Biological markers for the diagnosis of Alzheimer’s disease

  • C. Bancher
  • K. Jellinger
  • I. Wichart
Part of the Journal of Neural Transmission. Supplementa book series (NEURAL SUPPL, volume 53)


A diagnostic test for Alzheimer’s disease (AD) based on biochemical markers in the cerebrospinal fluid can help improve diagnostic accuracy, which currently is approximately 90%, leaving every tenth AD patient undiagnosed or falsely diagnosed as having the disease. From all biochemical abnormalities described in AD patients, those related to the hallmark neuropathologic lesions, deposition of amyloid and formation of paired helical filaments mainly consisting of abnormally phosphorylated tau protein, are the most promising and the best documented, eventhough other markers bear some potential and remain to be further studied. Determining an increase of tau and a reduction of Aβ42 bears satisfactory, eventhough not absolute specificity for AD and represents a true aid for clinicians in diagnosing AD during the patients lifetime. It remains open if these markers will be helpful for the most challenging goal, diagnosing AD in the preclinical phase, when, according to morphological data, high amounts of these pathological proteins are already deposited in the brain tissue.


Cerebrospinal Fluid Alzheimer Disease Multiple System Atrophy Vascular Dementia Paired Helical Filament 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Arai H, Terajima M, Miura M, Higuchi S, Muramatsu T, Machida N, Seiki H, Takase S, Clark CM, Lee VM-Y, Trojanowski JQ, Sasaki A (1995) Tau in cerebrospinal fluid: a potential diagnostic marker in Alzheimer’s disease. Ann Neurol 38: 649–652PubMedCrossRefGoogle Scholar
  2. Arai H, Higuchi S, Sasaki H (1997) Apolipoprotein E genotyping and cerebrospinal fluid tau protein — implications for the clinical diagnosis of Alzheimer’s disease. Gerontology 43 [Suppl 1]: 2–11PubMedCrossRefGoogle Scholar
  3. Bancher C, Brunner C, Lassmann H, Budka H, Jellinger K, Wiche G, Seitelberger F, Grundke-Iqbal I, Iqbal K, Wisniewski HM (1989) Accumulation of abnormally phosphorylated tau precedes the formation of neurofibrillary tangles in Alzheimer’s disease. Brain Res 477: 90–99PubMedCrossRefGoogle Scholar
  4. Bancher C, Wisniewski HM, Mehta PD, Kim KS, Grundke-Iqbal I, Iqbal K (1991) Biochemical markers for Alzheimer’s disease as reflection of the neuropathology in cerebrospinal fluid. In: Becker RE, Giacobini E (eds) Current research in Alzheimer therapy II. Early diagnosis. Taylor and Francis, New York, pp 195–216Google Scholar
  5. Blennow K, Hesse C, Fredman P (1994a) Cerebrospinal fluid apolipoprotein E is reduced in Alzheimer’s disease. Neuro Report 5: 2534–2536Google Scholar
  6. Blennow K, Davidsson P, Wallin A, Gottfries CG, Svennerholm L (1994b) First place. 1993 IPA research awards in psychogeriatrics: ubiquitin in cerebrospinal fluid in Alzheimer’s disease and vascular dementia. Int Psychogeriatr 6: 13–22PubMedCrossRefGoogle Scholar
  7. Blennow K, Wallin A, Ekman R (1994c) Neuron specific enolase in cerebrospinal fluid: a biochemical marker for neurronal degeneration in dementia disorders? J Neural Transm [P-D Sect] 8: 183–191CrossRefGoogle Scholar
