The early diagnosis of diseases frequently represents an important unmet clinical need supporting in-time treatment of pathologies. This also applies to neurodegenerative diseases such as Alzheimer's disease (AD), the most common form of dementia, estimated to affect millions of individuals worldwide. The respective diagnostic and prognostic markers, especially for the preclinical stages of AD, are expected to improve patients' outcome significantly. In the last decades, many approaches to detecting AD have been developed, including markers to discover changes in amyloid-β levels [from cerebrospinal fluid (CSF) or using positron emission tomography] or other brain imaging technologies such as structural magnetic resonance imaging (MRI), functional-connectivity MRI or task-related functional MRI. A major challenge is the detection of AD using minimally or even noninvasive biomarkers from body fluids such as plasma or serum. Circulating biomarker candidates based on mRNAs or proteins measured from blood cells, plasma or serum have been proposed for various pathologies including AD. As for other diseases, there is a tendency to use marker signatures obtained by high-throughput approaches, which allow the generation of profiles of hundreds to thousands of biomarkers simultaneously [microarrays, mass spectrometry or next-generation sequencing (NGS)]. Beyond mRNAs and proteins, recent approaches have measured small noncoding RNA (so-called microRNA) profiles in AD patients' blood samples using NGS or array-based technologies. Generally, the development of marker panels is in its early stages and requires further, substantial clinical validation. In this review, we provide an overview of different circulating AD biomarkers, starting with a brief summary of CSF markers and focusing on novel biomarker signatures such as small noncoding RNA profiles.

Keywords:
Biomarkers, Alzheimerߣs disease
1.
Alzheimer's Association: 2011 Alzheimer's disease facts and figures. Alzheimers Dement 2011;7:208-244.
2.
Huang HC, Jiang ZF: Accumulated amyloid-β peptide and hyperphosphorylated tau protein: relationship and links in Alzheimer's disease. J Alzheimers Dis 2009;16:15-27.
3.
Langbaum JB, et al: Ushering in the study and treatment of preclinical Alzheimer disease. Nat Rev Neurol 2013;9:371-381.
4.
Blennow K, et al: Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol 2010;6:131-144.
5.
Hampel H, et al: Core candidate neurochemical and imaging biomarkers of Alzheimer's disease. Alzheimers Dement 2008;4:38-48.
6.
Ma X, et al: DNA methylation data analysis and its application to cancer research. Epigenomics 2013;5:301-316.
7.
O'Bryant SE, et al: A blood-based screening tool for Alzheimer's disease that spans serum and plasma: findings from TARC and ADNI. PLoS One 2011;6:e28092.
8.
Snyder HM, et al: Developing novel blood-based biomarkers for Alzheimer's disease. Alzheimers Dement 2014;10:109-114.
9.
McNeill E, Van Vactor D: MicroRNAs shape the neuronal landscape. Neuron 2012;75:363-379.
10.
Augustin R, et al: Computational identification and experimental validation of microRNAs binding to the Alzheimer-related gene ADAM10. BMC Med Genet 2012;13:35.
11.
Leidinger P, et al: A blood based 12-miRNA signature of Alzheimer disease patients. Genome Biol 2013;14:R78.
12.
Etheridge A, et al: Extracellular microRNA: a new source of biomarkers. Mutat Res 2011;717:85-90.
13.
Guzman-Martinez L, Farias GA, Maccioni RB: Emerging noninvasive biomarkers for early detection of Alzheimer's disease. Arch Med Res 2012;43:663-666.
14.
Henriksen K, et al: The future of blood-based biomarkers for Alzheimer's disease. Alzheimers Dement 2014;10:115-131.
15.
Rye PD, et al: A novel blood test for the early detection of Alzheimer's disease. J Alzheimers Dis 2011;23:121-129.
16.
Lunnon K, et al: A blood gene expression marker of early Alzheimer's disease. J Alzheimers Dis 2013;33:737-753.
17.
Brys M, et al: Magnetic resonance imaging improves cerebrospinal fluid biomarkers in the early detection of Alzheimer's disease. J Alzheimers Dis 2009;16:351-362.
18.
Wright BL, Lai JT, Sinclair AJ: Cerebrospinal fluid and lumbar puncture: a practical review. J Neurol 2012;259:1530-1545.
19.
Anoop A, et al: CSF biomarkers for Alzheimer's disease diagnosis. Int J Alzheimers Dis 2010;2010:606802.
20.
Rosen C, et al: Fluid biomarkers in Alzheimer's disease - current concepts. Mol Neurodegener 2013;8:20.
21.
Formichi P, et al: Cerebrospinal fluid tau, Aβ, and phosphorylated tau protein for the diagnosis of Alzheimer's disease. J Cell Physiol 2006;208:39-46.
22.
Brys M, et al: Prediction and longitudinal study of CSF biomarkers in mild cognitive impairment. Neurobiol Aging 2009;30:682-690.
23.
Blennow K: CSF biomarkers for mild cognitive impairment. J Intern Med 2004;256:224-234.
24.
Liu CC, et al: Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 2013;9:106-118.
25.
Schmidt C, et al: Cerebrospinal fluid apolipoprotein E concentration and progression of Alzheimer's disease. J Alzheimers Dis 2015;43:1229-1236.
26.
Vanderstichele H, et al: Analytical performance and clinical utility of the INNOTEST® PHOSPHO-TAU(181P) assay for discrimination between Alzheimer's disease and dementia with Lewy bodies. Clin Chem Lab Med 2006;44:1472-1480.
27.
