一、AD痴呆诊断
一）满足痴呆（认知障碍）诊断标准[1]
1、一个或多个认知域（复合性注意、执行能力、学习与记忆、语言、感知觉和社会认知）与个人以往相比明显减退
2、影响日常生活独立性（如工具性生活能力：付账）
3、排除谵妄期，认知损害发生不是在谵妄期
4、上述损害不能用其他精神及情感性疾病来解释（如：抑郁症、精神分裂症等）
二）临床表现：晚发型好发于80-90岁，早发型好发于50-60岁，隐匿起病，渐进发展，无长时间平台期，一个或多个认知领域受损，典型表现为遗忘，主要为情景记忆障碍，非典型表现包括双侧顶叶变异型，为视空间能力显著受损伴有Gerstman综合征、肢体失用/忽视；少词变异型 AD中的少词型原发进行性失语，为进行性单个词语提取和句子重复障碍，而语义、语法、语言能力正常；额叶变异型AD以行为变异型额颞叶痴呆的表现为特征，包括进行性淡漠、脱抑制、刻板行为、执行功能减退；唐氏综合征变异型 AD多伴早期行为改变、执行功能障碍。可伴有精神行为症状，早期常表现为淡漠和抑郁，晚期多为易怒、易激惹、好斗、精神恍惚等表现，疾病末期可出现步态异常，吞咽困难，失禁、肌阵挛和癫痫。[1,2-6]
三）神经心理学量表：
1、认知功能评估：
简易精神状态检查（mini-mental state examination, MMSE）[7]：≤17分（文盲），≤20分（1-6年），≤24分（﹥6年）[8]
蒙特利尔认知评估(MOCA)[7]：13分（文盲），19分（小学毕业）或24分（初中毕业及以上）及以下[9]
临床痴呆评定量表（clinical dementia rating scales, CDR）：无痴呆（0），可疑痴呆（0.5），轻度痴呆（1.0），中度痴呆（2.0），重度痴呆（3.0）[10]
Mattis痴呆评定量表 (Mattis Dementia Rating Scale, Mattis DRS)、7 min认知检测量表、Addenbrooke’s认知检查(Addenbrooke's Cognitive Examination, ACE)、画钟试验（Clock drawing）、TheConsortium to Establish a Registry for Alzheimer's Disease neuropsychologicalbattery（CERAD）、5词测试（5 words test）[7]
2、情景记忆[5-7]：逻辑记忆、Rey听觉词语学习测验、California词语学习测验、自由和线索选择性回忆测试、分类线索回忆
3、语言[1,7]：波士顿命名测验、词语流畅性测验
4、视空间及执行功能[7]：Benton视觉保留测试（BentonVisual Retention Test, BVRT）、语言流畅测试（Verbal fluency tests）、威斯康辛卡片分类测试（Wisconsin Card Sorting test, WCST）、线索标记测试（Trail Making Test, TMT）、Stroop测试（Stroop test）
5、精神行为症状：神经精神症状问卷(neuropsychiatric inventory, NPI)、汉密尔顿抑郁量表、老年抑郁量表
6、日常生活能力：日常生活能力量表(activity of daily living，ADL)四）生物标记物[3-6]：
1、结构磁共振：主要表现为内侧颞叶萎缩（包括海马、内嗅皮层、杏仁核等），尤其是海马萎缩[11,12]
2、FDG-PET：局部脑区低代谢：颞顶皮层，以记忆受损为主要表现的AD患者通常表现为颞顶联合区、楔前叶、扣带回后部低代谢，而以局灶性功能受损为表现的AD患者（语言、视空间等）表现为相应新皮层的低代谢[13,14]
3、PIB-PET：阳性，滞留增加[15]
4、脑脊液：Aβ1-42下降，Aβ1-42/Aβ1-40下降，t-tau升高，p-tau升高，[16]，2014版诊断指南提出单一的Aβ1-42不能单独作为诊断标记物，需结合t-tau或p-tau。其中p-tau181是鉴别AD痴呆和非AD痴呆的最佳指标[17]。目前诊断阈值尚未统一。
5、基因：家族性遗传基因：PSEN1、PSEN2、APP[18]，可据此诊断很可能AD[1]，早发型AD；散发型基因：ApoEƐ4，仅为危险因素，不能单独作为诊断标记物[19]
2014版诊断标准将生物标记物分为诊断标记物和进展标记物，其中FDG-PET和结构磁共振为进展标记物，可以用来预测MCI向AD的转化。
目前临床诊断以临床表现及神经心理学量表检查为主
