Research Progress of Early Biomarkers of Alzheimer's Disease in Peripheral Blood

doi:10.12114/j.issn.1007-9572.2019.00.264

Abstract

Abstract: The onset of Alzheimer's disease is concealed，and a series of pathological changes have occurred in the body several decades before the onset of dementia symptoms.Once patients are in the dementia period，there are currently no ideal drugs and therapies to alleviate the condition.Alzheimer's disease is positively correlated with aging，and the older the patient，the higher the risk of this illness.Screening appropriate biomarkers of Alzheimer's disease for its early diagnosis，prevention，detection，and treatment is important for preventing and delaying the development of Alzheimer's disease.Peripheral blood biomarkers are easy and repeatable to collect and detect，which makes them the most ideal source of biomarkers.In this paper，based on the classical Aβ and Tau protein mechanisms of Alzheimer's disease，the potential biomarkers in peripheral blood were reviewed.

Key words: Alzheimer disease, Biological markers, Early diagnosis, Review

摘要： 阿尔茨海默病发病隐匿，在痴呆症状出现前数十年，体内已产生一系列病理变化，一旦进入痴呆期，目前尚无理想的药物和疗法可缓解病情。其与衰老呈正相关，年龄越大，患病风险越高。筛选合适的生物标志物进行早期诊断、早预防、早发现、早治疗，对预防和延缓阿尔茨海默病的发展有着重要意义。外周血生物标志物易采集、易检测、可重复，是最理想的生物标志物来源。本文根据阿尔茨海默病经典的β淀粉样蛋白（Aβ）和Tau蛋白机制，梳理了部分外周血中潜在的生物标志物。

关键词: 阿尔茨海默病, 生物学标记, 早期诊断, 综述

WANG Xuesong,KONG Lihong,YU Chaochao, et al. Research Progress of Early Biomarkers of Alzheimer's Disease in Peripheral Blood　[J]. Chinese General Practice, 2020, 23(2): 136-140. DOI: 10.12114/j.issn.1007-9572.2019.00.264.
王雪松,孔立红,余超超等. 阿尔茨海默病外周血早期生物标志物的研究进展[J]. 中国全科医学, 2020, 23(2): 136-140. DOI: 10.12114/j.issn.1007-9572.2019.00.264.

