Skip to main content

Advertisement

Springer Nature Link
Log in
Menu
Find a journal Publish with us Track your research
Search
Cart
  1. Home
  2. NeuroRX
  3. Article

Biomarkers of Alzheimer disease in plasma

  • Published: April 2004
  • Volume 1, pages 226–234, (2004)
  • Cite this article
Download PDF
NeuroRX
Biomarkers of Alzheimer disease in plasma
Download PDF
  • Michael C. Irizarry1 

  • 2136 Accesses

  • 12 Altmetric

  • Explore all metrics

Summary

Plasma and serum biochemical markers proposed for Alzheimer disease (AD) are based on pathophysiologic processes such as amyloid plaque formation [amyloid β-protein (Aβ), Aβ autoantibodies, platelet amyloid precursor protein (APP) isoforms], inflammation (cytokines), oxidative stress (vitamin E, isoprostanes), lipid metabolism (apolipoprotein E, 24S-hydroxycholesterol), and vascular disease [homocysteine, lipoprotein (a)]. Most proteins or metabolites evaluated in plasma or serum thus far are, at best, biological correlates of AD: levels are statistically different in AD versus controls in some cohorts, but they lack sensitivity or specificity for diagnosis or for tracking response to therapy. Approaches combining panels of existing biomarkers or surveying the range of proteins in plasma (proteomics) show promise for discovering biomarker profiles that are characteristic of AD, yet distinct from nondemented patients or patients with other forms of dementia.

Article PDF

Download to read the full article text

Similar content being viewed by others

Changes in the plasma proteome at asymptomatic and symptomatic stages of autosomal dominant Alzheimer’s disease

Article Open access 06 July 2016

Multiplex proteomics identifies novel CSF and plasma biomarkers of early Alzheimer’s disease

Article Open access 06 November 2019

Plasma biomarkers for Alzheimer’s Disease in relation to neuropathology and cognitive change

Article Open access 23 February 2022
Use our pre-submission checklist

Avoid common mistakes on your manuscript.

References

  1. The Ronald and Nancy Reagan Research Institute of the Alzheimer’s Association and the National Institute on Aging Working Group. Consensus report of the Working Group on: Molecular and biochemical markers of Alzheimer’s disease.Neurobiol Aging 19: 109–116, 1998.

    Google Scholar 

  2. Gravina SA, Ho L, Eckman CB, Long KE, Otvos LJ, Younkin LH et al. Amyloid β protein (Aβ) in Alzheimer’s disease brain. Biochemical and immunocytochemical analysis with antibodies specific for forms ending at Aβ 40 or Aβ 42(43).J Biol Chem 270: 7013–7016, 1995.

    PubMed  CAS  Google Scholar 

  3. Fukumoto H, Asami-Odaka A, Suzuki N, Shimada H, Ihara Y, Iwatsubo T. Amyloid β protein deposition in normal aging has the same characteristics as that in Alzheimer’s disease. Predominance of Aβ 42(43) and association of Aβ 40 with cored plaques.Am J Pathol 148: 259–265, 1996.

    PubMed  CAS  Google Scholar 

  4. Jarrett JT, Berger EP, Lansbury PT Jr. The carboxy terminus of the β amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer’s disease.Biochemistry 32: 4693–4697, 1993.

    PubMed  CAS  Google Scholar 

  5. Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N et al. Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease.Nat Med 2: 864–870, 1996.

    PubMed  CAS  Google Scholar 

  6. Kosaka T, Imagawa M, Seki K, Arai H, Sasaki H, Tsuji S et al. The β APP717 Alzheimer mutation increases the percentage of plasma amyloid-β protein ending at Aβ42(43).Neurology 48: 741–745, 1997.

    PubMed  CAS  Google Scholar 

  7. Schupf N, Patel B, Silverman W, Zigman WB, Zhong N, Tycko B et al. Elevated plasma amyloid β-peptide 1–42 and onset of dementia in adults with Down syndrome.Neurosci Lett 301: 199–203, 2001.

