Amyloid Beta and Tau as Alzheimer’s Disease Blood Biomarkers: Promise From New Technologies

The utility of the levels of amyloid beta (Aβ) peptide and tau in blood for diagnosis, drug development, and assessment of clinical trials for Alzheimer’s disease (AD) has not been established. The lack of availability of ultra-sensitive assays is one critical issue that has impeded progress. The levels of Aβ species and tau in plasma and serum are much lower than levels in cerebrospinal fluid. Furthermore, plasma or serum contain high levels of assay-interfering factors, resulting in difficulties in the commonly used singulex or multiplex ELISA platforms. In this review, we focus on two modern immune-complex-based technologies that show promise to advance this field. These innovative technologies are immunomagnetic reduction technology and single molecule array technology. We describe the technologies and discuss the published studies using these technologies. Currently, the potential of utilizing these technologies to advance Aβ and tau as blood-based biomarkers for AD requires further validation using already collected large sets of samples, as well as new cohorts and population-based longitudinal studies.

[1]  James Robert Brašić,et al.  An In Vivo Evaluation of Cerebral Cortical Amyloid with [18F]Flutemetamol Using Positron Emission Tomography Compared with Parietal Biopsy Samples in Living Normal Pressure Hydrocephalus Patients , 2013, Molecular Imaging and Biology.

[2]  Murray Grossman,et al.  CSF biomarkers cutoffs: the importance of coincident neuropathological diseases , 2012, Acta Neuropathologica.

[3]  J. Kaye,et al.  High cerebrospinal fluid tau and low amyloid beta42 levels in the clinical diagnosis of Alzheimer disease and relation to apolipoprotein E genotype. , 1998, Archives of neurology.

[4]  Philip S. Insel,et al.  Plasma tau in Alzheimer disease , 2016, Neurology.

[5]  J. Trojanowski,et al.  Improved protocol for measurement of plasma β-amyloid in longitudinal evaluation of Alzheimer’s Disease Neuroimaging Initiative study patients , 2012, Alzheimer's & Dementia.

[6]  M. Lubberink,et al.  Imaging β-amyloid using [18F]flutemetamol positron emission tomography: from dosimetry to clinical diagnosis , 2016, European Journal of Nuclear Medicine and Molecular Imaging.

[7]  R. Carare,et al.  Afferent and efferent immunological pathways of the brain. Anatomy, Function and Failure , 2014, Brain, Behavior, and Immunity.

[8]  H. Wiśniewski,et al.  Cerebrospinal fluid concentrations of soluble amyloid beta-protein and apolipoprotein E in patients with Alzheimer's disease: correlations with amyloid load in the brain. , 1996, Archives of neurology.

[9]  J. Trojanowski,et al.  Effect of Genetic Risk Factors and Disease Progression on the Cerebrospinal Fluid Tau Levels in Alzheimer's Disease , 1997, Journal of the American Geriatrics Society.

[10]  A. Fagan,et al.  Clinical utility of cerebrospinal fluid biomarkers in the diagnosis of early Alzheimer's disease , 2015, Alzheimer's & Dementia.

[11]  K. Blennow,et al.  Detailed comparison of amyloid PET and CSF biomarkers for identifying early Alzheimer disease , 2015, Neurology.

[12]  K. Blennow,et al.  Impact of cerebrospinal fluid matrix on the detection of Alzheimer's disease with Aβ42 and influence of disease on the total‐Aβ42/Aβ40 ratio , 2015, Journal of neurochemistry.

[13]  Charles DeCarli,et al.  Existing Pittsburgh Compound-B positron emission tomography thresholds are too high: statistical and pathological evaluation. , 2015, Brain : a journal of neurology.

[14]  P. Yip,et al.  New assay for old markers-plasma beta amyloid of mild cognitive impairment and Alzheimer's disease. , 2012, Current Alzheimer research.

[15]  S. Younkin,et al.  Plasma amyloid beta protein is elevated in late-onset Alzheimer disease families. , 2008, Neurology.

