Lymphocytes, Platelets, Erythrocytes, and Exosomes as Possible Biomarkers for Alzheimer’s Disease Clinical Diagnosis

  • Ryszard PlutaEmail author
  • Marzena Ułamek-Kozioł
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1118)


In the aging world population, Alzheimer’s disease accounts for more than 70% of all cases of dementia and is the sixth leading cause of death. The neurodegenerative processes of this disorder can begin 10–20 years before the clinical symptoms develop. Postmortem brain autopsy of Alzheimer’s disease cases reveals characteristic hallmarks like extracellular amyloid plaques and intraneuronal neurofibrillary tangles and synaptic and neuronal disintegration with severe brain atrophy. Some studies have reported that platelets contain the amyloid protein precursor and the secretase enzymes required for the amyloidogenic processing of this protein. Thus, platelets can be a good blood cell-based marker to investigate the onset of Alzheimer’s disease. Other studies have indicated cellular and molecular alterations in erythrocytes and lymphocytes from Alzheimer’s disease subjects, which emphasize the systemic nature of the disorder. In addition, small extracellular vesicles called exosomes appear to be an important factor during the progression of the disease. These vesicles contain disease-associated molecules such as the amyloid protein precursor and tau protein. In this chapter, we will summarize the recent knowledge on the involvement of lymphocytes, erythrocytes, platelets, and exosomes in the development of Alzheimer’s disease. The data will be reviewed with a view to applying the above elements as Alzheimer’s disease early preclinical and late-stage biomarkers with potential use for clinical diagnosis, prognosis, and monitoring disease progression and treatment responses.


Alzheimer’s disease Biomarkers Platelets Lymphocytes Erythrocytes Exosomes Plasma 



The authors acknowledge the support provided by the Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland (T3).


  1. 1.
    Engedal K, Barca ML, Laks J, Selbaek G (2011) Depression in Alzheimer’s disease: specificity of depressive symptoms using three different clinical criteria. Int J Geriatr Psychiatry 26:944–951PubMedCrossRefGoogle Scholar
  2. 2.
    Villemagne VL, Pike KE, Chetelat G, Ellis KA, Mulligan RS, Bourgeat P et al (2011) Longitudinal assessment of Abeta and cognition in aging and Alzheimer disease. Ann Neurol 69:181–192PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA, Salvado O et al (2013) Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol 12:357–367PubMedCrossRefGoogle Scholar
  4. 4.
    Rushing NC, Sachs-Ericsson N, Steffens DC (2014) Neuropsychological indicators of preclinical Alzheimer’s disease among depressed older adults. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn 21:99–128PubMedCrossRefGoogle Scholar
  5. 5.
    Zhao QF, Tan L, Wang HF, Jiang T, Tan MS, Tan L et al (2016) The prevalence of neuropsychiatric symptoms in Alzheimer’s disease: systematic review and meta-analysis. J Affect Disord 190:264–271PubMedCrossRefGoogle Scholar
  6. 6.
    Landeiro F, Walsh K, Ghinai I, Mughal S, Nye E, Wace H et al (2018) Measuring quality of life of people with predementia and dementia and their caregivers: a systematic review protocol. BMJ Open 8:e019082. Scholar
  7. 7.
  8. 8.
    Hu Z, Zeng L, Huang Z, Zhang J, Li T (2007) The study of Golgi apparatus in Alzheimer’s disease. Neurochem Res 32:1265–1277PubMedCrossRefGoogle Scholar
  9. 9.
    Hebert LE, Beckett LA, Scherr PA, Evans DA (2001) Annual incidence of Alzheimer disease in the United States projected to the years 2000 through 2050. Alzheimer Dis Assoc Disord 15:169–173PubMedCrossRefGoogle Scholar
  10. 10.
    Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP (2013) The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement 9:63–75.e62. Scholar
  11. 11.
    Winblad B, Amouyel P, Andrieu S, Ballard C, Brayne C, Brodaty H et al (2016) Defeating Alzheimer’s disease and other dementias: a priority for European science and society. Lancet Neurol 15:455–532PubMedCrossRefGoogle Scholar
  12. 12.
    Canobbio I, Abubaker AA, Visconte C, Torti M, Pula G (2015) Role of amyloid peptides in vascular dysfunction and platelet dysregulation in Alzheimer’s disease. Front Cell Neurosci 9:65. Scholar
  13. 13.