    PubMed  CAS  Google Scholar 

  8. Tamaoka A, Fukushima T, Sawamura N, Ishikawa K, Oguni E, Komatsuzaki Y et al. Amyloid β protein in plasma from patients with sporadic Alzheimer’s disease.J Neurol Sci 141: 65–68, 1996.

    PubMed  CAS  Google Scholar 

  9. Mayeux R, Tang MX, Jacobs DM, Manly J, Bell K, Merchant C et al. Plasma amyloid β-peptide 1–42 and incipient Alzheimer’s disease.Ann Neurol 46: 412–416, 1999.

    PubMed  CAS  Google Scholar 

  10. Mehta PD, Pirttila T, Mehta SP, Sersen EA, Aisen PS, Wisniewski HM. Plasma and cerebrospinal fluid levels of amyloid β proteins 1–40 and 1–42 in Alzheimer disease.Arch Neurol 57: 100–105, 2000.

    PubMed  CAS  Google Scholar 

  11. Vanderstichele H, Van Kerschaver E, Hesse C, Davidsson P, Buyse MA, Andreasen N et al. Standardization of measurement of β-amyloid(l–42) in cerebrospinal fluid and plasma.Amyloid 7: 245–258, 2000.

    PubMed  CAS  Google Scholar 

  12. Fukumoto H, Tennis M, Locascio JJ, Hyman BT, Growdon JH, Irizarry MC. Age but not diagnosis is the main predictor of plasma amyloid β-protein levels.Arch Neurol 60: 958–964, 2003.

    PubMed  Google Scholar 

  13. Mayeux R, Honig LS, Tang MX, Manly J, Stern Y, Schupf N et al. Plasma Aβ40 and Aβ42 and Alzheimer’s disease: relation to age, mortality, and risk.Neurology 61: 1185–1190, 2003.

    PubMed  CAS  Google Scholar 

  14. Younkin SG, Eckman CB, Ertekin-Taner N, Kawarabayashi T, Yager D, Baker M et al. Genetic elevation of plasma amyloid β protein in typical late onset Alzheimer’s disease.Soc Neurosci Abstr 24: 263, 1998.

    Google Scholar 

  15. Arvanitakis Z, Lucas JA, Younkin LH, Younkin SG, Graff-Radford NR. Serum creatinine levels correlate with plasma amyloid β protein.Alzheimer Dis Assoc Disord 16: 187–190, 2002.

    PubMed  CAS  Google Scholar 

  16. Mehta PD, Pirttila T, Patrick BA, Barshatzky M, Mehta SP. Amyloid β protein 1–40 and 1–42 levels in matched cerebrospinal fluid and plasma from patients with Alzheimer disease.Neurosci Lett 304: 102–106, 2001.

    PubMed  CAS  Google Scholar 

  17. Tokuda T, Tamaoka A, Matsuno S, Sakurai S, Shimada H, Morita H et al. Plasma levels of amyloid β proteins did not differ between subjects taking statins and those not taking statins.Ann Neurol 49: 546–547, 2001.

    PubMed  CAS  Google Scholar 

  18. Buxbaum JD, Cullen EI, Friedhoff LT. Pharmacological concentrations of the HMG-CoA reductase inhibitor lovastatin decrease the formation of the Alzheimer β-amyloid peptide in vitro and in patients.Front Biosci 7: a50–59, 2002.

    PubMed  CAS  Google Scholar 

  19. Baker LD, Sambamurti K, Craft S, Cherrier M, Raskind MA, Stanczyk FZ et al. 17β-Estradiol reduces plasma Aβ40 for HRT-naive postmenopausal women with Alzheimer disease: a preliminary study.Am J Geriatr Psychiatry 11: 239–244, 2003.