[16]  Henrik Zetterberg,et al.  The past and the future of Alzheimer's disease CSF biomarkers—a journey toward validated biochemical tests covering the whole spectrum of molecular events , 2015, Front. Neurosci..

[17]  Robert A. Dean,et al.  Florbetapir positron emission tomography and cerebrospinal fluid biomarkers , 2015, Alzheimer's & Dementia.

[18]  K. Blennow,et al.  CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis , 2016, The Lancet Neurology.

[19]  Henrik Zetterberg,et al.  Plasma tau levels in Alzheimer's disease , 2013, Alzheimer's Research & Therapy.

[20]  C. Jack,et al.  Update on the biomarker core of the Alzheimer's Disease Neuroimaging Initiative subjects , 2010, Alzheimer's & Dementia.

[21]  Anders Wallin,et al.  Simultaneous measurement of beta-amyloid(1-42), total tau, and phosphorylated tau (Thr181) in cerebrospinal fluid by the xMAP technology. , 2005, Clinical chemistry.

[22]  D. Sparks,et al.  Tau is reduced in AD plasma and validation of employed ELISA methods. , 2012, American journal of neurodegenerative disease.

[23]  Michael W. Weiner,et al.  2014 Update of the Alzheimer's Disease Neuroimaging Initiative: A review of papers published since its inception , 2015, Alzheimer's & Dementia.

[24]  M. Tabaton,et al.  Soluble amyloid beta-protein is a marker of Alzheimer amyloid in brain but not in cerebrospinal fluid. , 1994, Biochemical and biophysical research communications.

[25]  Thomas Wisniewski,et al.  Clearance systems in the brain—implications for Alzheimer disease , 2015, Nature Reviews Neurology.

[26]  K. Blennow,et al.  The clinical use of cerebrospinal fluid biomarker testing for Alzheimer's disease diagnosis: A consensus paper from the Alzheimer's Biomarkers Standardization Initiative , 2014, Alzheimer's & Dementia.

[27]  A. Nakamura,et al.  Novel plasma biomarker surrogating cerebral amyloid deposition , 2014, Proceedings of the Japan Academy. Series B, Physical and biological sciences.

[28]  A. Roses,et al.  Binding of IgG to amyloid βA4 peptide via the heavy-chain hinge region with preservation of antigen binding , 1993, Journal of Neuroimmunology.

[29]  P. Patel,et al.  Biomarkers in the Diagnosis and Prognosis of Alzheimer’s Disease , 2015, Journal of laboratory automation.

[30]  Chengjie Xiong,et al.  Longitudinal Cerebrospinal Fluid Biomarker Changes in Preclinical Alzheimer Disease During Middle Age. , 2015, JAMA neurology.

[31]  Ming-Jang Chiu,et al.  Combined plasma biomarkers for diagnosing mild cognition impairment and Alzheimer's disease. , 2013, ACS chemical neuroscience.

[32]  A. Monsch,et al.  Biomarkers of dementia: comparison of electrochemiluminescence results and reference ranges with conventional ELISA. , 2012, Methods.

[33]  J. Trojanowski,et al.  Association between in vivo fluorine 18-labeled flutemetamol amyloid positron emission tomography imaging and in vivo cerebral cortical histopathology. , 2011, Archives of neurology.

[34]  J. Morris,et al.  The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's disease , 2011, Alzheimer's & Dementia.

[35]  R. Petersen,et al.  Association of low plasma Abeta42/Abeta40 ratios with increased imminent risk for mild cognitive impairment and Alzheimer disease. , 2007, Archives of neurology.

[36]  David M. Rissin,et al.  Single-Molecule enzyme-linked immunosorbent assay detects serum proteins at subfemtomolar concentrations , 2010, Nature Biotechnology.

[37]  R. Petersen,et al.  Association of Low Plasma Aβ42/Aβ40 Ratios With Increased Imminent Risk for Mild Cognitive Impairment and Alzheimer Disease , 2007 .

[38]  Murray Grossman,et al.  Comparison of cerebrospinal fluid levels of tau and Aβ 1-42 in Alzheimer disease and frontotemporal degeneration using 2 analytical platforms. , 2012, Archives of neurology.

