Skip to main content
SpringerLink
Log in

Molecular Markers of Early Diagnosis of Alzheimer Disease: Prospects for Research in Peripheral Tissues

  • Published:
Advances in Gerontology Aims and scope Submit manuscript

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of elderly and old-aged people. Cerebrospinal fluid (CSF) and peripheral tissues—lymphocytes and platelets, buccal and olfactory epithelium, and skin fibroblasts—are used for intravital diagnostics of the expression of signaling molecules (AD markers). There are several changes in the production of hyperphosphorylated τ-protein form, BACE1, and peptide Aβ42 in CSF in the case of AD, but CSF sampling can have a number of side effects. Biopsies of the epithelium and portions of blood are a less traumatic method of obtaining tissue samples for AD diagnosis. An increase in the expression of the hyperphosphorylated form of τ-protein is shown in the blood lymphocytes of AD patients. An increase in the content of high molecular forms of phosphorylated τ protein and amyloid precursor protein (APP) was also detected in the platelets of AD patients. Changes in the amount of two miRNA families, miR-132 and miR-134, were detected in blood cells 1–5 years before the manifestation of clinical signs of AD. An increase in the bound-calcium concentration, Aβ40 and Aβ42 peptide synthesis, and τ protein was observed in AD skin fibroblasts. In olfactory and buccal epithelia, an increase in the expression of hyperphosphorylated τ-protein form and Aβ peptide was detected in AD patients. The detection of AD markers in peripheral tissues available for biopsy is highly important for intravital diagnostics, prevention, and targeted treatment of AD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Illarioshkin, S.N., Early diagnosis of neurodegenerative diseases, Nervy, 2008, no. 1, pp. 11–13

    Google Scholar 

  2. Kvetnoy, I.M., Ernandes-Yago, Kh., Kventaya, T.V., et al., Diagnostic value of immunocytochemical identification of Tau-protein in human peripheral blood lymphocytes in Alzheimer’s disease, Immunologiya, 2001, vol. 22, no. 2, pp. 46–48

    Google Scholar 

  3. Pal’tsev, M.A., Kvetnoy, I.M., Polyakova, V.O., et al., Signaling molecules in buccal epithelium: optimized diagnostics of socially significant diseases, Mol. Med., 2012, no. 4, pp. 18–23

    Google Scholar 

  4. Alzheimer’s Association, 2016 Alzheimer’s disease facts and figures, Alzheimer’s Dementia, 2016, vol. 12, no. 4, pp. 459–509

    Google Scholar 

  5. Andreasen, N. and Blennow, K., ß-Amyloid (Aß) protein in cerebrospinal fluid as a biomarker for Alzheimer’s disease, Peptides, 2002, vol. 23, pp. 1205–1214

    Article  PubMed  CAS  Google Scholar 

  6. Arnold, S.E., Lee, E.B., Moberg, P.J., et al., Olfactory epithelium amyloid-beta and paired helical filamenttau pathology in Alzheimer disease, Ann. Neurol., 2010, vol. 67, no. 4, pp. 462–469

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Bezprozvanny, I., Calcium signaling and neurodegenerative diseases, Trends Mol. Med., 2009, vol. 15, no. 3, pp. 89–100

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Blennow, K. and Zetterberg, H., Cerebrospinal fluid biomarkers for Alzheimer’s disease, J. Alzheimer’s Dis., 2009, vol. 18, no. 2, pp. 413–417

    Article  CAS  Google Scholar 

  9. Blennow, K., Dubois, B., Fagan, A.M., et al., Clinical utility of cerebrospinal fluid biomarkers in the diagnosis of early Alzheimer’s disease, Alzheimer’s Dementia, 2015, vol. 11, pp. 58–69

    Article  PubMed  Google Scholar 

  10. Blennow, K. and Hampel, H., CSF markers for incipient Alzheimer’s disease, Lancet Neurol., 2003, vol. 2, pp. 605–613

    Article  PubMed  CAS  Google Scholar 

  11. Borchelt, D.R., Thinakaran, G., Eckman, C.B., et al., Familial Alzheimer’s disease-linked presenilin 1 variants elevate Aß1–42/1–40 ratio in vitro and in vivo, Neuron, 1996, vol. 17, no. 5, pp. 1005–1013