    PubMed  Google Scholar 

  20. DeMattos RB, Bales KR, Cummins DJ, Paul SM, Holtzman DM. Brain to plasma amyloid-β efflux: a measure of brain amyloid burden in a mouse model of Alzheimer’s disease.Science 295: 2264–2267, 2002.

    PubMed  CAS  Google Scholar 

  21. Ghersi-Egea JF, Gorevic PD, Ghiso J, Frangione B, Patlak CS, Fenstermacher JD. Fate of cerebrospinal fluid-borne amyloid β-peptide: rapid clearance into blood and appreciable accumulation by cerebral arteries.J Neurochem 67: 880–883, 1996.

    PubMed  CAS  Google Scholar 

  22. Maness LM, Banks WA, Podlisny MB, Selkoe DJ, Kastin AJ. Passage of human amyloid β-protein 1–40 across the murine blood-brain barrier.Life Sci 55: 1643–1650, 1994.

    PubMed  CAS  Google Scholar 

  23. Matsuoka Y, Saito M, LaFrancois J, Gaynor K, Olm V, Wang L et al. Novel therapeutic approach for the treatment of Alzheimer’s disease by peripheral administration of agents with an affinity to beta-amyloid.J Neurosci 23: 29–33, 2003.

    PubMed  CAS  Google Scholar 

  24. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T et al. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse.Nature 400: 173–177, 1999.

    PubMed  CAS  Google Scholar 

  25. Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H et al. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease.Nat Med 6: 916–919, 2000.

    PubMed  CAS  Google Scholar 

  26. Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report.Nat Med 9: 448–452, 2003.

    PubMed  CAS  Google Scholar 

  27. Hock C, Konietzko U, Papassotiropoulos A, Wollmer A, Streffer J, von Rotz RC et al. Generation of antibodies specific for β-amyloid by vaccination of patients with Alzheimer disease.Nat Med 8: 1270–1275, 2002.

    PubMed  CAS  Google Scholar 

  28. Du Y, Dodel R, Hampel H, Buerger K, Lin S, Eastwood B et al. Reduced levels of amyloid β-peptide antibody in Alzheimer disease.Neurology 57: 801–805, 2001.

    PubMed  CAS  Google Scholar 

  29. Hyman BT, Smith C, Buldyrev I, Whelan C, Brown H, Tang MX et al. Autoantibodies to amyloid-β and Alzheimer’s disease.Ann Neurol 49: 808–810, 2001.

    PubMed  CAS  Google Scholar 

  30. Hock C, Konietzko U, Streffer JR, Tracy J, Signorell A, Muller-Tillmanns B et al. Antibodies against β-amyloid slow cognitive decline in Alzheimer’s disease.Neuron 38: 547–554, 2003.

    PubMed  CAS  Google Scholar 

  31. Orgogozo JM, Gilman S, Dartigues JF, Laurent B, Puel M, Kirby LC et al. Subacute meningoencephalitis in a subset of patients with AD after Aβ42 immunization.Neurology 61: 46–54, 2003.

    PubMed  CAS  Google Scholar 

  32. Rosenberg RN, Baskin F, Fosmire JA, Risser R, Adams P, Svetlik D et al. Altered amyloid protein processing in platelets of patients with Alzheimer disease.Arch Neurol 54: 139–144, 1997.

    PubMed  CAS  Google Scholar 

  33. Padovani A, Pastorino L, Borroni B, Colciaghi F, Rozzini L, Monastero R et al. Amyloid precursor protein in platelets: a peripheral marker for the diagnosis of sporadic AD.Neurology 57: 2243–2248, 2001.

    PubMed  CAS  Google Scholar 

  34. Padovani A, Borroni B, Colciaghi F, Pettenati C, Cottini E, Agosti C et al. Abnormalities in the pattern of platelet amyloid precursor protein forms in patients with mild cognitive impairment and Alzheimer disease.Arch Neurol 59: 71–75, 2002.