[39]  Holly Soares,et al.  Cerebrospinal fluid beta-amyloid1-42 and tau in control subjects at risk for Alzheimer's disease: the effect of APOE epsilon4 allele. , 2004, Biological psychiatry.

[40]  Leslie M. Shaw,et al.  Standardization of preanalytical aspects of cerebrospinal fluid biomarker testing for Alzheimer's disease diagnosis: A consensus paper from the Alzheimer's Biomarkers Standardization Initiative , 2012, Alzheimer's & Dementia.

[41]  B. Zlokovic,et al.  Impaired vascular-mediated clearance of brain amyloid beta in Alzheimer’s disease: the role, regulation and restoration of LRP1 , 2015, Front. Aging Neurosci..

[42]  C. Jack,et al.  Factors affecting Aβ plasma levels and their utility as biomarkers in ADNI , 2011, Acta Neuropathologica.

[43]  Ming-Jang Chiu,et al.  Plasma Aβ but not tau is related to brain PiB retention in early Alzheimer's disease. , 2014, ACS chemical neuroscience.

[44]  Holly Soares,et al.  Cerebrospinal fluid β-amyloid1–42 and tau in control subjects at risk for Alzheimer’s disease: The effect of APOE ε4 allele , 2004, Biological Psychiatry.

[45]  K. Blennow,et al.  Plasma β-amyloid in Alzheimer’s disease and vascular disease , 2016, Scientific Reports.

[46]  Ramon Diaz-Arrastia,et al.  Increases of Plasma Levels of Glial Fibrillary Acidic Protein, Tau, and Amyloid β up to 90 Days after Traumatic Brain Injury. , 2017, Journal of neurotrauma.

[47]  Kazuhiko Yanai,et al.  Advances in the development of tau PET radiotracers and their clinical applications , 2016, Ageing Research Reviews.

[48]  Clifford R. Jack,et al.  Clinicopathologic and 11C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer’s disease spectrum , 2015, Brain : a journal of neurology.

[49]  M. Delgado-Rodríguez,et al.  Systematic review and meta-analysis. , 2017, Medicina intensiva.

[50]  S. Younkin,et al.  Plasma amyloid β protein is elevated in late-onset Alzheimer disease families , 2008, Neurology.

[51]  Simone Lista,et al.  Comparing biological markers of Alzheimer's disease across blood fraction and platforms: Comparing apples to oranges , 2015, Alzheimer's & dementia.

[52]  Harald Hampel,et al.  Biological markers of amyloid β-related mechanisms in Alzheimer's disease , 2010, Experimental Neurology.

[53]  Philip S. Insel,et al.  Independent information from cerebrospinal fluid amyloid-β and florbetapir imaging in Alzheimer's disease. , 2015, Brain : a journal of neurology.

[54]  Mark E. Schmidt,et al.  The Alzheimer's Disease Neuroimaging Initiative: A review of papers published since its inception , 2012, Alzheimer's & Dementia.

[55]  K. Blennow,et al.  CSF A beta 42/A beta 40 and A beta 42/A beta 38 ratios: better diagnostic markers of Alzheimer disease , 2016 .

[56]  Joanne S. Robertson,et al.  Alzheimer's Disease Normative Cerebrospinal Fluid Biomarkers Validated in PET Amyloid-β Characterized Subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. , 2015, Journal of Alzheimer's disease : JAD.

[57]  C. Jack,et al.  LEVELS OF TAU PROTEIN IN PLASMA ARE ASSOCIATED WITH NEURODEGENERATION AND COGNITIVE FUNCTION IN A POPULATION-BASED ELDERLY COHORT , 2016, Alzheimer's & Dementia.

[58]  Michael W. Weiner,et al.  The future of blood-based biomarkers for Alzheimer's disease , 2014, Alzheimer's & Dementia.

[59]  S. Krishnan,et al.  Evaluation of Selenium, Redox Status and Their Association with Plasma Amyloid/Tau in Alzheimer’s Disease , 2014, Biological Trace Element Research.