  8. Blennow K, Wallin A, Agren H, Spenger C, Siegfried J, Vanmechelen E (1995a) Tau protein in cerebrospinal fluid. A biochemical marker for axonal degeneration in Alzheimer disease? Mol Chem Neuropathol 26: 231–245Google Scholar
  9. Blennow K, Davidsson P, Wallin A, Ekman R (1995b) Chromogranin A in cerebrospinal fluid: a biochemical marker for synaptic degeneration in Alzheimer’s disease. Dementia 6: 306–311PubMedGoogle Scholar
  10. Blennow K, Wallin A, Chong JK (1995c) Cerebrospinal fluid “neuronal thread protein” comes from serum by passage over the blood-brain barrier. Neurodegeneration 4: 187–193PubMedCrossRefGoogle Scholar
  11. Blomberg M, Jensen M, Basun H, Lannfelt L, Wahlund LO (1996) Increasing cerebrospinal fluid tau levels in a subgroup of Alzheimer patients with apolipoprotein E allele epsilon 4 during 14 months follow-up. Neurosci Lett 214: 163–166PubMedCrossRefGoogle Scholar
  12. Blum-Degen D, Muller T, Kuhn W, Gerlach M, Przuntek H, Riederer P (1995) Interleukin-lbeta and interleukin 6 are elevated in the cerebrospinal fluid of Alzheimer’s and de novo Parkinson’s disease patients. Neurosci Lett 202: 17–20PubMedCrossRefGoogle Scholar
  13. Csernansky JG, Bardgett ME, Sheline YI, Morris JC, Olney JW (1996) CSF excitatory amino acids and severity of illness in Alzheimer’s disease. Neurology 46: 1715–1720PubMedCrossRefGoogle Scholar
  14. Davidsson P, Jahn R, Bergquist J, Ekman R, Blennow K (1996) Synaptotagmin, a synaptiv vesicle protein, is present in human ceerebrospinal fluid: a new biochemichal marker for synaptic pathology in Alzheimer disease? Mol Chem Neuropathol 27: 195–210PubMedCrossRefGoogle Scholar
  15. De la Monte SM, Volicer L, Hauser SR, Wands JR (1992) Incresed levels of neuronal thread protein in cerebrospinal fluid of patients with Alzheimer’s disease. Ann Neurol 32: 733–742PubMedCrossRefGoogle Scholar
  16. Elble R, Giacobini E, Scarsella GF (1987) Cholinesterases in cerebrospinal fluid. A longitudinal study in Alzheimer disease. Arch Neurol 44: 403–407PubMedCrossRefGoogle Scholar
  17. Galasko D, Clark C, Chang L, Miller B, Green RC, Motter R, Seubert P (1997) Assessmant of cerebrospinal fluid levels of tau in mildly demented patients with Alzheimer’s disease. Neurology 48: 632–635PubMedCrossRefGoogle Scholar
  18. Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI (1986) Abnormal phosphorylation of microtubule-associated protein tau in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 83: 4913–4917PubMedCrossRefGoogle Scholar
  19. Gunnersen D, Haley B (1992) Detection of glutamine synthetase in the cerebrospinal fluid of Alzheimer diseased patients: a potential diagnostic biochemical marker. Proc Natl Acad Sci USA 89: 11949–11953PubMedCrossRefGoogle Scholar
  20. Hahne S, Nordsted C, Ahlin A, Nyback H (1997) Levels of cerebrospinal fluid apolipoprotein E in patients with Alzheimer’s disease and healthy controls. Neurosci Lett 224: 99–102PubMedCrossRefGoogle Scholar
  21. Hampel H, Schoen D, Schwarz MJ, Kotter HU, Schneider C, Sunderland T, Dukoff R, Levy J, Padberg F, Stubner S, Buch K, Muller N, Moller HJ (1997) Interleukin-6 is not altered in cerebrospinal fluid of first-degree relatives and patients with Alzheimer’s disease. Neurosci Lett 228: 143–146PubMedCrossRefGoogle Scholar