    Article  PubMed  CAS  Google Scholar 

  12. Brion, J.P., The role of neurofibrillary tangles in Alzheimer disease, Acta Neurol. Belg., 1998, vol. 98, no. 2, pp. 165–174

    PubMed  CAS  Google Scholar 

  13. Buerger, K., Alafuzoff, I., Ewers, M., et al., No correlation between CSF tau protein phosphorylated at threonine 181 with neocortical neurofibrillary pathology in Alzheimer disease, Brain, 2007, vol. 130, p. e82.

    Article  PubMed  Google Scholar 

  14. Buerger, K., Ewers, M., Andreasen, N., et al., Phosphorylated tau predicts rate of cognitive decline in MCI subjects: a comparative CSF study, Neurology, 2005, vol. 65, pp. 1502–1503

    Article  PubMed  CAS  Google Scholar 

  15. Citron, M., Westaway, D., Xia, W., et al., Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid ß-protein in both transfected cells and transgenic mice, Nat. Med., 1997, vol. 3, no. 1, pp. 67–72

    Article  PubMed  CAS  Google Scholar 

  16. Clark, L.F. and Kodadek, T., Advances in blood-based protein biomarkers for Alzheimer’s disease, Alzheimer’s Res. Ther., 2013, vol. 5, no. 3, p. 1.

    Google Scholar 

  17. Giannakopoulos, P., Kövari, E., Gold, G., et al., Pathological substrates of cognitive decline in Alzheimer’s disease, Front. Neurol. Neurosci., 2009, vol. 24, pp. 20–29

    Article  PubMed  Google Scholar 

  18. Giau, V.V., Bagyinszky, E., An, S.S., and Kim, S.Y., Role of apolipoprotein E in neurodegenerative diseases, Neuropsychiat. Dis. Treat., 2015, vol. 11, pp. 1723–1737

    Article  CAS  Google Scholar 

  19. Hampel, H., Buerger, K., Pruessner, J.C., et al., Correlation of cerebrospinal fluid levels of tau protein phosphorylated at threonine 231 with rates of hippocampal atrophy in Alzheimer disease, Arch. Neurol., 2005, vol. 62, pp. 770–773

    Article  PubMed  Google Scholar 

  20. Hampel, H., Buerger, K., Zinkowski, R., et al., Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study, Arch. Gen. Psychiatry, 2004, vol. 61, pp. 95–102

    Article  PubMed  CAS  Google Scholar 

  21. Hardy, J. and Selkoe, D.J., The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics, Science, 2002, vol. 297, no. 5580, pp. 353–356

    Article  PubMed  CAS  Google Scholar 

  22. Hattori, H., Matsumoto, M., Iwai, K., et al., The tau protein of oral epithelium increases in Alzheimer’s disease, J. Gerontol., Ser. A, 2002, vol. 57, no. 1, pp. 64–70

    Article  Google Scholar 

  23. Johnson, G.V. and Stoothoff, W.H., Tau phosphorylation in neuronal cell function and dysfunction, J. Cell Sci., 2004, vol. 117, no. 24, pp. 5721–5729

    Article  PubMed  CAS  Google Scholar 

  24. Kishi, T., Matsunaga, S., and Iwata, N., The effects of memantine on behavioral disturbances in patients with Alzheimer’s disease: a meta-analysis, Neuropsychiatr. Dis. Treat., 2017, vol. 13, pp. 1909–1928

    Article  PubMed  PubMed Central  Google Scholar 

  25. Kohnken, R., Buerger, K., Zinkowski, R., et al., Detection of tau phosphorylated at threonine 231 in cerebrospinal fluid of Alzheimer’s disease patients, Neurosci. Lett., 2000, vol. 287, pp. 187–190

    Article  PubMed  CAS  Google Scholar 

  26. Kventaia, T.V., Zuev, V.A., Kukanova, E.O., et al., Buccal epithelium as an object for early diagnostic of Alzheimers’s disease, V Int. Symp. “Interaction of the Nervous and Immune Systems in Health and Disease,” St. Petersburg, 2017, p. 44.

