Review

The potential of circulating autoantibodies in the early diagnosis of Alzheimer’s disease

  • Received: 19 July 2017 Accepted: 21 August 2017 Published: 24 August 2017
  • Alzheimer’s disease (AD) is a devastating neurodegenerative disorder frequently diagnosed among the aged suffering with cognitive loss. Managing the disease has considerable economic impact on society. AD is characterized by the presence of amyloid plaque and neurofibrillary tangles, which accompany neuronal loss. There is currently no routine blood test to help to diagnose the disease. Direct tracking of AD-related molecules is difficult and costly because they are confined to the central nervous system. However, in early stage AD patients, some autoantibodies can cross the blood brain barrier to build the bridge from internal brain molecules to blood by crossing the blood brain barrier. Recent studies showed that autoantibodies which target AD-related molecules change quantitatively in the periphery along with AD pathology. More importantly, autoantibodies with different targets show diverse features in different stages of AD and in other similar kinds of dementias. This review introduces four main AD-related autoantibodies recognizing separately, amyloid-β precursor proteins, τ protein, S100b and phospholipid. While there is limited specificity and sensitivity for a single autoantibody biomarker for AD diagnosis, a combination analysis using several autoantibodies and traditional clinical diagnostics at the same time can be a promising topic for prospective research into early stage AD diagnosis.

    Citation: Wen Yin, Cordula M. Stover. The potential of circulating autoantibodies in the early diagnosis of Alzheimer’s disease[J]. AIMS Allergy and Immunology, 2017, 1(2): 62-70. doi: 10.3934/Allergy.2017.2.62

    Related Papers:

  • Alzheimer’s disease (AD) is a devastating neurodegenerative disorder frequently diagnosed among the aged suffering with cognitive loss. Managing the disease has considerable economic impact on society. AD is characterized by the presence of amyloid plaque and neurofibrillary tangles, which accompany neuronal loss. There is currently no routine blood test to help to diagnose the disease. Direct tracking of AD-related molecules is difficult and costly because they are confined to the central nervous system. However, in early stage AD patients, some autoantibodies can cross the blood brain barrier to build the bridge from internal brain molecules to blood by crossing the blood brain barrier. Recent studies showed that autoantibodies which target AD-related molecules change quantitatively in the periphery along with AD pathology. More importantly, autoantibodies with different targets show diverse features in different stages of AD and in other similar kinds of dementias. This review introduces four main AD-related autoantibodies recognizing separately, amyloid-β precursor proteins, τ protein, S100b and phospholipid. While there is limited specificity and sensitivity for a single autoantibody biomarker for AD diagnosis, a combination analysis using several autoantibodies and traditional clinical diagnostics at the same time can be a promising topic for prospective research into early stage AD diagnosis.


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    [1] Bateman RJ, Aisen PS, Strooper BD, et al. (2011) Autosomal-dominant Alzheimer's disease: A review and proposal for the prevention of Alzheimer's disease. Alzheimers Res Ther 3: 13–25. doi: 10.1186/alzrt72
    [2] Weiner HL, Frenkel D (2006) Immunology and immunotherapy of Alzheimer's disease. Nat Rev Immunol 6: 404–416. doi: 10.1038/nri1843
    [3] McKhann GM, Knopman DS, Chertkow H, et al. (2011) 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. Alzheimers Dement 7: 263–269. doi: 10.1016/j.jalz.2011.03.005
    [4] Prince M, Comas-Herrera A, Knapp M, et al. (2016) World Alzhemier Report 2016: Improving healthcare for people living with dementia.