    PubMed  Google Scholar 

  35. Baskin F, Rosenberg RN, Iyer L, Hynan L, Cullum CM. Platelet APP isoform ratios correlate with declining cognition in AD.Neurology 54: 1907–1909, 2000.

    PubMed  CAS  Google Scholar 

  36. Borroni B, Colciaghi F, Pastorino L, Pettenati C, Cottini E, Rozzini L et al. Amyloid precursor protein in platelets of patients with Alzheimer disease: effect of acetylcholinesterase inhibitor treatment.Arch Neurol 58: 442–446, 2001.

    PubMed  CAS  Google Scholar 

  37. Baskin F, Rosenberg RN, Fang X, Hynan LS, Moore CB, Weiner M et al. Correlation of statin-increased platelet APP ratios and reduced blood lipids in AD patients.Neurology 60: 2006–2007, 2003.

    PubMed  CAS  Google Scholar 

  38. Borroni B, Colciaghi F, Lenzi GL, Caimi L, Cattabeni F, Di Luca M et al. High cholesterol affects platelet APP processing in controls and in AD patients.Neurobiol Aging 24: 631–636, 2003.

    PubMed  CAS  Google Scholar 

  39. Bush AI, Tanzi RE. Alzheimer disease-related abnormalities of amyloid β precursor protein isoforms in the platelet: the brain’s delegate in the periphery?Arch Neurol 55: 1179–1180, 1998.

    PubMed  CAS  Google Scholar 

  40. Birkenhager WH, Forette F, Seux ML, Wang JG, Staessen JA. Blood pressure, cognitive functions, and prevention of dementias in older patients with hypertension.Arch Intern Med 161: 152–156, 2001.

    PubMed  CAS  Google Scholar 

  41. Notkola IL, Sulkava R, Pekkanen J, Erkinjuntti T, Ehnholm C, Kivinen P et al. Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer’s disease.Neuroepidemiology 17: 14–20, 1998.

    PubMed  CAS  Google Scholar 

  42. Hofman A, Ott A, Breteler MM, Bots ML, Slooter AJ, van Harskamp F et al. Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer’s disease in the Rotterdam Study.Lancet 349: 151–154, 1997.

    PubMed  CAS  Google Scholar 

  43. Kivipelto M, Helkala EL, Laakso MP, Hanninen T, Hallikainen M, Alhainen K et al. Midlife vascular risk factors and Alzheimer’s disease in later life: longitudinal, population-based study.BMJ 322: 1447–1451, 2001.

    PubMed  CAS  Google Scholar 

  44. Evans RM, Emsley CL, Gao S, Sahota A, Hall KS, Farlow MR et al. Serum cholesterol, APOE genotype, and the risk of Alzheimer’s disease: a population-based study of African Americans.Neurology 54: 240–242, 2000.

    PubMed  CAS  Google Scholar 

  45. Yaffe K, Barrett-Connor E, Lin F, Grady D. Serum lipoprotein levels, statin use, and cognitive function in older women.Arch Neurol 59: 378–384, 2002.

    PubMed  Google Scholar 

  46. Tan ZS, Seshadri S, Beiser A, Wilson PW, Kiel DP, Tocco M et al. Plasma total cholesterol level as a risk factor for Alzheimer disease: the Framingham Study.Arch Intern Med 163: 1053–1057, 2003.

    PubMed  CAS  Google Scholar 

  47. Romas SN, Tang MX, Berglund L, Mayeux R. APOE genotype, plasma lipids, lipoproteins, and AD in community elderly.Neurology 53: 517–521, 1999.

    PubMed  CAS  Google Scholar 

  48. Solfrizzi V, Panza F, D’Introno A, Colacicco AM, Capurso C, Basile AM et al. Lipoprotein(a), apolipoprotein E genotype, and risk of Alzheimer’s disease.J Neurol Neurosurg Psychiatry 72: 732–736, 2002.