    Google Scholar 

  27. Kvetnoy, I.M., Hernandez-Yago, J., Kvetnaia, T.V., et al., Tauprotein expression in human blood lymphocytes: promising marker and suitable sample for lifetime diagnosis of Alzheimer’s disease, Neuroendocrinol. Lett., 2000, vol. 21, pp. 313–318

    PubMed  CAS  Google Scholar 

  28. Lawrence, E., Vegvari, C., Ower, A., et al., A systematic review of longitudinal studies which measure Alzheimer’s disease biomarkers, J. Alzheimer’s Dis., 2017, vol. 59, no. 4, pp. 1359–1379 doi 10.3233/JAD–170261

    Article  CAS  Google Scholar 

  29. Lee, J.K. and Kim, N.J., Recent advances in the inhibition of p38 MAPK as a potential strategy for the treatment of Alzheimer’s disease, Molecules, 2017, vol. 22, no. 8, p. E1287. doi 10.3390/molecules22081287

    Article  PubMed  CAS  Google Scholar 

  30. Leidinger, P., Backes, C., Deutscher, S., et al., A blood based 12-miRNA signature of Alzheimer disease patients, Genome Biol., 2013, vol. 14, no. 7, p. 78.

    Article  CAS  Google Scholar 

  31. Lin, H., Li, Q., Gu, K., et al., Design of multi-target agents for the treatment of Alzheimer’s disease based on tacrine, Curr. Top. Med. Chem., 2017, vol. 17, no. 24, p. 2715. doi 10.2174/1568026617666170717114944

    Google Scholar 

  32. Lo, R.Y., The borderland between normal aging and dementia, Tzu Chi Med. J., 2017, vol. 29, no. 2, pp. 65–71

    PubMed Central  Google Scholar 

  33. Maddalena, A., Papaßsotiropoulos, A., Muller-Tillmanns, B., et al., Biochemical diagnosis of Alzheimer disease by measuring the cerebrospinal fluid ratio of phosphorylated tau protein to ß-amyloid peptide42, Arch. Neurol., 2003, vol. 60, pp. 1202–1206

    Article  PubMed  Google Scholar 

  34. Mandelkow, E.M., Stamer, K., Vogel, R., et al., Clogging of axons by tau, inhibition of axonal traffic and starvation of synapses, Neurobiol. Aging, 2003, vol. 24, no. 8, pp. 1079–1085

    Article  PubMed  CAS  Google Scholar 

  35. Morris, G.P., Clark, I.A., and Vissel, B., Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer’s disease, Acta Neuropath. Commun., 2014, vol. 2, no. 135, pp. 1–21

    Google Scholar 

  36. Neumann, K., Farias, G., Slachevsky, A., et al., Human platelets tau: a potential peripheral marker for Alzheimer’s disease, J. Alzheimer’s Dis., 2011, vol. 25, no. 1, pp. 103–109

    Article  CAS  Google Scholar 

  37. Nguyen, T.T., Giau, V.V., and Vo, T.K., Current advances in transdermal delivery of drugs for Alzheimer’s disease, Indian J. Pharmacol., 2017, vol. 49, no. 2, pp. 145–154

    PubMed  PubMed Central  Google Scholar 

  38. Padovani, A., Borroni, B., Colciaghi, F., et al., Abnormalities in the pattern of platelet amyloid precursor protein forms in patients with mild cognitive impairment and Alzheimer disease, Arch. Neurol., 2002, vol. 59, no. 1, pp. 71–75

    Article  PubMed  Google Scholar 

  39. Pani, A., Dessi, S., Diaz, G., et al., Altered cholesterol ester cycle in skin fibroblasts from patients with Alzheimer’s disease, J. Alzheimer’s Dis., 2009, vol. 8, no. 4, pp. 829–841