References

［1］胡以松.我国痴呆流行病学调查现况［J］．内科理论与实践，2015，10（2）：80-86．DOI：10.16138/j.1673-6087.2015.02.002.
HU Y S.Epidemiological investigation of dementia in China［J］．Journal of Internal Medicine Concepts & Practice，2015，10（2）：80-86．DOI：10.16138/j.1673-6087.2015.02.002.
［2］Alzheimer's Association.2018 Alzheimer's disease facts and figures［J］．Alzheimer Dement，2018，14（3）：367-429.DOI：10.1016/j.jalz.2018.02.001.
［3］REIMAN E M，MCKHANN G M，ALBERT M S，et al．Alzheimer's disease：implications of the updated diagnostic and research criteria［J］．J Clin Psychiatry，2011，72（9）：1190-1196．DOI：10.4088/JCP.10087co1c.
［4］HONIG L S，VELLAS B，WOODWARD M，et al．Trial of solanezumab for mild dementia due to Alzheimer's disease［J］．N Engl J Med，2018，378（4）：321-330．DOI：10.1056/NEJMoa1705971.
［5］MCDADE E，BATEMAN R J.Stop Alzheimer's before it starts［J］．Nature，2017，547（7662）：153-155．DOI：10.1038/547153a.
［6］SPERLING R A，JOHNSON K A.Dementia：new criteria but no new treatments［J］．Lancet Neurol，2012，11（1）：4-5．DOI：10.1016/s1474-4422（11）70272-1.
［7］DUBOIS B，FELDMAN H H，JACOVA C，et al．Research criteria for the diagnosis of Alzheimer's disease：revising the NINCDS-ADRDA criteria［J］．Lancet Neurol，2007，6（8）：734-746．DOI：10.1016/S1474-4422（07）70178-3.
［8］DUBOIS B，FELDMAN H H，JACOVA C，et al．Revising the definition of Alzheimer's disease：a new lexicon［J］．Lancet Neurol，2010，9（11）：1118-1127．DOI：10.1016/S1474-4422（10）70223-4.
［9］DUBOIS B，FELDMAN H H，JACOVA C，et al．Advancing research diagnostic criteria for Alzheimer's disease：the IWG-2 criteria［J］．Lancet Neurol，2014，13（6）：614-629．DOI：10.1016/S1474-4422（14）70090-0.
［10］JACK C R Jr，KNOPMAN D S，JAGUST W J，et al．Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade［J］．Lancet Neurol，2010，9（1）：119-128．DOI：10.1016/S1474-4422（09）70299-6.
［11］DUBOIS B，HAMPEL H，FELDMAN H H，et al．Preclinical Alzheimer's disease：definition，natural history，and diagnostic criteria［J］．Alzheimers Dement，2016，12（3）：292-323．DOI：10.1016/j.jalz.2016.02.002.
［12］OLSSON B，LAUTNER R，ANDREASSON U，et al．CSF and blood biomarkers for the diagnosis of Alzheimer's disease：a systematic review and meta-analysis［J］．Lancet Neurol，2016，15（7）：673-684．DOI：10.1016/S1474-4422（16）00070-3.
［13］TEIPEL S，DRZEZGA A，GROTHE M J，et al．Multimodal imaging in Alzheimer's disease：validity and usefulness for early detection［J］．Lancet Neurol，2015，14（10）：1037-1053．DOI：10.1016/S1474-4422（15）00093-9.
［14］JACK C R Jr，BENNETT D A，BLENNOW K，et al．A/T/N：an unbiased descriptive classification scheme for Alzheimer disease biomarkers［J］．Neurology，2016，87（5）：539-547．DOI：10.1212/WNL.0000000000002923.
［15］JACK C R Jr，THERNEAU T M，WISTE H J，et al．Transition rates between amyloid and neurodegeneration biomarker states and to dementia：a population-based，longitudinal cohort study［J］．Lancet Neurol，2016，15（1）：56-64．DOI：10.1016/S1474-4422（15）00323-3.
［16］王俊，王延江.阿尔茨海默病生物标志物的研究进展、问题和展望［J］．中国医学前沿杂志（电子版），2016，8（11）：1-3．DOI：10.12037/YXQY.2016.11-01.
WANG J，WANG Y J.Research progress，problems and prospects of biomarkers for Alzheimer's disease［J］．Chinese Journal of the Frontiers of Medical Science（Electronic Version），2016，8（11）：1-3．DOI：10.12037/YXQY.2016.11-01.
［17］沈怡君.Aβ蛋白在阿尔兹海默病中的损伤机制以及研究进展［J］．中国实用神经疾病杂志，2015，18（1）：127-129．DOI：10.3969/j.issn.1673-5110.2015.01.082.
［18］LEISSRING M A.The AβCs of aβ-cleaving proteases［J］．J Biol Chem，2008，283（44）：29645-29649．DOI：10.1074/jbc.r800022200.
［19］MEHTA P.Amyloid beta protein as a marker or risk factor of Alzheimers disease［J］．CAR，2007，4（4）：359-363．DOI：10.2174/156720507781788891.
［20］SCHUPF N，TANG M X，FUKUYAMA H，et al．Peripheral Aβ subspecies as risk biomarkers of Alzheimer's disease［J］．Proc Natl Acad Sci USA，2008，105（37）：14052-14057．DOI：10.1073/pnas.0805902105.
［21］BLASKO I，KEMMLER G，JUNGWIRTH S，et al．Plasma amyloid beta-42 independently predicts both late-onset depression and Alzheimer disease［J］．Am J Geriatr Psychiatry，2010，18（11）：973-982．DOI：10.1097/JGP.0b013e3181df48be.
［22］ASSINI A，CAMMARATA S，VITALI A，et al．Plasma levels of amyloid beta-protein 42 are increased in women with mild cognitive impairment［J］．Neurology，2004，63（5）：828-831.
［23］JANELIDZE S，STOMRUD E，PALMQVIST S，et al．Plasma β-amyloid in Alzheimer's disease and vascular disease［J］．Sci Rep，2016，6：26801．DOI：10.1038/srep26801.