    PubMed  CAS  Google Scholar 

  49. Jarvik GP, Wijsman EM, Kukull WA, Schellenberg GD, Yu C, Larson EB. Interactions of apolipoprotein E genotype, total cholesterol level, age, and sex in prediction of Alzheimer’s disease: a case-control study.Neurology 45: 1092–1096, 1995.

    PubMed  CAS  Google Scholar 

  50. Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of dementia.Lancet 356: 1627–1631, 2000.

    PubMed  CAS  Google Scholar 

  51. Rockwood K, Kirkland S, Hogan DB, MacKnight C, Merry H, Verreault R et al. Use of lipid-lowering agents, indication bias, and the risk of dementia in community-dwelling elderly people.Arch Neurol 59: 223–227, 2002.

    PubMed  Google Scholar 

  52. Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.Arch Neurol 52: 1439–1443, 2000.

    Google Scholar 

  53. Heart Protection Study Collaborative Group. MRC/BHF heart protection study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.Lancet 360: 7–22, 2002.

    Google Scholar 

  54. Dietschy JM, Turley SD. Cholesterol metabolism in the brain.Curr Opin Lipidol 12: 105–112, 2001.

    PubMed  CAS  Google Scholar 

  55. Leoni V, Masterman T, Patel P, Meaney S, Diczfalusy U, Bjorkhem I. Side chain oxidized oxysterols in cerebrospinal fluid and the integrity of blood-brain and blood-cerebrospinal fluid barriers.J Lipid Res 44: 793–799, 2003.

    PubMed  CAS  Google Scholar 

  56. Papassotiropoulos A, Lutjohann D, Bagli M, Locatelli S, Jessen F, Buschfort R et al. 24S-hydroxycholesterol in cerebrospinal fluid is elevated in early stages of dementia.J Psychiatr Res 36: 27–32, 2002.

    PubMed  CAS  Google Scholar 

  57. Schonknecht P, Lutjohann D, Pantel J, Bardenheuer H, Hartmann T, von Bergmann K et al. Cerebrospinal fluid 24S-hydroxycholesterol is increased in patients with Alzheimer’s disease compared to healthy controls.Neurosci Lett 324: 83–85, 2002.

    PubMed  CAS  Google Scholar 

  58. Lutjohann D, Papassotiropoulos A, Bjorkhem I, Locatelli S, Bagli M, Oehring RD et al. Plasma 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients.J Lipid Res 41: 195–198, 2000.

    PubMed  CAS  Google Scholar 

  59. Simons M, Schwarzler F, Lutjohann D, von Bergmann K, Beyreuther K, Dichgans J et al. Treatment with simvastatin in normocholesterolemic patients with Alzheimer’s disease: a 26-week randomized, placebo-controlled, double-blind trial.Ann Neurol 52: 346–350, 2002.

    PubMed  CAS  Google Scholar 

  60. Locatelli S, Lutjohann D, Schmidt HH, Otto C, Beisiegel U, von Bergmann K. Reduction of plasma 24S-hydroxycholesterol (cerebrosterol) levels using high-dosage simvastatin in patients with hypercholesterolemia: evidence that simvastatin affects cholesterol metabolism in the human brain.Arch Neurol 59: 213–216, 2002.

    PubMed  Google Scholar 

  61. Vega GL, Weiner MF, Lipton AM, Von Bergmann K, Lutjohann D, Moore C et al. Reduction in levels of 24S-hydroxycholesterol by statin treatment in patients with Alzheimer disease.Arch Neurol 60: 510–515, 2003.

    PubMed  Google Scholar 

  62. Saunders A, Strittmater W, Schmechel D, St. George-Hyslop P, Pericak-Vance M, Joo S et al. Association of apolipoprotein E allele e4 with late-onset familial and sporadic Alzheimer’s disease.Neurology 43: 1467–1472, 1993.

    PubMed  CAS  Google Scholar 

  63. Gomez-Isla T, West HL, Rebeck GW, Harr SD, Growdon JH, Locasio JT et al. Clinical and pathological correlates of apolipoprotein E e4 in Alzheimer’s disease.Ann Neurol 39: 62–70, 1996.