    Article  CAS  Google Scholar 

  40. Panossian, L.A., Porter, V.R., Valenzuela, H.F., et al., Telomere shortening in T cells correlates with Alzheimer’s disease status, Neurobiol. Aging, 2003, vol. 24, no. 1, pp. 77–84

    Article  PubMed  CAS  Google Scholar 

  41. Peterson, C. and Goldman, J.E., Alterations in calcium content and biochemical processes in cultured skin fibroblasts from aged and Alzheimer donors, Proc. Natl. Acad. Sci. U.S.A., 1986, vol. 83, no. 8, pp. 2758–2762

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Peterson, C., Ratan, R.R., Shelanski, M.L., and Goldman, J.E., Cytosolic free calcium and cell spreading decrease in fibroblasts from aged and Alzheimer donors, Proc. Natl. Acad. Sci. U.S.A., 1986, vol. 83, no. 20, pp. 7999–8001

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Pouryamout, L., Dams, J., Wasem, J., et al., Economic evaluation of treatment options in patients with Alzheimer’s disease: a systematic review of cost-effectiveness analyses, Drugs, 2012, vol. 72, no. 6, pp. 789–802

    Article  PubMed  Google Scholar 

  44. Prati, F., Bottegoni, G., Bolognesi, M.L., and Cavalli, A., BACE-1 inhibitors: from recent single-target molecules to multitarget compounds for Alzheimer’s disease, J. Med. Chem., 2017. doi 10.1021/acs.jmedchem. 7b00393

    Google Scholar 

  45. Prince, M., Bryce, R., Albanese, E., et al., The global prevalence of dementia: a systematic review and metaanalysis, Alzheimer’s Dementia, 2013, vol. 9, no. 1, pp. 63–75

    Article  PubMed  Google Scholar 

  46. Prvulovic, D. and Hampel, H., Amyloid ß (Aß) and phospho-tau (p-tau) as diagnostic biomarkers in Alzheimer’s disease, Clin. Chem. Lab. Med., 2011, vol. 49, no. 3, pp. 367–374

    Article  PubMed  CAS  Google Scholar 

  47. Riemenschneider, M., Lautenschlager, N., Wagenpfeil, S., et al., Cerebrospinal fluid tau and beta-amyloid 42 proteins identify Alzheimer disease in subjects with mild cognitive impairment, Arch. Neurol., 2002, vol. 59, pp. 1729–1734

    Article  PubMed  CAS  Google Scholar 

  48. Ruan, Q., D’Onofrio, G., Sancarlo, D., et al., Potential neuroimaging biomarkers of pathologic brain changes in Mild Cognitive Impairment and Alzheimer’s disease: a systematic review, BMC Geriatr., 2016, vol. 16, p. 104.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Schupf, N., Tang, M.X., Fukuyama, H., et al., Peripheral Aß subspecies as risk biomarkers of Alzheimer’s disease, Proc. Natl. Acad. Sci. U.S.A., 2008, vol. 105, no. 37, pp. 14052–14057

    Article  PubMed  PubMed Central  Google Scholar 

  50. Sisodia, S.S., ß-Amyloid precursor protein cleavage by a membrane-bound protease, Proc. Natl. Acad. Sci. U.S.A., 1992, vol. 89, no. 13, pp. 6075–6079

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Sjögren, M., Vanderstichele, H., Agren, H., et al., Tau and Aß42 in cerebrospinal fluid from healthy adults 21–93 years of age: establishment of reference values, Clin. Chem., 2001, vol. 47, pp. 1776–1781

    PubMed  Google Scholar 

  52. Spires-Jones, T.L., Stoothoff, W.H., de Calignon, A., et al., Tau pathophysiology in neurodegeneration: a tangle disuse, Trends Neurosci., 2009, vol. 32, no. 3, pp. 150–159

    Article  PubMed  CAS  Google Scholar 

  53. Thomas, P., O’Callaghan, N.J., and Fenech, M., Telomere length in white blood cells, buccal cells and brain tissue and its variation with ageing and Alzheimer’s disease, Mech. Ageing Dev., 2008, vol. 129, no. 4, pp. 183–190.