五）排除标准：病史：急性起病，早期出现以下症状：步态异常、癫痫、重度行为改变；临床特点：局灶神经症状、早期出现椎体外系表现，早期出现幻觉，认知水平波动其他情况导致的记忆及相关症状：非AD痴呆，重度抑郁、脑血管疾病、中毒、炎症、代谢障碍、内侧颞叶MRI FLAIR或T2信号与传染或血管损害一致
六）危险因素：头颅外伤，年龄，性别（女），易感基因，唐氏综合症患者，多种血管危险因素（高血压、高血脂、动脉硬化、冠心病、肥胖、糖尿病），脑血管病，高半胱氨酸血症，低教育，缺乏运动的生活方式及不良的饮食习惯，易感性格，接触有毒物质[1,20]
二、AD痴呆前期轻度认知障碍诊断
一）临床表现：患者、知情者或临床医生可感知的认知变化，单域或多域认知功能减退，如记忆、执行功能、注意、语言、视空间，其中情境记忆障碍损伤尤其是延迟回忆缺陷更常见于源于AD的MCI，有记忆减退的客观检查证据(记忆下降程度低于年龄和文化相匹配的对照1.5个标准差以上)，进行性加重，日常生活能力保留，未达到痴呆的诊断标准[4,6,21,22] 。
二）神经心理学量表：
总体认知评估、日常生活能力、精神行为症状同AD痴呆
针对延迟回忆量表（2011版诊断标准推荐量表）：
自由和暗示选择性提醒测试（thefree and cued selective reminding test, FCSRT）、Rey听觉词语学习测验（The rey auditory verbal learning test, RAVLT）、California词语学习测验（Californiaverbal learning test, CVLT）
其他情景记忆测试量表（2011版诊断标准推荐量表）：
韦氏记忆量表逻辑记忆分测验（Logical memory of the wechsler memory scalerevised）、韦氏记忆量表视觉再生测验（Visual Reproduction subtests of theWechsler Memory Scale）、视觉延迟匹配其他认知领域（2011版诊断标准推荐量表）
连线测验（the Trail Making Test）：执行功能；波士顿命名测验（the Boston Naming Test）：语言；语义流畅性分类测验（letter and category fluency）：语言；图形临摹(交叉五边形、立方体、Rey-Osterreith复杂图形)：视空间；数字广度记忆（digit span forward）：注意
三）生物标记物[3,4,6,21]：
结构磁共振：内侧颞叶萎缩伴随海马体积缩小是预测MCI向AD转化的较好指标[23]，海马萎缩的速率是区分MCI和NC的最佳标志[24]，研究发现在海马萎缩基础上加入皮层变薄模式（左侧楔前叶，左侧颞上沟和右侧海马旁回前部），可以提高预测MCI向AD转化的准确率[25]，sMRI结合多元模式识别等数据分析证实对MCI诊断有效[26]。
FDG-PET：颞顶区低代谢率[27]
PIB-PET：阳性，滞留增加[28]
脑脊液：Aβ1-42：下降结合T-tau/P-tau：上升[16]
基因：家族型基因PSEN1，PSEN2，APP；散发型基因：ApoE Ɛ4
排除标准：与痴呆期排除标准类似，需排除血管性疾病、外伤、药物等其他原因引起的认知下降，需排除已达到痴呆人群
三、AD临床前期
Jack等提出的生物标记物动态模型将AD临床前期分为三个阶段[29] ：
无症状脑内淀粉样蛋白沉积：仅能检测到脑脊液Aβ下降及amyloid-PET显示Aβ沉积。
淀粉样蛋白沉积+突触损伤和/或神经退行性变：除阶段1中的变化外，脑脊液t-tau和p-tau上升，FDG-PET在后扣带回、楔前叶、颞顶区等脑区表现为低代谢率，出现皮层变薄和脑区灰质体积减少（外侧和内侧顶叶、后扣带回、外侧颞叶）及海马萎缩[30] 。
淀粉样蛋白+神经退行性变+轻微认知下降
除上述生物标记物一个或多个阳性外，出现轻微的认知下降，即主观认知下降，主要表现为自我感觉与以往认知水平相比有所下降，与急性事件无关，无海马型以往综合征及非典型AD的临床表现，MCI相关量表检查正常，排除MCI、AD痴呆前期及AD，排除其他精神或神经源性疾病，内科疾病、药物治疗和药物滥用引起的主观认知下降[6,31,32]。
基因：家族型基因PSEN1，PSEN2，APP及其他如唐氏综合症21三体，根据2014版诊断标准可诊断症状前期AD（presymptomatic AD）；散发型基因ApoE Ɛ4
未纳入诊断标准的生物标记物，其诊断效率尚待进一步确定，这些因子单独都不足以诊断AD，需互相组合，但组合方式仍在研究中。
