一、AD癡呆診斷
一）滿足癡呆（認知障礙）診斷標準[1]
1、一個或多個認知域（復合性注意、執行能力、學習與記憶、語言、感知覺和社會認知）與個人以往相比明顯減退
2、影響日常生活獨立性（如工具性生活能力：付賬）
3、排除譫妄期，認知損害發生不是在譫妄期
4、上述損害不能用其他精神及情感性疾病來解釋（如：抑郁癥、精神分裂癥等）
二）臨床表現：晚發型好發于80-90歲，早發型好發于50-60歲，隱匿起病，漸進發展，無長時間平臺期，一個或多個認知領域受損，典型表現為遺忘，主要為情景記憶障礙，非典型表現包括雙側頂葉變異型，為視空間能力顯著受損伴有Gerstman綜合征、肢體失用/忽視；少詞變異型 AD中的少詞型原發進行性失語，為進行性單個詞語提取和句子重復障礙，而語義、語法、語言能力正常；額葉變異型AD以行為變異型額顳葉癡呆的表現為特征，包括進行性淡漠、脫抑制、刻板行為、執行功能減退；唐氏綜合征變異型 AD多伴早期行為改變、執行功能障礙。可伴有精神行為癥狀，早期常表現為淡漠和抑郁，晚期多為易怒、易激惹、好斗、精神恍惚等表現，疾病末期可出現步態異常，吞咽困難，失禁、肌陣攣和癲癇。[1,2-6]
三）神經心理學量表：
1、認知功能評估：
簡易精神狀態檢查（mini-mental state examination, MMSE）[7]：≤17分（文盲），≤20分（1-6年），≤24分（﹥6年）[8]
蒙特利爾認知評估(MOCA)[7]：13分（文盲），19分（小學畢業）或24分（初中畢業及以上）及以下[9]
臨床癡呆評定量表（clinical dementia rating scales, CDR）：無癡呆（0），可疑癡呆（0.5），輕度癡呆（1.0），中度癡呆（2.0），重度癡呆（3.0）[10]
Mattis癡呆評定量表 (Mattis Dementia Rating Scale, Mattis DRS)、7 min認知檢測量表、Addenbrooke’s認知檢查(Addenbrooke's Cognitive Examination, ACE)、畫鐘試驗（Clock drawing）、TheConsortium to Establish a Registry for Alzheimer's Disease neuropsychologicalbattery（CERAD）、5詞測試（5 words test）[7]
2、情景記憶[5-7]：邏輯記憶、Rey聽覺詞語學習測驗、California詞語學習測驗、自由和線索選擇性回憶測試、分類線索回憶
3、語言[1,7]：波士頓命名測驗、詞語流暢性測驗
4、視空間及執行功能[7]：Benton視覺保留測試（BentonVisual Retention Test, BVRT）、語言流暢測試（Verbal fluency tests）、威斯康辛卡片分類測試（Wisconsin Card Sorting test, WCST）、線索標記測試（Trail Making Test, TMT）、Stroop測試（Stroop test）
5、精神行為癥狀：神經精神癥狀問卷(neuropsychiatric inventory, NPI)、漢密爾頓抑郁量表、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）生物標記物[3-6]：
1、結構磁共振：主要表現為內側顳葉萎縮（包括海馬、內嗅皮層、杏仁核等），尤其是海馬萎縮[11,12]
2、FDG-PET：局部腦區低代謝：顳頂皮層，以記憶受損為主要表現的AD患者通常表現為顳頂聯合區、楔前葉、扣帶回后部低代謝，而以局灶性功能受損為表現的AD患者（語言、視空間等）表現為相應新皮層的低代謝[13,14]
3、PIB-PET：陽性，滯留增加[15]
4、腦脊液：Aβ1-42下降，Aβ1-42/Aβ1-40下降，t-tau升高，p-tau升高，[16]，2014版診斷指南提出單一的Aβ1-42不能單獨作為診斷標記物，需結合t-tau或p-tau。其中p-tau181是鑒別AD癡呆和非AD癡呆的最佳指標[17]。目前診斷閾值尚未統一。
5、基因：家族性遺傳基因：PSEN1、PSEN2、APP[18]，可據此診斷很可能AD[1]，早發型AD；散發型基因：ApoE?4，僅為危險因素，不能單獨作為診斷標記物[19]
2014版診斷標準將生物標記物分為診斷標記物和進展標記物，其中FDG-PET和結構磁共振為進展標記物，可以用來預測MCI向AD的轉化。
目前臨床診斷以臨床表現及神經心理學量表檢查為主