    Article  PubMed  CAS  Google Scholar 

  54. Trojanowski, J.Q., Newman, P.D., Hill, W.D., and Lee, V.M., Human olfactory epithelium in normal aging, Alzheimer’s disease, and other neurodegenerative disorders, J. Comp. Neurol., 1991, vol. 310, no. 3, pp. 365–376

    Article  PubMed  CAS  Google Scholar 

  55. Vigo-Pelfrey, C., Seubert, P., Barbour, R., et al., Elevation of microtubule-associated protein tau in the cerebrospinal fluid of patients with Alzheimer’s disease, Neurology, 1995, vol. 45, pp. 788–793

    Article  PubMed  CAS  Google Scholar 

  56. Wenk, G.L., Neuropathologic changes in Alzheimer’s disease, J. Clin. Psychiatry, 2003, vol. 64, no. 19, pp. 7–10

    PubMed  Google Scholar 

  57. Williams, D.R., Tauopathies: classification and clinical update on neurodegenerative diseases associated with microtubule-associated protein tau, Int. Med. J., 2006, vol. 36, no. 10, pp. 652–660

    Article  CAS  Google Scholar 

  58. Younkin, S.G., Evidence that A beta 42 is the real culprit in Alzheimer’s disease, Ann. Neurol., 1995, vol. 37, no. 3, pp. 287–288

    Article  PubMed  CAS  Google Scholar 

  59. Yu, E.Y., Liao, Z.L., Tan, Y.F., et al., Efficacy and tolerance of Memantine monotherapy and combination therapy with Reinhartdt and Sea Cucumber Capsule on agitation in moderate to severe Alzheimer disease, Chin. Med. J., 2017, vol. 97, no. 27, pp. 2091–2094

    CAS  Google Scholar 

  60. Zhong, Z., Ewers, M., Teipel, S., et al., Levels of ß-secretase (BACE1) in cerebrospinal fluid as a predictor of risk in mild cognitive impairment, Arch. Gen. Psychiatry, 2007, vol. 64, pp. 718–726

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Financial University of the Government of the Russian Federation, Moscow (GSP-3), 125993, Russia

    M. A. Paltsev

  2. St. Petersburg Institute of Bioregulation and Gerontology, St. Petersburg, 197110, Russia

    V. A. Zuev, E. O. Kozhevnikova, N. S. Linkova & T. V. Kvetnaia

  3. Peter the Great St. Petersburg Polytechnic University, St. Petersburg, 195251, Russia

    N. S. Linkova

  4. Ott Research Institute of Obstetrics, Gynecology and Reproductology, St. Petersburg, 199034, Russia

    V. O. Polyakova & I. M. Kvetnoy

  5. St. Petersburg University, St. Petersburg, 199034, Russia

    V. O. Polyakova & I. M. Kvetnoy

Authors
  1. M. A. Paltsev
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V. A. Zuev
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E. O. Kozhevnikova
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N. S. Linkova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T. V. Kvetnaia
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. V. O. Polyakova
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. I. M. Kvetnoy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to V. A. Zuev.

Additional information

Original Russian Text © M.A. Paltsev, V.A. Zuev, E.O. Kozhevnikova, N.S. Linkova, T.V. Kvetnaia, V.O. Polyakova, I.M. Kvetnoy, 2017, published in Uspekhi Gerontologii, 2017, Vol. 30, No. 6, pp. 809–817.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Paltsev, M.A., Zuev, V.A., Kozhevnikova, E.O. et al. Molecular Markers of Early Diagnosis of Alzheimer Disease: Prospects for Research in Peripheral Tissues. Adv Gerontol 8, 111–118 (2018). https://doi.org/10.1134/S2079057018020133

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S2079057018020133

Keywords

Search

Navigation