    PubMed  CAS  Google Scholar 

  64. Mann DM, Iwatsubo T, Pickering-Brown SM, Owen F, Saido TC, Perry RH. Preferential deposition of amyloid beta protein (Aβ) in the form Aβ40 in Alzheimer’s disease is associated with a gene dosage effect of the apolipoprotein E ε4 allele.Neurosci Lett 221: 81–84, 1997.

    PubMed  CAS  Google Scholar 

  65. Ordovas JM, Litwack-Klein L, Wilson PW, Schaefer MM, Schaefer EJ. Apolipoprotein E isoform phenotyping methodology and population frequency with identification of apoE1 and apoE5 isoforms.J Lipid Res 28: 371–380, 1987.

    PubMed  CAS  Google Scholar 

  66. Fukumoto H, Ingelsson M, Garevik N, Wahlund LO, Nukina N, Yaguchi Y et al. APOE epsilon 3/epsilon 4 heterozygotes have an elevated proportion of apolipoprotein E4 in cerebrospinal fluid relative to plasma, independent of Alzheimer’s disease diagnosis.Exp Neurol 183: 249–253, 2003.

    PubMed  CAS  Google Scholar 

  67. Ingelsson M, Lilius L, Forsell C, Shin Y, Irizarry M, Graff C et al. Genotyping of apolipoprotein E: comparative evaluation of different protocols.Curr Prot Hum Genet Unit 9.14, 2003.

  68. Schiele F, De Bacquer D, Vincent-Viry M, Beisiegel U, Ehnholm C, Evans A et al. Apolipoprotein E serum concentration and polymorphism in six European countries: the ApoEurope Project.Atherosclerosis 152: 475–488, 2000.

    PubMed  CAS  Google Scholar 

  69. Taddei K, Clarnette R, Gandy SE, Martins RN. Increased plasma apolipoprotein E (apoE) levels in Alzheimer’s disease.Neurosci Lett 223: 29–32, 1997.

    PubMed  Google Scholar 

  70. Scacchi R, Gambina G, Ruggeri M, Martini MC, Ferrari G, Silvestri M et al. Plasma levels of apolipoprotein E and genetic markers in elderly patients with Alzheimer’s disease.Neurosci Lett 259: 33–36, 1999.

    PubMed  CAS  Google Scholar 

  71. Slooter AJ, de Knijff P, Hofman A, Cruts M, Breteler MM, Van Broeckhoven C et al. Serum apolipoprotein E level is not increased in Alzheimer’s disease: the Rotterdam study.Neurosci Lett 248: 21–24, 1998.

    PubMed  CAS  Google Scholar 

  72. Panza F, Solfrizzi V, Colacicco AM, Basile AM, D’Introno A, Capurso C, et al. Apolipoprotein E (APOE) polymorphism influences serum APOE levels in Alzheimer’s disease patients and centenarians.NeuroReport 14: 605–608, 2003.

    PubMed  CAS  Google Scholar 

  73. Lehtimaki T, Pirttila T, Mehta PD, Wisniewski HM, Frey H, Nikkari T. Apolipoprotein E (apoE) polymorphism and its influence on ApoE concentrations in the cerebrospinal fluid in Finnish patients with Alzheimer’s disease.Hum Genet 95: 39–42, 1995.

    PubMed  CAS  Google Scholar 

  74. Siest G, Bertrand P, Qin B, Herbeth B, Serot JM, Masana L et al. Apolipoprotein E polymorphism and serum concentration in Alzheimer’s disease in nine European centres: the ApoEurope study. ApoEurope group.Clin Chem Lab Med 38: 721–730, 2000.