［24］MA F，WANG J H，MIAO R J，et al．The relationship of plasma Aβ levels to dementia in aging individuals with mild cognitive impairment［J］．J Neurol Sci，2011，305（1/2）：92-96．DOI：10.1016/j.jns.2011.03.005.
［25］YAMAZAKI C，TAMAOKI T，NUNOMURA A，et al．Plasma amyloid-β and Alzheimer's disease-related changes in late-life depression［J］．JAD，2017，58（2）：349-354．DOI：10.3233/jad-170111.
［26］L?VHEIM H，ELGH F，JOHANSSON A，et al．Plasma concentrations of free amyloid β cannot predict the development of Alzheimer's disease［J］．Alzheimers Dement，2017，13（7）：778-782．DOI：10.1016/j.jalz.2016.12.004.
［27］ZETTERBERG H，M?RTBERG E，SONG L N，et al．Hypoxia due to cardiac arrest induces a time-dependent increase in serum amyloid β levels in humans［J］．PLoS One，2011，6（12）：e28263．DOI：10.1371/journal.pone.0028263.
［28］SPILLANTINI M G，GOEDERT M.Tau pathology and neurodegeneration［J］．Lancet Neurol，2013，12（6）：609-622．DOI：10.1016/s1474-4422（13）70090-5.
［29］GRUNDKE-IQBAL I，IQBAL K，QUINLAN M，et al．Microtubule-associated protein tau.A component of Alzheimer paired helical filaments［J］．J Biol Chem，1986，261（13）：6084-6089.
［30］ITTNER L M，G?TZ J.Amyloid-β and tau—a toxic pas de deux in Alzheimer's disease［J］．Nat Rev Neurosci，2011，12（2）：65-72．DOI：10.1038/nrn2967.
［31］MATTSSON N，ZETTERBERG H，JANELIDZE S，et al．Plasma tau in Alzheimer disease［J］．Neurology，2016，87（17）：1827-1835．DOI：10.1212/WNL.0000000000003246.
［32］BLENNOW K，ZETTERBERG H，FAGAN A M.Fluid biomarkers in Alzheimer disease［J］．Cold Spring Harb Perspect Med，2012，2（9）：a006221．DOI：10.1101/cshperspect.a006221.
［33］BLENNOW K.Cerebrospinal fluid protein biomarkers for Alzheimer's disease［J］．NeuroRx，2004，1（2）：213-225．DOI：10.1602/neurorx.1.2.213.
［34］BUERGER K，EWERS M，PIRTTIL? T，et al．CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer's disease［J］．Brain，2006，129（Pt 11）：3035-3041．DOI：10.1093/brain/awl269.
［35］FIANDACA M S，KAPOGIANNIS D，MAPSTONE M，et al．Identification of preclinical Alzheimer's disease by a profile of pathogenic proteins in neurally derived blood exosomes：a case-control study［J］．Alzheimers Dement，2015，11（6）：600-607.e1．DOI：10.1016/j.jalz.2014.06.008.
［36］NOGUCHI-SHINOHARA M，HAMAGUCHI T，NOZAKI I，et al．
Serum tau protein as a marker for the diagnosis of Creutzfeldt-Jakob disease［J］．J Neurol，2011，258（8）：1464-1468．DOI：10.1007/s00415-011-5960-x.
［37］RANDALL J，M?RTBERG E，PROVUNCHER G K，et al．Tau proteins in serum predict neurological outcome after hypoxic brain injury from cardiac arrest：results of a pilot study［J］．Resuscitation，2013，84（3）：351-356．DOI：10.1016/j.resuscitation.2012.07.027.
［38］PASE M P，BEISER A S，HIMALI J J，et al．Assessment of plasma total Tau level as a predictive biomarker for dementia and related endophenotypes［J］．JAMA Neurol，2019．DOI：10.1001/jamaneurol.2018.4666.
［39］马腾，孙学华，孙顺昌，等．外周全血miR-29a/101在阿尔茨海默病中诊断价值的研究［J］．中华行为医学与脑科学杂志，2016，25（11）：1010-1014．DOI：10.3760/cma.j.issn.1674-6554.2016.11.011.
［40］XIE B，ZHOU H M，ZHANG R，et al．Serum miR-206 and miR-132 as potential circulating biomarkers for mild cognitive impairment［J］．J Alzheimers Dis，2015，45（3）：721-731．DOI：10.3233/JAD-142847.
［41］SHEINERMAN K S，TSIVINSKY V G，ABDULLAH L，et al．Plasma microRNA biomarkers for detection of mild cognitive impairment：biomarker validation study［J］．Aging （Albany NY），2013，5（12）：925-938．DOI：10.18632/aging.100624.
［42］WEINSTEIN G，BEISER A S，CHOI S H，et al．Serum brain-derived neurotrophic factor and the risk for dementia：the Framingham Heart Study［J］．JAMA Neurol，2014，71（1）：55-61．DOI：10.1001/jamaneurol.2013.4781.
［43］GEEKIYANAGE H，JICHA G A，NELSON P T，et al．Blood serum miRNA：non-invasive biomarkers for Alzheimer's disease［J］．Exp Neurol，2012，235（2）：491-496．DOI：10.1016/j.expneurol.2011.11.026.
［44］田代华（整理）.黄帝内经素问［M］．北京：人民卫生出版社，2017.
［45］SHARMA N，SINGH A N.Exploring biomarkers for Alzheimer's disease［J］．J Clin Diagn Res，2016，10（7）：KE01-6．DOI：10.7860/jcdr/2016/18828.8166.
［46］BURNHAM S C，ROWE C C，BAKER D，et al．Predicting Alzheimer disease from a blood-based biomarker profile：a 54-month follow-up［J］．Neurology，2016，87（11）：1093-1101．DOI：10.1212/WNL.0000000000003094.
［47］PETERSEN R C.Alzheimer's disease：progress in prediction［J］．Lancet Neurol，2010，9（1）：4-5．DOI：10.1016/S1474-4422（09）70330-8.