    [5] Kumar A, Singh A, Ekavali (2015) A review on Alzheimer's disease pathophysiology and its management: An update. Pharmacol Rep 67: 195–203. doi: 10.1016/j.pharep.2014.09.004
    [6] Hampel H, Wilcock G, Andrieu S, et al. (2011) Biomarkers for Alzheimer's disease therapeutic trials. Prog Neurobiol 95: 579–593. doi: 10.1016/j.pneurobio.2010.11.005
    [7] D'Andrea MR (2003) Evidence linking neuronal cell death to autoimmunity in Alzheimer's disease. Brain Res 982: 19–30. doi: 10.1016/S0006-8993(03)02881-6
    [8] Lopategui CI, Herrera BA, Pentón RG (2014) The role of glial cells in Alzheimer disease: Potential therapeutic implications. Neurologia 29: 305–309. doi: 10.1016/j.nrl.2012.10.006
    [9] Roopenian DC, Akilesh S (2007) FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol 7: 715–725. doi: 10.1038/nri2155
    [10] Bartos A, Fialova L, Svarcova J, et al. (2012) Patients with Alzheimer disease have elevated intrathecal synthesis of antibodies against tau protein and heavy neurofilament. J Neuroimmunol 252: 100–105. doi: 10.1016/j.jneuroim.2012.08.001
    [11] Montagne A, Barnes SR, Sweeney MD, et al. (2015) Blood-brain barrier breakdown in the aging human hippocampus. Neuron 85: 296–302. doi: 10.1016/j.neuron.2014.12.032
    [12] Brimberg L, Mader S, Fujieda Y, et al. (2015) Antibodies as mediators of brain pathology. Trends Immunol 36: 709–724. doi: 10.1016/j.it.2015.09.008
    [13] Deane R, Sagare A, Hamm K, et al. (2005) IgG-assisted age-dependent clearance of Alzheimer's amyloid beta peptide by the blood-brain barrier neonatal Fc receptor. J Neurosci 25: 11495–11503. doi: 10.1523/JNEUROSCI.3697-05.2005
    [14] Craft JM, Watterson DM, Hirsch E, et al. (2005) Interleukin 1 receptor antagonist knockout mice show enhanced microglial activation and neuronal damage induced by intracerebroventricular infusion of human beta-amyloid. J Neuroinflamm 2: 1–9. doi: 10.1186/1742-2094-2-1
    [15] Finucane TE (2003) Alzheimer disease: Current concepts and emerging diagnostic and therapeutic strategies. Ann Intern Med 138: 400–410. doi: 10.7326/0003-4819-138-5-200303040-00010
    [16] Oprisiu R, Serot JM, Godefroy O, et al. (2006) Plasma amyloid-beta concentrations in Alzheimer's disease: an alternative hypothesis. Lancet Neurol 5: 1002–1003. doi: 10.1016/S1474-4422(06)70613-5
    [17] Sagare A, Deane R, Bell RD, et al. (2007) Clearance of amyloid-beta by circulating lipoprotein receptors. Nat Med 13: 1029–1031. doi: 10.1038/nm1635
    [18] Oh ES, Troncoso JC, Tucker SMF (2008) Maximizing the potential of plasma amyloid-beta as a diagnostic biomarker for Alzheimer's disease. Neuromol Med 10: 195–207. doi: 10.1007/s12017-008-8035-0
    [19] Nath A, Hall E, Tuzova M, et al. (2003) Autoantibodies to amyloid beta-peptide (A beta) are increased in Alzheimer's disease patients and A beta antibodies can enhance A beta neurotoxicity-Implications for disease pathogenesis and vaccine development. Neuromol Med 3: 29–39. doi: 10.1385/NMM:3:1:29
    [20] Mruthinti S, Buccafusco JJ, Hill WD, et al. (2004) Autoimmunity in Alzheimer's disease: Increased levels of circulating IgGs binding A beta and RAGE peptides. Neurobiol Aging 25: 1023–1032. doi: 10.1016/j.neurobiolaging.2003.11.001