    Pluta R, Furmaga-Jabłońska W, Maciejewski R, Ułamek-Kozioł M, Jabłoński M (2013) Brain ischemia activates β- and γ-secretase cleavage of amyloid precursor protein: significance in sporadic Alzheimer’s disease. Mol Neurobiol 47:425–434PubMedCrossRefGoogle Scholar
  14. 14.
    Pluta R, Jabłoński M, Ułamek-Kozioł M, Kocki J, Brzozowska J, Januszewski S et al (2013) Sporadic Alzheimer’s disease begins as episodes of brain ischemia and ischemically dysregulated Alzheimer’s disease genes. Mol Neurobiol 48:500–515PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Pluta R, Ułamek-Kozioł M, Januszewski S, Czuczwar SJ (2018) Platelets, lymphocytes and erythrocytes from Alzheimer’s disease patients: the quest for blood cell-based biomarkers. Folia Neuropathol 56:14–20PubMedCrossRefGoogle Scholar
  16. 16.
    Scheltens P, Blennow K, Breteler MM, de Strooper B, Frisoni GB, Salloway S et al (2016) Alzheimer’s disease. Lancet 388:505–517PubMedCrossRefGoogle Scholar
  17. 17.
    Pluta R, Kida E, Lossinsky AS, Golabek AA, Mossakowski MJ, Wisniewski HM (1994) Complete cerebral ischemia with short-term survival in rats induced by cardiac arrest. I. Extracellular accumulation of Alzheimer’s β-amyloid protein precursor in the brain. Brain Res 649:323–328PubMedCrossRefGoogle Scholar
  18. 18.
    Pluta R (2007) Ischemia-reperfusion pathways in Alzheimer’s disease. Nova Science Publisher, Inc., New York ISBN-10:1600217443Google Scholar
  19. 19.
    Pluta R, Ułamek M, Jabłoński M (2009) Alzheimer’s mechanisms in ischemic brain degeneration. Anat Rec 292:1863–1881CrossRefGoogle Scholar
  20. 20.
    Kocki J, Ułamek-Kozioł M, Bogucka-Kocka A, Januszewski S, Jabłoński M, Gil-Kulik P et al (2015) Dysregulation of amyloid precursor protein, β-secretase, presenilin 1 and 2 genes in the rat selectively vulnerable CA1 subfield of hippocampus following transient global brain ischemia. J Alzheimers Dis 47:1047–1056PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Pluta R, Kocki J, Ułamek-Kozioł M, Bogucka-Kocka A, Gil-Kulik P, Januszewski S et al (2016) Alzheimer-associated presenilin 2 gene is dysregulated in rat medial temporal lobe cortex after complete brain ischemia due to cardiac arrest. Pharmacol Rep 68:155–161PubMedCrossRefGoogle Scholar
  22. 22.
    Pluta R, Kocki J, Ułamek-Kozioł M, Petniak A, Gil-Kulik P, Januszewski S et al (2016) Discrepancy in expression of β-secretase and amyloid-β protein precursor in Alzheimer-related genes in the rat medial temporal lobe cortex following transient global brain ischemia. J Alzheimers Dis 51:1023–1031PubMedCrossRefGoogle Scholar
  23. 23.
    Ułamek-Kozioł M, Kocki J, Bogucka-Kocka A, Petniak A, Gil-Kulik P, Januszewski S et al (2016) Dysregulation of autophagy, mitophagy and apoptotic genes in the medial temporal lobe cortex in an ischemic model of Alzheimer’s disease. J Alzheimers Dis 54:113–121PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Ułamek-Kozioł M, Kocki J, Bogucka-Kocka A, Januszewski S, Bogucki J, Czuczwar SJ et al (2017) Autophagy, mitophagy and apoptotic gene changes in the hippocampal CA1 area in a rat ischemic model of Alzheimer’s disease. Pharmacol Rep 69:1289–1294PubMedCrossRefGoogle Scholar
  25. 25.
    Pluta R, Bogucka-Kocka A, Ułamek-Kozioł M, Bogucki J, Januszewski S, Kocki J et al (2018) Ischemic tau protein gene induction as an additional key factor driving development of Alzheimer’s phenotype changes in CA1 area of hippocampus in an ischemic model of Alzheimer’s disease. Pharmacol 70:881–884Google Scholar
  26. 26.
