孔及多标志物联合检测策略,进一步增加了成本。上述问题限制了AD血液标志物在初级医疗机构中的普及。为应对上述挑战,需要制定针对性临床应用指南以指导AD血液标志物的规范化临床应用。指南应包括前文提到的标准化检测流程、统一的样本预处理流程以及在诊断、分期、预测及治疗中的规范化应用[69]。初级诊疗中心将血样运输至有条件的高级诊疗中心进行检测可增加AD血液标志物检测的可及性。包含中间不确定区(灰区)的双界值划定法呈现一定容错率,更符合临床实际。对血液pTau217等检测结果判读时,低于cutoff低值时考虑为阴性(排除AD),高于cutoff高值时考虑为阳性(确诊AD),而对灰区内人群建议行PET检查或CSF标志物检测进一步确认。上述基于双界值的两步法路径,可大大减少AD诊断对PET检查及CSF检测的需求,节省临床资源,增加诊断筛查可及性。在国际层面,应进加速验证AD血液标志物准确性及稳定性,加强在大样本量人群队列、纵向队列中的验证,在真实世界临床及社区人群中的验证,以及在不同地域、种族以及患病群体中的验证。在国内层面,除上述应对策略,亟需自主研发符合高效能、高稳定性临床应用标准,同时满足低成本、高通量等临床推广实际需求的检测平台,使AD血液标志物的临床应用更加可及。
中期应借助快速发展的AI技术,探索基于BB的多模态整合对AD诊断等准确性及稳定性的提升,同时推动BB应用于早期诊断等不同场景。单一BB(如pTau217)或BB比值(如pTau217/ Aβ42)虽然已达到AD诊断临床转化的标准,但在AD早期诊断等应用场景能力仍然有限。基于AI及机器学习的方法,在AD血液标志物基础上联合临床基础信息、影像学、认知评估、风险基因、共病情况及蛋白修饰组学等多组学数据等进行多模态整合,极大程度提升了AD早期诊断的应用潜力,上述综合模型在临床应用前需在大样本量队列中验证其稳健性[88] 。
AD血液标志物在临床诊断及社区筛查等应用中普及后,长期应进一步探索BB的个性化医疗潜力。AD的发生发展在个体层面具有显著的异质性,不同AD患者所处病程、病理改变及共患病状态各有不同,导致临床表现和治疗反应也存在较大差异,为临床鉴别诊断以及精准治疗带来挑战。BB具有特异性,能够指导AD精准诊断与靶向治疗;BB同时具有多样性,能够覆盖AD发生发展进程之中的各个阶段,应用于病程监测及疗效评估。AD血液标志物具有个性化医疗潜力,为AD精准治疗提供了重要支撑。
最后,AD 血液标志物的临床应用还需要全球和全国范围的协作,尤其在多中心、多种族和大规模验证方面,以确保研究结果的外部效度和广泛适用性。应建立覆盖全球和国内不同地区的多中心AD研究队列,整合各研究中心的BB及相关信息、开发数据共享平台、倡导政策支持、资金投入用以技术开发和学术资源整合,推动AD血液标志物的临床转化。
BB研究的快速发展为AD的诊断、临床分期及疗效评估提供了革命性的解决方案。其微创性、便捷性及可重复检测等优势,使其成为临床实践中的理想工具。然而,AD血液标志物的临床转化仍面临诸多挑战,包括血样采集与处理流程的标准化、检测技术的规范化、跨平台结果的一致性、外周生物干扰因素的排除以及成本效益的优化等关键问题。未来,随着检测技术的持续革新、基于AI的多模态数据整合分析以及国际多中心协作的深入推进,BB有望重塑AD诊疗体系,为AD的早期筛查和精准干预提供重要支撑。

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doi: 10.16016/j.2097-0927.202505045
  • 接收时间:2025-05-21
  • 首发时间:2026-10-28
  • 出版时间:2025-08-30
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  • 收稿日期:2025-05-21
  • 修回日期:2025-06-20
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    1陆军特色医学中心(第三军医大学大坪医院)神经内科,衰老与脑疾病重庆市重点实验室,重庆

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王延江,医学博士,主任医师、教授、博士生导师,陆军军医大学大坪医院神经内科主任。获得国家杰出青年科学基金资助,入选教育部“长江学者”特聘教授、国家“万人计划”领军人才。担任中华医学会神经病学分会常委、中国神经科学学会理事、Vas-Cog Asia(亚洲血管性认知障碍学会)理事。承担国家重点研发计划、国家自然科学基金重点项目等课题,从系统角度探索阿尔茨海默病,提出新理论,发现新药物,建立新技术,开展全国和国际多中心临床试验进行转化研究。以通讯作者在PNAS、Nat Aging、Nat Rev Neurol、Lancet Infect Dis、JAMA Neurol、Sci Adv等杂志发表论文100余篇,获得国家科技进步二等奖、省部级一等奖、第20届Alzheimer Award 。E-mail:
WANG Yanjiang,E-mail:
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2种不同金属材料的力学参数
科
Family
属数
Number of
genus
种数
Number of
species
占总种数比例
Percentage of
total species (%)
属
Genus
种数
Number of
species
占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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