    [21] Brettschneider S, Morgenthaler NG, Teipel SJ, et al. (2005) Decreased serum amyloid beta(1-42) autoantibody levels in Alzheimer's disease, determined by a newly developed immuno-precipitation assay with radiolabeled amyloid beta(1-42) peptide. Biol Psychiat 57: 813–816. doi: 10.1016/j.biopsych.2004.12.008
    [22] Li QY, Gordon M, Cao CH, et al. (2007) Improvement of a low pH antigen-antibody dissociation procedure for ELISA measurement of circulating anti-A beta antibodies. BMC Neurosci 8: 11–21. doi: 10.1186/1471-2202-8-11
    [23] Gustaw-Rothenberg KA, Siedlak SL, Bonda DJ, et al. (2010) Dissociated amyloid-beta antibody levels as a serum biomarker for the progression of Alzheimer's disease: A population-based study. Exp Gerontol 45: 47–52. doi: 10.1016/j.exger.2009.10.003
    [24] Ida N, Hartmann T, Pantel J, et al. (1996) Analysis of heterogeneous beta A4 peptides in human cerebrospinal fluid and blood by a newly developed sensitive Western blot assay. J Biol Chem 271: 22908–22914. doi: 10.1074/jbc.271.37.22908
    [25] Gruden MA, Davidova TB, Malisauskas M, et al. (2007) Differential neuroimmune markers to the onset of Alzheimer's disease neurodegeneration and dementia: Autoantibodies to Aβ (25–35) oligomers, S100b and neurotransmitters. J Neuroimmunol 186: 181–192. doi: 10.1016/j.jneuroim.2007.03.023
    [26] Deane R, Bell RD, Sagare A, et al. (2009) Clearance of amyloid-beta peptide across the blood-brain barrier: Implication for therapies in Alzheimer's disease. Cns Neurol Disord-Dr 8: 16–30. doi: 10.2174/187152709787601867
    [27] Cleveland DW, Hwo SY, Kirschner MW (1977) Purification of tau, a microtubule-associated protein that induces assembly of microtubules from purified tubulin. J Mol Biol 116: 207–225. doi: 10.1016/0022-2836(77)90213-3
    [28] Rosenmann H, Meiner Z, Geylis V, et al. (2006) Detection of circulating antibodies against tau protein in its unphosphorylated and in its neurofibrillary tangles-related phosphorylated state in Alzheimer' s disease and healthy subjects. Neurosci Lett 410: 90–93. doi: 10.1016/j.neulet.2006.01.072
    [29] Hromadkova L, Kolarova M, Jankovicova B, et al. (2015) Identification and characterization of natural antibodies against tau protein in an intravenous immunoglobulin product. J Neuroimmunol 289: 121–129. doi: 10.1016/j.jneuroim.2015.10.017
    [30] Pascual G, Wadia JS, Zhu XY, et al. (2017) Immunological memory to hyperphosphorylated tau in asymptomatic individuals. Acta Neuropathol 133: 767–783. doi: 10.1007/s00401-017-1705-y
    [31] Wang DD, Bordey A (2008) The astrocyte odyssey. Prog Neurobiol 86: 342–367.
    [32] Heizmann CW, Fritz G, Schafer BW (2002) S100 proteins: Structure, functions and pathology. Front Biosci 7: D1356–D1368.
    [33] Mrak RE, Griffin WST (2001) The role of activated astrocytes and of the neurotrophic cytokine S100B in the pathogenesis of Alzheimer's disease. Neurobiol Aging 22: 915–922. doi: 10.1016/S0197-4580(01)00293-7
    [34] Sheng JG, Mrak RE, Bales KR, et al. (2000) Overexpression of the neuritotrophic cytokine S100 beta precedes the appearance of neuritic beta-amyloid plaques in APPV717F mice. J Neurochem 74: 295–301.