[1]	LIAO Kexin, XIAO Yisheng. Effects of the Compatibility Extract of Huangjing Pill on the Hippocampal DG Region Stem Cells in Rats with Learning and Memory Impairments [J]. Chinese General Practice, 2025, 28(24): 3019-3025.
[2]	YUAN Yiqing, CHEN Honglin. Research Progress on Stigma of Cognitive Disorders [J]. Chinese General Practice, 2025, 28(05): 631-638.
[3]	PENG Hongye, JING Yanan, LIU Dianchun, WANG Ying, XUE Xue, LU Chunli. Domestic and International Advances and Challenges in Early Diagnosis of Prediabetes with Integrated Chinese and Western Medicine [J]. Chinese General Practice, 2025, 28(03): 262-272.
[4]	YU Ruxia, JIANG Jing, WANG Qiucheng, WANG Yue, ZHAO Xiaoyue. The Hotspots and Frontier Trends of Artificial Intelligence in the Clinical Diagnosis and Treatment of Alzheimer's Disease: Bibliometric Analysis of the Past 20 Years [J]. Chinese General Practice, 2024, 27(26): 3218-3226.
[5]	ZHANG Yun, CAI Xinyi, DING Jingnuo, LU Shengwei, CHEN Cuiying, WU Tingting, ZHANG Junli, ZHAO Weifeng. Study on the Value of Oligosaccharide Chain and Alpha-fetoprotein for Risk Screening and Diagnosis of Hepatitis B Virus-related Hepatocellular Carcinoma [J]. Chinese General Practice, 2024, 27(15): 1855-1860.
[6]	ZHANG Yong, WANG Senli, HUANG Ronghua, XU Fengping, LIU Dan. Intervention Effect of Music Therapy on Patients with Alzheimers Disease: a Meta-analysis [J]. Chinese General Practice, 2024, 27(12): 1511-1518.
[7]	LI Yaping, LI Xia. Research Progress of Correlation and Underlying Mechanisms between Metabolic Syndrome and Alzheimer's Disease [J]. Chinese General Practice, 2024, 27(03): 268-272.
[8]	FAN Yun, DOU Runpeng, HU Jiulue, HOU Zijun, ZHOU Chunxiang. Modulation of Iron Death by Poric Acid through Nrf2/SLC7A11/GPX4 Signal Pathway in the Improvement of Cognitive Impairment of Alzheimer's Disease Rats [J]. Chinese General Practice, 2024, 27(02): 177-183.
[9]	XIN Gongkai, CONG Xin, YUAN Lei, CHENG Yuetong, NI Cuiping, ZHANG Weiwei, ZHANG Pingping, LIU Yu. Research Progress on Comprehensive Assessment Tools for the Elderly with Dementia [J]. Chinese General Practice, 2023, 26(33): 4103-4109.
[10]	ZHOU Sijing, LUO Bangan, CAO Hui, ZHANG Xi, WANG Dongxin. Epidemiological Characteristics of Dementia and Its Correlation with Multimorbidity among Residents Aged 65 and Above [J]. Chinese General Practice, 2023, 26(29): 3616-3621.
[11]	LI Yafeng. Clinical Manifestations and Experience of Diagnosis and Treatment of Lymphoid Tissue Infection Caused by Pseudomonas Aeruginosa [J]. Chinese General Practice, 2023, 26(15): 1923-1926.
[12]	YANG Haopeng, SUO Jingdong, SHEN Xianlei, WANG Dan, ZHU Xuemin, LIU Yuehua, LIANG Wannian. A Recommended "Dementia Prevention and Treatment Action Plan" Task List for China: WHO Global Action Perspective [J]. Chinese General Practice, 2023, 26(07): 775-779.
[13]	Dan WANG, Yuehua LIU, Xuemin ZHU, Haopeng YANG, Jingdong SUO, Xianlei SHEN, Wannian LIANG. Action Plans on Dementia from the WHO and 25 Countries (Regions) and Implications for China [J]. Chinese General Practice, 2022, 25(25): 3075-3082.
[14]	Jingwei LI, Qun LI, Shuo YANG, Zhirong RAN, Mingming ZHENG, Nannan ZHU, Peng CHENG, Yuanyuan CHEN, Li SHI, Xulai ZHANG. Amide Proton Transfer-weighted Imaging of Patients with Alzheimer's Disease [J]. Chinese General Practice, 2022, 25(24): 3005-3012.
[15]	Zhengting CAI, Lianxin HU, Zefeng WANG, Guangdong XIE, Xianwei LIN. Comparative Analysis of Several Common Screening and Assessment Scales for Childhood Autism Spectrum Disease [J]. Chinese General Practice, 2022, 25(24): 2998-3004.