    Schaffer C, Sarad N, DeCrumpe A, Goswami D, Herrmann S, Morales J et al (2015) Biomarkers in the diagnosis and prognosis of Alzheimer’s disease. J Lab Autom 20:589–600PubMedCrossRefGoogle Scholar
  27. 27.
    McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH 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 7:263–269PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Blennow K, Hampel H, Weiner M, Zetterberg H (2010) Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol 6:131–144PubMedCrossRefGoogle Scholar
  29. 29.
    Fiandaca MS, Kapogiannis D, Mapstone M, Boxer A, Eitan E, Schwartz JB et al (2014) Identification of preclinical Alzheimer’s disease by a profile of pathogenic proteins in neurally derived blood exosomes: a case-control study. Alzheimers Dement 11:600–607PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Seeburger JL, Holder DJ, Combrinck M, Joachim C, Laterza O, Tanen M et al (2015) Cerebrospinal fluid biomarkers distinguish postmortem-confirmed Alzheimer’s disease from other dementias and healthy controls in the optima cohort. J Alzheimers Dis 44:525–539PubMedCrossRefGoogle Scholar
  31. 31.
    Perneczky R, Guo LH (2016) Plasma proteomics biomarkers in Alzheimer’s disease: latest advances and challenges. Methods Mol Biol 1303:521–529PubMedCrossRefGoogle Scholar
  32. 32.
    Mietelska-Porowska A, Wojda U (2017) T lymphocytes and inflammatory mediators in the interplay between brain and blood in Alzheimer’s disease: potential pools of new biomarkers. J Immunol Res 17. Scholar
  33. 33.
    Stevenson A, Lopez D, Khoo P, Kalaria RN, Mukaetova-Ladinska EB (2017) Exploring erythrocytes as blood biomarkers for Alzheimer’s disease. J Alzheimers Dis 60:845–857PubMedCrossRefGoogle Scholar
  34. 34.
    Wojsiat J, Laskowska-Kaszub K, Mietelska-Porowska A, Wojda U (2017) Search for Alzheimer’s disease biomarkers in blood cells: hypotheses-driven approach. Biomark Med 11:917–931PubMedCrossRefGoogle Scholar
  35. 35.
    Vella LJ, Hill AF, Cheng L (2016) Focus on extracellular vesicles: exosomes and their role in protein trafficking and biomarker potential in Alzheimer’s and Parkinson’s disease. Int J Mol Sci 17:173. Scholar
  36. 36.
    Yuyama K, Igarashi Y (2017) Exosomes as carriers of Alzheimer’s amyloid-β. Front Neurosci 11:229. Scholar
  37. 37.
    Veitinger M, Varga B, Guterres SB, Zellner M (2014) Platelets, a reliable source for peripheral Alzheimer’s disease biomarkers? Acta Neuropathol Commun 2:65. Scholar
  38. 38.
    Sakurai H, Hanyu H, Sato T, Kume K, Hirao K, Kanetaka H et al (2013) Effects of cilostazol on cognition and regional cerebral blood flow in patients with Alzheimer’s disease and cerebrovascular disease: a pilot study. Geriatr Gerontol Int 13:90–97PubMedCrossRefGoogle Scholar
  39. 39.
    Prodan CI, Szasz R, Vincent AS, Ross ED, Dale GL (2006) Coated platelets retain amyloid precursor protein on their surface. Platelets 17:56–60PubMedCrossRefGoogle Scholar
  40. 40.
    Prodan CI, Ross ED, Vincent AS, Dale GL (2008) Rate of progression in Alzheimer’s disease correlates with coated-platelet levels–a longitudinal study. Transl Res 152:99–102PubMedCrossRefGoogle Scholar
  41. 41.
    Neumann K, Farias G, Slachevsky A, Perez P, Maccioni RB (2011) Human platelet tau: a potential peripheral marker for Alzheimer’s disease. J Alzheimers Dis 25:103–109PubMedCrossRefGoogle Scholar
  42. 42.
    Farias G, Perez P, Slachevsky A, Maccioni RB (2012) Platelet tau pattern correlates with cognitive status in Alzheimer’s disease. J Alzheimers Dis 31:65–69PubMedCrossRefGoogle Scholar
  43. 43.