  22. Hawkins PN, Rossor MN, Gallimore JR, Miller B, Moore EG, Pepys MB (1994) Concentration of serum amyloid P component in the CSF as a possible marker of cerebral amyloid deposits in Alzheimer’s disease. Biochem Biophys Res Commun 201: 722–726PubMedCrossRefGoogle Scholar
  23. Isoe K, Urakami K, Shimomura T, Wakutani Y, Ji Y, Adachi Y, Takahashi K (1996) Tau proteins in cerebrospinal fluid from patients with Alzheimer’s disease: a longitudinal study. Dementia 7: 175–176PubMedGoogle Scholar
  24. Jensen M, Basun H, Lannfelt L (1995) Increased cerebrospinal fluid tau in patients with Alzheimer’s disease. J Neurol Sci 95: 239–258Google Scholar
  25. Jimenez-Jimenez FJ, Debustos F, Molina JA, Benitoleon J, Tallonbaranco A, Gasalla T, Ortipareja M, Guillamon F, Rubio JC, Arenas J, Enriquezdesalamanca R (1997) Cerebrospinal fluid levels of alpha-tocopherol (Vitamin E) in Alzheimer’s disease. J Neural Transm 104: 703–710PubMedCrossRefGoogle Scholar
  26. Kudo T, Iqbal K, Ravid R, Swaab DF, Grundke-Iqbal I (1994) Alzheimer disease: Correlation of cerebro-spinal fluid and brain ubiquitin levels. Brain Res 639: 1–7PubMedCrossRefGoogle Scholar
  27. Kuiper MA, Mulder C, Van Kamp GJ, Scheltens P, Wolters EC (1994) Cerebrospinal fluid ferritin levels of patients with Parkinsons’s disease, Alzheimer’s disease, and multiple system atrophy. J Neural Transm [P-D Sect] 7: 109–114CrossRefGoogle Scholar
  28. Landen M, Hesse C, Fredman P, Regland B, Wallin A, Blennow K (1996) Apolipoprotein E in cerebrospinal fluid from patients with Alzheimer’s disease and other forms of dementia is reduced but without any correlation to the apoE4 isoform. Dementia 7: 273–278PubMedGoogle Scholar
  29. Lannfelt L, Basun H, Vigo-Pelfrey C, Wahlund LO, Winblad B, Lieberburg I, Schenk D (1995) Amyloid beta-peptide in cerebrospinal fluid in individuals with the Swedish Alzheimer amyloid precursor protein mutation. Neurosci Lett 199: 203–206PubMedCrossRefGoogle Scholar
  30. Lefranc D, Vermersch P, Dallongeville J, Daems-Montpeurt C, Petit H, Delacourte A (1996) Relevance of the quantitation of apolipoprotein E in the cerebrospinal fluid in Alzheimer’s disease. Neurosci Lett 212: 91–94PubMedCrossRefGoogle Scholar
  31. Licastro F, Parnetti L, Morini MC, Davis LJ, Cucinotta D, Gaiti A, Senin U (1995) Acute phase reactant alpha-1-antichymotrypsin is increased in cerebrospinal fluid and serum of patients with probable Alzheimer disease. Alz Dis Assoc Disord 9: 112–118CrossRefGoogle Scholar
  32. Lindh M, Blomberg M, Jensen M, Basun H, Lannfelt L, Engvall B, Scharnagel H, Marz W, Wahlund LO, Cowburn RF (1997) Cerebrospinal fluid apolipoprotein E (ApoE) levels in Alzheimer’s disease patients are increased at follow-up and show a correlation with levels of tau protein. Neurosci Lett 229: 85–88PubMedCrossRefGoogle Scholar
  33. Loeffler DA, DeMaggio AJ, Juneau PL, Brickman CM, Mashour GA, Finkelman JH, Pomara N, LeWitt PA (1994) Ceruloplasmin is increased in cerebrospinal fluid in Alzheimer’s disease but not Parkinson’s disease. Alz Dis Assoc Disord 8: 190–197CrossRefGoogle Scholar
  34. Loeffler DA, Juneau PL, Nguyen HU, Najman D, Pomara N, LeWitt PA (1997) Immunocytochemical detection of anti-hippocampal antibodies in Alzheimer’s disease and normal cerebrospinal fluid. Neurochem Res 22: 209–214PubMedCrossRefGoogle Scholar