[60]  Ya-Fang Chen,et al.  Plasma tau as a window to the brain—negative associations with brain volume and memory function in mild cognitive impairment and early alzheimer's disease , 2014, Human brain mapping.

[61]  F. Grodstein,et al.  Plasma amyloid-beta as a predictor of dementia and cognitive decline: A systematic review and meta-analysis , 2011, Alzheimer's & Dementia.

[62]  O. Hansson,et al.  Cerebrospinal fluid analysis detects cerebral amyloid-β accumulation earlier than positron emission tomography , 2016, Brain : a journal of neurology.

[63]  H. Vanderstichele,et al.  Potential sources of interference on Abeta immunoassays in biological samples , 2012, Alzheimer's Research & Therapy.

[64]  Henry Brodaty,et al.  Plasma protein profiling of Mild Cognitive Impairment and Alzheimer’s disease using iTRAQ quantitative proteomics , 2014, Proteome Science.

[65]  Denise C. Park,et al.  Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease , 2011, Alzheimer's & Dementia.

[66]  Sterling C. Johnson,et al.  Cerebrospinal fluid ratios with Aβ42 predict preclinical brain β-amyloid accumulation , 2015, Alzheimer's & dementia.

[67]  A. Fagan,et al.  Comparison of analytical platforms for cerebrospinal fluid measures of β-amyloid 1-42, total tau, and p-tau181 for identifying Alzheimer disease amyloid plaque pathology. , 2011, Archives of neurology.

[68]  J. Molinuevo,et al.  Validation of the AD-CSF-index in autopsy-confirmed Alzheimer's disease patients and healthy controls. , 2014, Journal of Alzheimer's disease : JAD.

[69]  J. Trojanowski,et al.  Plasma amyloid beta measurements - a desired but elusive Alzheimer's disease biomarker , 2013, Alzheimer's Research & Therapy.

[70]  Anders Wallin,et al.  Evaluation of plasma Aβ40 and Aβ42 as predictors of conversion to Alzheimer's disease in patients with mild cognitive impairment , 2010, Neurobiology of Aging.

[71]  Deborah Blacker,et al.  Plasma amyloid-β as a predictor of dementia and cognitive decline: a systematic review and meta-analysis. , 2012, Archives of neurology.

[72]  Michael W. Weiner,et al.  The Alzheimer’s Disease Neuroimaging Initiative 2 Biomarker Core: A review of progress and plans , 2015, Alzheimer's & Dementia.

[73]  K. Blennow,et al.  Assessing the commutability of reference material formats for the harmonization of amyloid-β measurements , 2016, Clinical chemistry and laboratory medicine.

[74]  Linan Song,et al.  Multiplexed single molecule immunoassays. , 2013, Lab on a chip.

[75]  Ming-Jang Chiu,et al.  Biofunctionalized magnetic nanoparticles for specifically detecting biomarkers of Alzheimer's disease in vitro. , 2011, ACS chemical neuroscience.

[76]  R. Petersen,et al.  Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects , 2009, Annals of neurology.

[77]  K. Blennow,et al.  CSF Aβ42/Aβ40 and Aβ42/Aβ38 ratios: better diagnostic markers of Alzheimer disease , 2016, Annals of clinical and translational neurology.

[78]  D. Lubarsky.  Comparing apples to oranges. , 1995, Anesthesia and analgesia.

[79]  T. Sunderland,et al.  Apolipoprotein E ϵ4 allele in association with global cognitive performance and CSF markers in Alzheimer's disease , 1998, International journal of geriatric psychiatry.

[80]  P. Snyder,et al.  Blood-based biomarkers in Alzheimer disease: Current state of the science and a novel collaborative paradigm for advancing from discovery to clinic , 2017, Alzheimer's & Dementia.

[81]  L. Tjernberg,et al.  Endogenous proteins controlling amyloid beta-peptide polymerization. Possible implications for beta-amyloid formation in the central nervous system and in peripheral tissues. , 1999, The Journal of biological chemistry.