Maccioni RB, et al: Anomalously phosphorylated tau and Aβ fragments in the CSF correlates with cognitive impairment in MCI subjects. Neurobiol Aging 2006;27:237-244.
28.
de Leon MJ, et al: Longitudinal CSF and MRI biomarkers improve the diagnosis of mild cognitive impairment. Neurobiol Aging 2006;27:394-401.
29.
de Leon MJ, et al: MRI and CSF studies in the early diagnosis of Alzheimer's disease. J Intern Med 2004;256:205-223.
30.
Turnbull DK, Shepherd DB: Post-dural puncture headache: pathogenesis, prevention and treatment. Br J Anaesth 2003;91:718-729.
31.
Cedazo-Minguez A, Winblad B: Biomarkers for Alzheimer's disease and other forms of dementia: clinical needs, limitations and future aspects. Exp Gerontol 2010;45:5-14.
32.
Borroni B, et al: Blood cell markers in Alzheimer disease: amyloid precursor protein form ratio in platelets. Exp Gerontol 2010;45:53-56.
33.
Keller A, et al: A minimally invasive multiple marker approach allows highly efficient detection of meningioma tumors. BMC Bioinformatics 2006;7:539.
34.
Huang JX, et al: High-throughput genomic and proteomic analysis using microarray technology. Clin Chem 2001;47:1912-1916.
35.
Ray S, et al: Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins. Nat Med 2007;13:1359-1362.
36.
O'Bryant SE, et al: A serum protein-based algorithm for the detection of Alzheimer disease. Arch Neurol 2010;67:1077-1081.
37.
Hye A, et al: Plasma proteins predict conversion to dementia from prodromal disease. Alzheimers Dement 2014;10:799-807.
38.
Buerger K, et al: Blood-based microcirculation markers in Alzheimer's disease - diagnostic value of midregional pro-atrial natriuretic peptide/C-terminal endothelin-1 precursor fragment ratio. Biol Psychiatry 2009;65:979-984.
39.
Doecke JD, et al: Blood-based protein biomarkers for diagnosis of Alzheimer disease. Arch Neurol 2012;69:1318-1325.
40.
Di Paolo G, Kim TW: Linking lipids to Alzheimer's disease: cholesterol and beyond. Nat Rev Neurosci 2011;12:284-296.
41.
Wood PL: Lipidomics of Alzheimer's disease: current status. Alzheimers Res Ther 2012;4:5.
42.
Mapstone M, et al: Plasma phospholipids identify antecedent memory impairment in older adults. Nat Med 2014;20:415-418.
43.
Hartmann T, et al: A nutritional approach to ameliorate altered phospholipid metabolism in Alzheimer's disease. J Alzheimers Dis 2014;41:715-717.
44.
Sullivan PF, Fan C, Perou CM: Evaluating the comparability of gene expression in blood and brain. Am J Med Genet B Neuropsychiatr Genet 2006;141B:261-268.
45.
Booij BB, et al: A gene expression pattern in blood for the early detection of Alzheimer's disease. J Alzheimers Dis 2011;23:109-119.
46.
Grünblatt E, et al: Gene expression as peripheral biomarkers for sporadic Alzheimer's disease. J Alzheimers Dis 2009;16:627-634.
47.
Fehlbaum-Beurdeley P, et al: Validation of AclarusDx™, a blood-based transcriptomic signature for the diagnosis of Alzheimer's disease. J Alzheimers Dis 2012;32:169-181.
48.
Geekiyanage H, et al: Blood serum miRNA: non-invasive biomarkers for Alzheimer's disease. Exp Neurol 2012;235:491-496.
49.
Zen K, Zhang CY: Circulating microRNAs: a novel class of biomarkers to diagnose and monitor human cancers. Med Res Rev 2012;32:326-348.
50.
Tan L, et al: Circulating miR-125b as a biomarker of Alzheimer's disease. J Neurol Sci 2014;336:52-56.
51.
Tan L, et al: Genome-wide serum microRNA expression profiling identifies serum biomarkers for Alzheimer's disease. J Alzheimers Dis 2014;40:1017-1027.
52.
Kiko T, et al: MicroRNAs in plasma and cerebrospinal fluid as potential markers for Alzheimer's disease. J Alzheimers Dis 2014;39:253-259.
53.
Sheinerman KS, Umansky SR: Circulating cell-free microRNA as biomarkers for screening, diagnosis and monitoring of neurodegenerative diseases and other neurologic pathologies. Front Cell Neurosci 2013;7:150.
54.
McClean PL, et al: The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease. J Neurosci 2011;31:6587-6594.
55.
Beeri MS, et al: The effects of cardiovascular risk factors on cognitive compromise. Dialogues Clin Neurosci 2009;11:201-212.
56.
Kumar P, et al: Circulating miRNA biomarkers for Alzheimer's disease. PLoS One 2013;8:e69807.
57.
Alexandrov PN, et al: MicroRNA (miRNA) speciation in Alzheimer's disease (AD) cerebrospinal fluid (CSF) and extracellular fluid (ECF). Int J Biochem Mol Biol 2012;3:365-373.
58.
Teplyuk NM, et al: MicroRNAs in cerebrospinal fluid identify glioblastoma and metastatic brain cancers and reflect disease activity. Neuro Oncol 2012;14:689-700.
59.
Galimberti D, et al: Circulating miRNAs as potential biomarkers in Alzheimer's disease. J Alzheimers Dis 2014;42:1261-1267.
© 2015 S. Karger AG, Basel
2015
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.