五）排除標準：病史：急性起病，早期出現以下癥狀：步態異常、癲癇、重度行為改變；臨床特點：局灶神經癥狀、早期出現椎體外系表現，早期出現幻覺，認知水平波動其他情況導致的記憶及相關癥狀：非AD癡呆，重度抑郁、腦血管疾病、中毒、炎癥、代謝障礙、內側顳葉MRI FLAIR或T2信號與傳染或血管損害一致
六）危險因素：頭顱外傷，年齡，性別（女），易感基因，唐氏綜合癥患者，多種血管危險因素（高血壓、高血脂、動脈硬化、冠心病、肥胖、糖尿病），腦血管病，高半胱氨酸血癥，低教育，缺乏運動的生活方式及不良的飲食習慣，易感性格，接觸有毒物質[1,20]
二、AD癡呆前期輕度認知障礙診斷
一）臨床表現：患者、知情者或臨床醫生可感知的認知變化，單域或多域認知功能減退，如記憶、執行功能、注意、語言、視空間，其中情境記憶障礙損傷尤其是延遲回憶缺陷更常見于源于AD的MCI，有記憶減退的客觀檢查證據(記憶下降程度低于年齡和文化相匹配的對照1.5個標準差以上)，進行性加重，日常生活能力保留，未達到癡呆的診斷標準[4,6,21,22] 。
二）神經心理學量表：
總體認知評估、日常生活能力、精神行為癥狀同AD癡呆
針對延遲回憶量表（2011版診斷標準推薦量表）：
自由和暗示選擇性提醒測試（thefree and cued selective reminding test, FCSRT）、Rey聽覺詞語學習測驗（The rey auditory verbal learning test, RAVLT）、California詞語學習測驗（Californiaverbal learning test, CVLT）
其他情景記憶測試量表（2011版診斷標準推薦量表）：
韋氏記憶量表邏輯記憶分測驗（Logical memory of the wechsler memory scalerevised）、韋氏記憶量表視覺再生測驗（Visual Reproduction subtests of theWechsler Memory Scale）、視覺延遲匹配其他認知領域（2011版診斷標準推薦量表）
連線測驗（the Trail Making Test）：執行功能；波士頓命名測驗（the Boston Naming Test）：語言；語義流暢性分類測驗（letter and category fluency）：語言；圖形臨摹(交叉五邊形、立方體、Rey-Osterreith復雜圖形)：視空間；數字廣度記憶（digit span forward）：注意
三）生物標記物[3,4,6,21]：
結構磁共振：內側顳葉萎縮伴隨海馬體積縮小是預測MCI向AD轉化的較好指標[23]，海馬萎縮的速率是區分MCI和NC的最佳標志[24]，研究發現在海馬萎縮基礎上加入皮層變薄模式（左側楔前葉，左側顳上溝和右側海馬旁回前部），可以提高預測MCI向AD轉化的準確率[25]，sMRI結合多元模式識別等數據分析證實對MCI診斷有效[26]。
FDG-PET：顳頂區低代謝率[27]
PIB-PET：陽性，滯留增加[28]
腦脊液：Aβ1-42：下降結合T-tau/P-tau：上升[16]
基因：家族型基因PSEN1，PSEN2，APP；散發型基因：ApoE ?4
排除標準：與癡呆期排除標準類似，需排除血管性疾病、外傷、藥物等其他原因引起的認知下降，需排除已達到癡呆人群
三、AD臨床前期
Jack等提出的生物標記物動態模型將AD臨床前期分為三個階段[29] ：
無癥狀腦內淀粉樣蛋白沉積：僅能檢測到腦脊液Aβ下降及amyloid-PET顯示Aβ沉積。
淀粉樣蛋白沉積+突觸損傷和/或神經退行性變：除階段1中的變化外，腦脊液t-tau和p-tau上升，FDG-PET在后扣帶回、楔前葉、顳頂區等腦區表現為低代謝率，出現皮層變薄和腦區灰質體積減少（外側和內側頂葉、后扣帶回、外側顳葉）及海馬萎縮[30] 。
淀粉樣蛋白+神經退行性變+輕微認知下降
除上述生物標記物一個或多個陽性外，出現輕微的認知下降，即主觀認知下降，主要表現為自我感覺與以往認知水平相比有所下降，與急性事件無關，無海馬型以往綜合征及非典型AD的臨床表現，MCI相關量表檢查正常，排除MCI、AD癡呆前期及AD，排除其他精神或神經源性疾病，內科疾病、藥物治療和藥物濫用引起的主觀認知下降[6,31,32]。
基因：家族型基因PSEN1，PSEN2，APP及其他如唐氏綜合癥21三體，根據2014版診斷標準可診斷癥狀前期AD（presymptomatic AD）；散發型基因ApoE ?4