    [35] Wu H, Brown EV, Acharya NK, et al. (2016) Age-dependent increase of blood-brain barrier permeability and neuron-binding autoantibodies in S100B knockout mice. Brain Res 1637: 154–167. doi: 10.1016/j.brainres.2016.02.026
    [36] Mecocci P, Parnetti L, Romano G, et al. (1995) Serum anti-GFAP and anti-S100 autoantibodies in brain aging, alzheimers-disease and vascular dementia. J Neuroimmunol 57: 165–170. doi: 10.1016/0165-5728(94)00180-V
    [37] McIntyre JA, Wagenknecht DR, Faulk WP (2006) Redox-reactive autoantibodies: Detection and physiological relevance. Autoimmun Rev 5: 76–83. doi: 10.1016/j.autrev.2005.07.009
    [38] Dekosky ST, Marek K (2003) Looking backward to move forward: Early detection of neurodegenerative disorders. Science 302: 830–834. doi: 10.1126/science.1090349
    [39] McIntyre JA, Wagenknecht DR, Faulk WP (2005) Autoantibodies unmasked by redox reactions. J Autoimmun 24: 311–317. doi: 10.1016/j.jaut.2005.03.005
    [40] Cabiedes J, Cabral AR, Alarcon-Segovia D (1998) Hidden anti-phospholipid antibodies in normal human sera circulate as immune complexes whose antigen can be removed by heat, acid, hypermolar buffers or phospholipase treatments. Eur J Immunol 28: 2108–2114. doi: 10.1002/(SICI)1521-4141(199807)28:07<2108::AID-IMMU2108>3.0.CO;2-R
    [41] Ischiropoulos H, Beckman JS (2003) Oxidative stress and nitration in neurodegeneration: Cause, effect, or association? J Clin Invest 111: 163–169. doi: 10.1172/JCI200317638
    [42] Cuajungco MP, Faget KY, Huang XD, et al. (2000) Metal chelation as a potential therapy for Alzheimer's disease. In: Growdon JH, Wurtman RJ, Corkin S, et al. Molecular Basis of Dementia. New York: New York Acad Sciences, 292–304.
    [43] McIntyre JA, Chapman J, Shavit E, et al. (2007) Redox-reactive autoantibodies in Alzheimer's patients'cerebrospinal fluids: Preliminary studies. Autoimmunity 40: 390–396. doi: 10.1080/08916930701421020
    [44] McIntyre JA, Ramsey CJ, Gitter BD, et al. (2015) Antiphospholipid autoantibodies as blood biomarkers for detection of early stage Alzheimer's disease. Autoimmunity 48: 344–351. doi: 10.3109/08916934.2015.1008464
    [45] Kankaanpaa J, Turunen SP, Moilanen V, et al. (2009) Cerebrospinal fluid antibodies to oxidized LDL are increased in Alzheimer's disease. Neurobiol Dis 33: 467–472. doi: 10.1016/j.nbd.2008.12.001
    [46] Weiner MW, Veitch DP, Aisen PS, et al. (2015) 2014 Update of the Alzheimer's disease neuroimaging initiative: A review of papers published since its inception. Alzheimers Dementn 11: e1–120. doi: 10.1016/j.jalz.2014.11.001
    [47] El Kadmiri N, Said N, Slassi I, et al. (2017) Biomarkers for Alzheimer disease: Classical and novel candidates' review. Neuroscience.
    [48] Nagele E, Han M, DeMarshall C, et al. (2011) Diagnosis of Alzheimer's disease based on disease-specific autoantibody profiles in human sera. PLoS One 6: e23112. doi: 10.1371/journal.pone.0023112
    [49] Oliveira-Júnior LCD, Santos FDAA, Goulart LR, et al. (2015) Epitope fingerprinting for recognition of the polyclonal serum autoantibodies of Alzheimer's disease. Biomed Res Int 2015: 1–8.
    [50] Reddy MM, Wilson R, Wilson J, et al. (2011) Identification of candidate IgG biomarkers for Alzheimer's disease via combinatorial library screening. Cell 144: 132–142. doi: 10.1016/j.cell.2010.11.054
    [51] Dubois B, Padovani A, Scheltens P, et al. (2016) Timely diagnosis for Alzheimer's disease: A literature review on benefits and challenges. J Alzheimers Dis 49: 617–631.
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