    PubMed  CAS  Google Scholar 

  75. Milionis HJ, Winder AF, Mikhailidis DP. Lipoprotein (a) and stroke.J Clin Pathol 53: 487–496, 2000.

    PubMed  CAS  Google Scholar 

  76. Ramharack R, Spahr MA, Kreick JS, Sekerke CS. Expression of apolipoprotein (a) and plasminogen mRNAs in cynomolgus monkey liver and extrahepatic tissues.J Lipid Res 37: 2029–2040, 1996.

    PubMed  CAS  Google Scholar 

  77. Sarti C, Pantoni L, Pracucci G, Di Carlo A, Vanni P, Inzitari D. Lipoprotein(a) and cognitive performances in an elderly white population: cross-sectional and follow-up data.Stroke 32: 1678–1683, 2001.

    PubMed  CAS  Google Scholar 

  78. Diaz-Arrastia R. Homocysteine and neurologic disease.Arch Neurol 57: 1422–1427, 2000.

    PubMed  CAS  Google Scholar 

  79. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes.JAMA 274: 1049–1057, 1995.

    PubMed  CAS  Google Scholar 

  80. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D’Agostino RB et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease.N Engl J Med 346: 476–483, 2002.

    PubMed  CAS  Google Scholar 

  81. Bonilla E, Tanji K, Hirano M, Vu TH, DiMauro S, Schon EA. Mitochondrial involvement in Alzheimer’s disease.Biochim Biophys Acta 1410: 171–182, 1999.

    PubMed  CAS  Google Scholar 

  82. Butterfield DA, Castegna A, Lauderback CM, Drake J. Evidence that amyloid β-peptide-induced lipid peroxidation and its sequelae in Alzheimer’s disease brain contribute to neuronal death.Neurobiol Aging 23: 655–664, 2002.

    PubMed  Google Scholar 

  83. Zaman Z, Roche S, Fielden P, Frost PG, Niriella DC, Cayley AC. Plasma concentrations of vitamins A and E and carotenoids in Alzheimer’s disease.Age Ageing 21: 91–94, 1992.

    PubMed  CAS  Google Scholar 

  84. Jeandel C, Nicolas MB, Dubois F, Nabet-Belleville F, Penin F, Cuny G. Lipid peroxidation and free radical scavengers in Alzheimer’s disease.Gerontology 35: 275–282, 1989.

    PubMed  CAS  Google Scholar 

  85. Foy CJ, Passmore AP, Vahidassr MD, Young IS, Lawson JT. Plasma chain-breaking antioxidants in Alzheimer’ s disease, vascular dementia and Parkinson’s disease.QJM 92: 39–45, 1999.

    PubMed  CAS  Google Scholar 

  86. McGrath LT, McGleenon BM, Brennan S, McColl D, McIlroy S, Passmore AP. Increased oxidative stress in Alzheimer’s disease as assessed with 4-hydroxynonenal but not malondialdehyde.QJM 94: 485–490, 2001.

    PubMed  CAS  Google Scholar 

  87. Polidori MC, Mecocci P. Plasma susceptibility to free radical-induced antioxidant consumption and lipid peroxidation is increased in very old subjects with Alzheimer disease.J Alzheimers Dis 4: 517–522, 2002.

    PubMed  CAS  Google Scholar 

  88. Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, Grundman M, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study.N Engl J Med 336: 1216–1222, 1997.

    PubMed  CAS  Google Scholar 

  89. Heart Protection Study Collaborative Group. MRC/BHF heart protection study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial.Lancet 360: 23–33, 2002.

    Google Scholar 

  90. Greco A, Minghetti L, Levi G. Isoprostanes, novel markers of oxidative injury, help understanding the pathogenesis of neuro-degenerative diseases.Neurochem Res 25: 1357–1364, 2000.

    PubMed  CAS  Google Scholar 

  91. Pratico D, Lee VM-Y, Trojanowski JQ, Rokach J, Fitzgerald GA. Increased F2-isoprostanes in Alzheimer’s disease: evidence for enhanced lipid peroxidation in vivo.FASEB J 12: 1777–1783, 1998.