未納入診斷標準的生物標記物，其診斷效率尚待進一步確定，這些因子單獨都不足以診斷AD，需互相組合，但組合方式仍在研究中。
炎癥相關因子：AD患者在臨床前期在腦內即發生炎癥反應，其腦內和外周血中可發現由神經小膠質細胞細胞而引起的多種細胞因子改變[33]。
腫瘤壞死因子：TNF-α在AD患者中外周血含量上升[34,35]，腦脊液中TNF-α明顯上升的患者更傾向于發展為AD[36]。
2、轉化因子：TGF-β是一種抗炎細胞因子，該因子的下降預示MCI更易發展為AD[36]；
3、白介素：IL-10：有研究發現AD和NC之間外周血IL-10含量存在差異[37,38]，但有研究發現NC與AD差異無明顯統計學意義[35]；IL-6：有研究認為IL-6是AD危險因素[38]，但也有研究發現其在NC和AD之間沒有差異[37]。
4、趨化因子如CCL5，CCL7，CCL15，CCL18，CXCL8[39,40]。
5、生長因子如血小板源性生長因子（PDGF）、粒細胞集落刺激因子（G-CSF）、表皮生長因子（EGF）、神經膠質細胞源性的神經營養因子（GDNF）、胰島素樣生長因子結合蛋白2（Insulin-like growth factor binding protein 2, IGFBP-2）、IGFBP-6[39,40]
6、補體因子H（complement factor H, CFH）：研究在AD和MCI中發生改變，但其在外周血中含量與AD呈正相關或負相關尚未得到統一結論[34,41]。
7、人類軟骨糖蛋白-39（YKL-40）：AD患者腦脊液中上升[42]，與Aβ42結合作為預測AD發展的生物標記物[43]。
二、AD病理相關如：
DYRK1A (dual specificitytyrosine-phosphorylation-regulated kinase 1A)：AD患者中含量較低[44]。
血漿類Aβ多肽APP669-711：其與血漿 Aβ1-42 比值的升高，鑒別pib+和pib-人群時，敏感性0.925,特異性0.955[45]。
外周血Aβ40、Aβ42及Aβ40/Aβ42可否作為生物標記物仍存在爭議，其研究結果存在較大變異性[30]
血小板APP：已知Aβ來源于APP，而血小板是人體APP的第二大來源，也是最主要的外周來源，因此血小板APP可成為十分有潛力的生物標記物[46]。
三、脂類組學：研究發現一些脂類對AD和aMCI的診斷也有一定幫助，如磷脂改變提示細胞膜完整性的破壞可能對臨床前期AD檢測敏感[47]，鏈甾醇下降[48]、神經鞘磷脂（尤其是長鏈脂肪酸）在AD患者中下降，神經酰胺在AD患者中含量上升[49]、異前列腺素改變，有氧化應激發生[50]。
四、基因組學
1、散發型AD相關基因：BIN1,CLU, CR1, PICALM, ABCA7, MS4A6A,EPHA1, CD33, CD2AP, PLD3[51-60]。中國漢族人群中 TREM2基因的變異可能增加AD發病風險[61]，這些基因只能作為一種危險因素，對疾病發展的預測沒有決定性作用。
2、miRNA：許多與APP相關的基因，均受miRNA影響，目前在AD患者局部腦區[62]、腦脊液(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]）均發現有miRNA改變
四、影像生物標記物
功能磁共振：多用于AD早期診斷研究，主要表現為DMN區域功能連接及活性下降，AD臨床前期和AD癡呆前期可同時伴有其他腦區活動的增強，作為代償[68,69]。
彌散張量成像：徑向擴散系數、平均彌散率和各向異性發生改變，顳葉、頂葉，額葉和胼胝體白質的破壞已證實有助于早期診斷aMCI，而在臨床前期僅有徑向擴散系數、平均彌散率的廣泛改變，受累范圍較小，主要在后扣帶回和內側顳葉[70-72]。
五、其他
叢生蛋白：在AD動物模型中發現有所上升[73]，但在 presymptomaticAD期亦未發現變化[74]；腦源性神經營養因子：變化存在爭議，有研究發現血清含量增高，有研究發現血清含量降低[35, 75]；類視錐蛋白：腦脊液中含量上升，預測NC和MCI認知的下降[76,77]；可溶性內皮細胞蛋白C受體（ Soluble endothelial protein C receptor,sEPCR）：具有促凝血和促炎作用，在AD患者中顯著增加[78]；血管緊張素：外周血含量增加[79]；NT-proBNP ：AD和MCI患者中均明顯增加[80]。
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