  35. Lopez OL, Kaufer D, Reiter CT, Carra J, DeKosky ST, Palmer AM (1996) Relationship between CSF neurotransmitter metabolites and aggressive behavior in Alzheimer’s disease. Eur J Neurol 3: 153–155CrossRefGoogle Scholar
  36. McRae A, Eng-Ang-Ling, Wigander A, Dahlstrom A (1993) Microglial cerebrospinal antibodies: significance for Alzheimer disease. Mol Chem Neuropathol 28: 98–95Google Scholar
  37. Mehta PD, Thal L, Wisniewski HM, Grundke-Iqbal I, Iqbal K (1985) Paired helical filament antigen in CSF. Lancet ii: 35CrossRefGoogle Scholar
  38. Merched A, Blain H, Visvikis S, Herbeth B, Jeandel C, Siest G (1997) Cerebrospinal fluid apolipoprotein E level is increased in late-onset Alzheimer’s disease. J Neurol Sci 145: 33–39PubMedCrossRefGoogle Scholar
  39. Mirra SS, Hart MN, Terry RD (1993) Making the diagnosis of Alzheimer’s disease: a primer for practicing pathologists. Arch Pathol Lab Med 117: 132–144PubMedGoogle Scholar
  40. Mochizuki Y, Oishi M, Hara M, Takasu T (1996) Amino acid concentration in dementia of the Alzheimer type and multi-infarct dementia. Ann Clin Lab Sci 26: 275–278PubMedGoogle Scholar
  41. Molchan SE, Hill LJ, Martinez RA, Lawlor BA, Mellow AM, Rubinow DR, Bissette G, Nemeroff CB, Sunderland T (1993) CSF somatoatatin in Alzheimer’s disease and major depression: relationship to hypothalamic-pituitary-adrenal axis and clinical measures. Psychoneuroendocrinology 18: 509–519PubMedCrossRefGoogle Scholar
  42. Mori H, Hosada K, Matsubara E, Nakamoto T, Furiya Y, Endih R, Usami M, Shoji M, Maruyama S, Hirai S (1995) Tau in cerebrospinal fluids: establishment of the sandwich ELISA with antibody to the repeat sequence in tau. Neurosci Lett 186: 181–183PubMedCrossRefGoogle Scholar
  43. Motter R, Vigo-Pelfrey C, Kholodenko D, Barbour R, Johnson-Wood K, Galasko D, Chang L, Miller B, Clark C, Green R, Olson D, Southwick P, Wolfert R, Munroe B, Lieberburg I, Seubert P, Schenk D (1995) Reduction of beta-amyloid peptide 42 in the cerebrospinal fluid of patients with Alzheimer’s disease. Ann Neurol 38: 643–648PubMedCrossRefGoogle Scholar
  44. Munroe WA, Southwick PC, Chang L, Scharre DW, Echols CL, Jr, Fu PC, Whaley JM, Wolfert RL (1995) Tau protein in cerebrospinal fluid as an aid in the diagnosis of Alzheimer disease. Ann Clin Lab Sci 25: 207–217PubMedGoogle Scholar
  45. National Institute on Aging and Reagan Institute Working Group on diagnostic criteria for the neuropathological assessment of Alzheimer’s disease (1997) Consensus recommendations for the post mortem diagosis of Alzheimer’s disease. Neurobiol Aging 18: S1–S3CrossRefGoogle Scholar
  46. Oishi M, Mochizuki Y, Yoshihashi H, Takasu T, Nakano E (1996) Laboratory examinations correlated with severity of dementia. Ann Clin Lab Sci 26: 340–345PubMedGoogle Scholar
  47. Otto M, Wiltfang J, Tumani H, Zerr I, Lautsch M, Kornhuber J, Weber T, Kretschmer HA, Poser S (1997) Elevated levels of tau-protein in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Neurosci Lett 225: 210–212PubMedCrossRefGoogle Scholar
  48. Parnetti L, Gaiti A, Polidori MC, Brunetti M, Palumbo B, Chionne F, Cadini D, Cecchetti R, Senin U (1995a) Increased cerebrospinal fluid pyruvate levels in Alzheimer’s disease. Neurosci Lett 199: 231–233PubMedCrossRefGoogle Scholar
  49. Parnetti L, Palumbo B, Cardinali L, Foreti F, Chionne F, Cechetti R, Senin U (1995b) Cerebrospinal fluid neuron-specific enolase in Alzheimer’s disease and vascular dementia. Neurosci Lett 183: 43–45PubMedCrossRefGoogle Scholar