炎症相关因子：AD患者在临床前期在脑内即发生炎症反应，其脑内和外周血中可发现由神经小胶质细胞细胞而引起的多种细胞因子改变[33]。
肿瘤坏死因子：TNF-α在AD患者中外周血含量上升[34,35]，脑脊液中TNF-α明显上升的患者更倾向于发展为AD[36]。
2、转化因子：TGF-β是一种抗炎细胞因子，该因子的下降预示MCI更易发展为AD[36]；
3、白介素：IL-10：有研究发现AD和NC之间外周血IL-10含量存在差异[37,38]，但有研究发现NC与AD差异无明显统计学意义[35]；IL-6：有研究认为IL-6是AD危险因素[38]，但也有研究发现其在NC和AD之间没有差异[37]。
4、趋化因子如CCL5，CCL7，CCL15，CCL18，CXCL8[39,40]。
5、生长因子如血小板源性生长因子（PDGF）、粒细胞集落刺激因子（G-CSF）、表皮生长因子（EGF）、神经胶质细胞源性的神经营养因子（GDNF）、胰岛素样生长因子结合蛋白2（Insulin-like growth factor binding protein 2, IGFBP-2）、IGFBP-6[39,40]
6、补体因子H（complement factor H, CFH）：研究在AD和MCI中发生改变，但其在外周血中含量与AD呈正相关或负相关尚未得到统一结论[34,41]。
7、人类软骨糖蛋白-39（YKL-40）：AD患者脑脊液中上升[42]，与Aβ42结合作为预测AD发展的生物标记物[43]。
二、AD病理相关如：
DYRK1A (dual specificitytyrosine-phosphorylation-regulated kinase 1A)：AD患者中含量较低[44]。
血浆类Aβ多肽APP669-711：其与血浆 Aβ1-42 比值的升高，鉴别pib+和pib-人群时，敏感性0.925,特异性0.955[45]。
外周血Aβ40、Aβ42及Aβ40/Aβ42可否作为生物标记物仍存在争议，其研究结果存在较大变异性[30]
血小板APP：已知Aβ来源于APP，而血小板是人体APP的第二大来源，也是最主要的外周来源，因此血小板APP可成为十分有潜力的生物标记物[46]。
三、脂类组学：研究发现一些脂类对AD和aMCI的诊断也有一定帮助，如磷脂改变提示细胞膜完整性的破坏可能对临床前期AD检测敏感[47]，链甾醇下降[48]、神经鞘磷脂（尤其是长链脂肪酸）在AD患者中下降，神经酰胺在AD患者中含量上升[49]、异前列腺素改变，有氧化应激发生[50]。
四、基因组学
1、散发型AD相关基因：BIN1,CLU, CR1, PICALM, ABCA7, MS4A6A,EPHA1, CD33, CD2AP, PLD3[51-60]。中国汉族人群中 TREM2基因的变异可能增加AD发病风险[61]，这些基因只能作为一种危险因素，对疾病发展的预测没有决定性作用。
2、miRNA：许多与APP相关的基因，均受miRNA影响，目前在AD患者局部脑区[62]、脑脊液(miRNA-9, miRNA-125b, miRNA-146a, miRNA-155等)[63]、外周血(miRNA128[64]、miRNA-125b[65]、miRNA-34a 和181b[66] 、 miRNA-342-3p[67]）均发现有miRNA改变
四、影像生物标记物
功能磁共振：多用于AD早期诊断研究，主要表现为DMN区域功能连接及活性下降，AD临床前期和AD痴呆前期可同时伴有其他脑区活动的增强，作为代偿[68,69]。
弥散张量成像：径向扩散系数、平均弥散率和各向异性发生改变，颞叶、顶叶，额叶和胼胝体白质的破坏已证实有助于早期诊断aMCI，而在临床前期仅有径向扩散系数、平均弥散率的广泛改变，受累范围较小，主要在后扣带回和内侧颞叶[70-72]。
五、其他
丛生蛋白：在AD动物模型中发现有所上升[73]，但在 presymptomaticAD期亦未发现变化[74]；脑源性神经营养因子：变化存在争议，有研究发现血清含量增高，有研究发现血清含量降低[35, 75]；类视锥蛋白：脑脊液中含量上升，预测NC和MCI认知的下降[76,77]；可溶性内皮细胞蛋白C受体（ Soluble endothelial protein C receptor,sEPCR）：具有促凝血和促炎作用，在AD患者中显著增加[78]；血管紧张素：外周血含量增加[79]；NT-proBNP ：AD和MCI患者中均明显增加[80]。
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