    Slachevsky A, Guzman-Martınez L, Delgado C, Reyes P, Farıas GA, Munoz-Neira C et al (2017) Tau platelets correlate with regional brain atrophy in patients with Alzheimer’s disease. J Alzheimers Dis 55:1595–1603PubMedCrossRefGoogle Scholar
  44. 44.
    Mota SI, Costa RO, Ferreira IL, Santana I, Caldeira GL, Padovano C et al (2015) Oxidative stress involving changes in Nrf2 and ER stress in early stages of Alzheimer’s disease. Biochim Biophys Acta 1852:1428–1441PubMedCrossRefGoogle Scholar
  45. 45.
    Wojsiat J, Prandelli C, Laskowska-Kaszub K, Martín Requero A, Wojda U (2015) Oxidative stress and aberrant cell cycle in Alzheimer’s disease lymphocytes: diagnostic prospects. J Alzheimers Dis 46:329–350PubMedCrossRefGoogle Scholar
  46. 46.
    Wojda U (2016) Alzheimer’s disease lymphocytes: potential for biomarkers. Biomark Med 10:1–4PubMedCrossRefGoogle Scholar
  47. 47.
    Kuhla A, Ludwig SC, Kuhla B, Münch G, Vollmar B (2015) Advanced glycation end products are mitogenic signals and trigger cell cycle reentry of neurons in Alzheimer’s disease brain. Neurobiol Aging 36:753–761PubMedCrossRefGoogle Scholar
  48. 48.
    Zhang J, Kong Q, Zhang Z, Ge P, Ba D, He W (2003) Telomere dysfunction of lymphocytes in patients with Alzheimer disease. Cogn Behav Neurol 16:170–176PubMedCrossRefGoogle Scholar
  49. 49.
    Richartz-Salzburger E, Batra A, Stransky E, Laske C, Köhler N, Bartels M et al (2007) Altered lymphocyte distribution in Alzheimer’s disease. J Psychiatr Res 41:174–178PubMedCrossRefGoogle Scholar
  50. 50.
    Da Mesquita SA, Ferreira C, Sousa JC, Correia-Neves M, Sousa N, Marques F (2016) Insights on the pathophysiology of Alzheimer’s disease: the crosstalk between amyloid pathology, neuroinflammation and the peripheral immune system. Neurosci Biobehav Rev 68:547–562PubMedCrossRefGoogle Scholar
  51. 51.
    Licastro F, Porcellini E (2016) Persistent infections, immune-senescence and Alzheimer’s disease. Oncoscience 3:135–142PubMedPubMedCentralGoogle Scholar
  52. 52.
    Schwartz M, Deczkowska A (2016) Neurological disease as a failure of brain-immune crosstalk: the multiple faces of neuroinflammation. Trends Immunol 37:668–679PubMedCrossRefGoogle Scholar
  53. 53.
    Deardorff WJ, Grossberg GT (2017) Targeting neuroinflammation in Alzheimer’s disease: evidence for NSAIDs and novel therapeutics. Expert Rev Neurother 17:17–32PubMedCrossRefGoogle Scholar
  54. 54.
    Kiko T, Nakagawa K, Satoh A, Tsuduki T, Furukawa K, Arai H et al (2012) Amyloid beta levels in human red blood cells. PLoS One 7(11):e49620. Scholar
  55. 55.
    Nakagawa K, Kiko T, Kuriwada S, Miyazawa T, Kimura F, Miyazawa T (2011) Amyloid β induces adhesion of erythrocytes to endothelial cells and affects endothelial viability and functionality. Biosci Biotechnol Biochem 75:2030–2033PubMedCrossRefGoogle Scholar
  56. 56.
    Nakagawa K, Kiko T, Miyazawa T, Sookwong P, Tsuduki T, Satoh A et al (2011) Amyloid β-induced erythrocytic damage and its attenuation by carotenoids. FEBS Lett 585:1249–1254PubMedCrossRefGoogle Scholar
  57. 57.
    Street JM, Barran PE, Mackay CL, Weidt S, Balmforth C, Walsh TS et al (2012) Identification and proteomic profiling of exosomes in human cerebrospinal fluid. J Transl Med 10. Scholar
  58. 58.
    Cheng L, Sun X, Scicluna BJ, Coleman BM, Hill AF (2013) Characterization and deep sequencing analysis of exosomal and non-exosomal miRNA in human urine. Kidney Int 86:433–444PubMedCrossRefGoogle Scholar
  59. 59.