  50. Riemenschneider NM, Buch K, Schmolke M, Kurz A, Guder WG (1996) Cerebrospinal fluid tau is elevated in early Alzheimer’s disease. Neurosci Lett 212: 209–211PubMedCrossRefGoogle Scholar
  51. Rosengren LE, Karlsson JE. Karlsson JO, Persson LI, Wikkels C (1996) Patients with amyotrophic lateral sclerosis and other neurodegenerative diseases have increased levels of neurofilament protein in CSF. J Neurochem 67: 2013–2018PubMedCrossRefGoogle Scholar
  52. Rösier N, Wichart I, Jellinger K (1996a) Total tau protein immunoreactivity in lumbar cerebrospinal fluid of patients with Alzheimer’s disease. J Neurol Neurosurg Psychiatry 60: 237–238Google Scholar
  53. Rösier N, Wichart I, Jellinger K (1996b) Intra vitam lumbar cerebrospinal fluid and serum and post mortem ventricular immunoreactive apolipoprotein E in patients with Alzheimer’s disease. J Neurol Neurosurg Psychiatry 60: 452–454CrossRefGoogle Scholar
  54. Sahu RN, Pandey RS, Subhash MN, Arya BYT, Padmashree TS, Srinivas KN (1988) CSF zinc in Alzheimer’s type dementia. Biol Psychiatry 24: 480–482PubMedCrossRefGoogle Scholar
  55. Schröder J, Pantel J, Ida N, Essig M, Hartmann T, Knopp MV, Schad LR, Sandbrink R, Sauer H, Masters CL, Beyreuther K (1997) Cerebral changes and cerebrospinal fluid beta-amyloid in Alzheimer’s disease: a study with quantitative magnetic resonance imaging. Mol Psychiat 2: 505–507CrossRefGoogle Scholar
  56. Shen ZX (1996) The significance of the activity of CSF cholinesterases in dementias. Med Hypotheses 47: 363–376PubMedCrossRefGoogle Scholar
  57. Shen ZX, Ding Q, Wei CZ, Ding MC, Meng JM (1993) CSF cholinesterase in early-onset and late-onset Alzheimer’s disease and multi-infarct dementia of Chinese patients. Acta Neurol Scand 87: 19–24PubMedCrossRefGoogle Scholar
  58. Shetti HU, Holloway HW, Schapiro MB (1996) Cerebrospinal fluid and plasma distribution of myo-inositol and other polyols in Alzheimer disease. Clin Chem 42: 298–302Google Scholar
  59. Skoog I, Hesser C, Fredman P, Andreasson LA, Palmertz B, Blennow K (1997) Apolipoprotein E in cerebrospinal fluid in 85-year-old subjects — relation to dementia, apolipoprotein E polymorphism, cerebral atrophy, and white matter lesions. Arch Neurol 54: 267–272PubMedCrossRefGoogle Scholar
  60. Smyth MD, Cribbs DH, Tenner AJ, Rodman-Shankle W, Dick M, Kesslak JP, Cotman CW (1994) Decreased levels of C1q in cerebrospinal fluid of living Alzheimer patients correlate with disease state. Neurobiol Aging 15: 609–614PubMedCrossRefGoogle Scholar
  61. Soininen H, Lehtovirta M, Helisalmi S, Linnaranta K, Heinonen O, Riekinnen Sr P (1995) Increased acetylcholinesterase activity in the CSF of Alzheimer patients carrying apolipoprotein epsilon 4 allele. NeuroReport 6: 2518–2520PubMedCrossRefGoogle Scholar
  62. Song H, Saito K, Seishima M, Noma A, Urakami K, Nakashima K (1997) Cerebrospinal fluid Apo E and Apo A1 concentrations in early and late-onset Alzheimer’s disease. Neurosci Lett 231: 175–178PubMedCrossRefGoogle Scholar
  63. Southwick PC, Yamagata SK, Echols Jr CL, Higson GJ, Neynaber SA, Parson RE, Munroe WA (1996) Assessment of amyloid beta protein in cerebrospinal fluid as an aid in the diagnosis of Alzheimer’s disease. J Neurochem 66: 259–265PubMedCrossRefGoogle Scholar