    Cheng L, Sharples RA, Scicluna BJ, Hill AF (2014) Exosomes provide a protective and enriched source of miRNA for biomarker profiling compared to intracellular and cell-free blood. J Extracell Vesicles 3. Scholar
  60. 60.
    Kalra H, Drummen GPC, Mathivanan S (2016) Focus on extracellular vesicles: introducing the next small big thing. Int J Mol Sci 17:170. Scholar
  61. 61.
    Chiasserini D, van Weering JR, Piersma SR, Pham TV, Malekzadeh A, Teunissen CE et al (2014) Proteomic analysis of cerebrospinal fluid extracellular vesicles: a comprehensive dataset. J Proteome 106:191–204CrossRefGoogle Scholar
  62. 62.
    Saman S, Kim W, Raya M, Visnick Y, Miro S, Saman S et al (2012) Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J Biol Chem 287:3842–3849PubMedCrossRefGoogle Scholar
  63. 63.
    Lopez-Font I, Cuchillo-Ibanez I, Sogorb-Esteve A, Garcia-Ayllon MS, Saez-Valero J (2015) Transmembrane amyloid-related proteins in CSF as potential biomarkers for Alzheimer’s disease. Front Neurol 6:125. Scholar
  64. 64.
    Cheng L, Doecke JD, Sharples RA, Villemagne VL, Fowler CJ, Rembach A et al (2014) Prognostic serum miRNA biomarkers associated with Alzheimer’s disease shows concordance with neuropsychological and neuroimaging assessment. Mol Psychiatry 20:1188–1196PubMedCrossRefGoogle Scholar
  65. 65.
    Vingtdeux V, Sergeant N, Buee L (2012) Potential contribution of exosomes to the prion-like propagation of lesions in Alzheimer’s disease. Front Physiol 3:229. Scholar
  66. 66.
    Hamaguchi T, Eisele YS, Varvel NH, Lamb BT, Walker LC, Jucker M (2012) The presence of Aβ seeds, and not age per se, is critical to the initiation of Aβ deposition in the brain. Acta Neuropathol 123:31–37PubMedCrossRefGoogle Scholar
  67. 67.
    Nath S, Agholme L, Kurudenkandy FR, Granseth B, Marcusson J, Hallbeck M (2012) Spreading of neurodegenerative pathology via neuron-to-neuron transmission of β-amyloid. J Neurosci 32:8767–8777PubMedCrossRefGoogle Scholar
  68. 68.
    Domert J, Rao SB, Agholme L, Brorsson AC, Marcusson J, Hallbeck M et al (2014) Spreading of amyloid-β peptides via neuritic cell-to-cell transfer is dependent on insufficient cellular clearance. Neurobiol Dis 65:82–92PubMedCrossRefGoogle Scholar
  69. 69.
    Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A et al (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11:909–913PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Liu L, Drouet V, Wu JW, Witter MP, Small SA, Clelland C et al (2012) Trans-synaptic spread of tau pathology in vivo. PLoS One 7:e31302. doi: 10.1371/journal.pone.0031302PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Heneka TM, Carson MJ, Khoury JE, Landreth GE, Brosseron F, Feinstein DL et al (2015) Neuroinflammation in Alzheimer’s disease. Lancet Neurol 14:388–405PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Ghidoni R, Squitti R, Siotto M, Benussi L (2018) Innovative biomarkers for Alzheimer’s disease: focus on the hidden disease biomarkers. J Alzheimers Dis 62:1507–1518PubMedCrossRefGoogle Scholar
  73. 73.
    Polanco JC, Li C, Durisic N, Sullivan R, Götz J (2018) Exosomes taken up by neurons hijack the endosomal pathway to spread to interconnected neurons. Acta Neuropathol Commun 6(1):10. Scholar
  74. 74.
    Zheng T, Wu X, Wei X, Wang M, Zhang B (2018) The release and transmission of amyloid precursor protein via exosomes. Neurochem Int 114:18–253PubMedCrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Laboratory of Ischemic and Neurodegenerative Brain Research, Mossakowski Medical Research CentrePolish Academy of SciencesWarsawPoland
  2. 2.First Department of NeurologyInstitute of Psychiatry and NeurologyWarsawPoland

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