  64. Strittmatter M, Hamann GF, Grauer MT, Cramer H, Schimrigk K (1997a) Neurochemical differences in the CSF between Binswanger’s and Alzheimer’s disease. Dementia Geriatr Cogn Disord 8: 34–42CrossRefGoogle Scholar
  65. Strittmatter M, Cramer H, Reuner C, Strubel D, Hamann G, Schimrigk K (1997b) Molecular forms of somatostatin-like immunoreactivity in the cerebrospinal fluid of patients with senile dementia of the Alzheimer type. Biol Psychiatry 41: 1124–1130PubMedCrossRefGoogle Scholar
  66. Tamaoka A, Sawamura N, Fukushima T, Shoji S, Matsubara E, Shoji M, Hirai S, Furiya Y, Endoh H, Mori H (1997) Amyloid beta protein 42(43) in cerebrospinal fluid of patients with Alzheimer’s disease. J Neurol Sci 148: 4–45CrossRefGoogle Scholar
  67. Tapiola T, Lehtovirta M, Ramberg J, et al. (1998) CSF tau is related to apolipoprotein E genotype in early Alzheimer’s disease. Neurology 50: 169–174PubMedCrossRefGoogle Scholar
  68. Tato RE, Frank A, Hernanz A (1995) Tau protein concentrations in cerebrospinal fluid of patients with dementia of the Alzheimer type. J Neurol Neurosurg Psychiatry 59: 280–283PubMedCrossRefGoogle Scholar
  69. Toghi H, Abe T, Hashiguchi K, Saheki M, Takahashi S (1994) Remarkable reduction in acetylcholine concentration in the cerebrospinal fluid from patients with Alzheimer type dementia. Neurosci Lett 177: 1-2: 139–142CrossRefGoogle Scholar
  70. Toghi H, Abe T, Kimura M, Saheki M, Takahashi S (1996) Cerebrospinal fluid acetylcholine and choline in vascular dementia of Binswanger and multiple small infarct types as compared with Alzheimer-type dementia. J Neural Transm 103: 1211–1220CrossRefGoogle Scholar
  71. Vandermeeren M, Mercken M, Vanmechelen E, Six J, Van-de-Voorde A, Martin JJ, Cras P (1993) Detection of tau proteins in normal and Alzheimer’s disease cerebrospinal fluid with a sensitive sandwich enzyme-linked immunosorbent assay. J Neurochem 61: 1828–1834PubMedCrossRefGoogle Scholar
  72. Wisniewski HM, Mehta PD, Kim KS, Merz GS (1989) Cerebrospinal fluid based laboratory test for Alzheimer disease. In: Christen Y (ed) Research and perspectives in Alzheimer disease. Biological markers of Alzheimer disease. Springer, Berlin Heidelberg New York Tokyo, pp 23–29CrossRefGoogle Scholar
  73. Yamada K, Kono K, Umegaki H, Yamada K, Iguchi A, Fukatsu T, Nakashima N, Nishiwaki H, Shimada Y, Sugita Y, Yamamoto T, Hasegawa T, Nabeshima T (1995) Decreased interleukin-6 level in the cerebrospinal fluid of patients with Alzheimer-type dementia. Neurosci Lett 186: 219–221PubMedCrossRefGoogle Scholar
  74. Yasuda M, Maeda K, Kakigi T, Minamitani N, Kawaguchi T, Tanaka C (1995) Low cerebrospinal fluid concentrations of peptide histidine valine and somatostatin-28 in Alzheimer’s disease: Altered processing of prepro-vasoactive intestinal polypeptide and prepro-somatostatin. Neuropeptides 29: 325–330PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 1998

Authors and Affiliations

  • C. Bancher
    • 1
    • 2
  • K. Jellinger
    • 1
  • I. Wichart
    • 1
  1. 1.Ludwig Boltzmann Institute of Clinical Neurobiology and Department of NeurologyLainz HospitalWienAustria
  2. 2.Department of NeurologyLainz HospitalWienAustria

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