    PubMed  CAS  Google Scholar 

  92. Montine TJ, Beal MF, Cudkowicz ME, O’Donnell H, Margolin RA, McFarland L et al. Increased CSF F2-isoprostane concentration in probable AD.Neurology 52: 562–565, 1999.

    PubMed  CAS  Google Scholar 

  93. Pratico D, Clark CM, Lee VM, Trojanowski JQ, Rokach J, FitzGerald GA. Increased 8,12-iso-iPF2alpha-VI in Alzheimer’s disease: correlation of a noninvasive index of lipid peroxidation with disease severity.Ann Neurol 48: 809–812, 2000.

    PubMed  CAS  Google Scholar 

  94. Pratico D, Clark CM, Liun F, Rokach J, Lee VY, Trojanowski JQ. Increase of brain oxidative stress in mild cognitive impairment: a possible predictor of Alzheimer disease.Arch Neurol 59: 972–976, 2002.

    PubMed  Google Scholar 

  95. Montine TJ, Quinn JF, Milatovic D, Silbert LC, Dang T, Sanchez S et al. Peripheral F2-isoprostanes and F4-neuroprostanes are not increased in Alzheimer’s disease.Ann Neurol 52: 175–179, 2002.

    PubMed  CAS  Google Scholar 

  96. Cracowski JL, Durand T, Bessard G. Isoprostanes as a biomarker of lipid peroxidation in humans: physiology, pharmacology and clinical implications.Trends Pharmacol Sci 23: 360–366, 2002.

    PubMed  CAS  Google Scholar 

  97. Weiner HL, Selkoe DJ. Inflammation and therapeutic vaccination in CNS diseases.Nature 420: 879–884, 2002.

    PubMed  CAS  Google Scholar 

  98. Teunissen CE, de Vente J, Steinbusch HW, De Bruijn C. Biochemical markers related to Alzheimer’s dementia in serum and cerebrospinal fluid.Neurobiol Aging 23: 485–508, 2002.

    PubMed  CAS  Google Scholar 

  99. Licastro F, Pedrini S, Caputo L, Annoni G, Davis LJ, Ferri C et al. Increased plasma levels of interleukin-1, interleukin-6 and α-1-antichymotrypsin in patients with Alzheimer’s disease: peripheral inflammation or signals from the brain?J Neuroimmunol 103: 97–102, 2000.

    PubMed  CAS  Google Scholar 

  100. Singh VK, Guthikonda P. Circulating cytokines in Alzheimer’s disease.J Psychiatr Res 31: 657–660, 1997.

    PubMed  CAS  Google Scholar 

  101. Tarkowski E, Blennow K, Wallin A, Tarkowski A. Intracerebral production of tumor necrosis factor-α, a local neuroprotective agent, in Alzheimer disease and vascular dementia.J Clin Immunol 19: 223–230, 1999.

    PubMed  CAS  Google Scholar 

  102. Maes M, DeVos N, Wauters A, Demedts P, Maurits VW, Neels H et al. Inflammatory markers in younger vs elderly normal volunteers and in patients with Alzheimer’s disease.J Psychiatr Res 33: 397–405, 1999.

    PubMed  CAS  Google Scholar 

  103. Kalman J, Juhasz A, Laird G, Dickens P, Jardanhazy T, Rimanoczy A et al. Serum interleukin-6 levels correlate with the severity of dementia in Down syndrome and in Alzheimer’s disease.Acta Neurol Scand 96: 236–240, 1997.

    PubMed  CAS  Google Scholar 

  104. Bonaccorso S, Lin A, Song C, Verkerk R, Kenis G, Bosmans E et al. Serotonin-immune interactions in elderly volunteers and in patients with Alzheimer’s disease (DAT): lower plasma tryptophan availability to the brain in the elderly and increased serum interleukin-6 in DAT.Aging (Milano) 10: 316–323, 1998.

    CAS  Google Scholar 

  105. Blum-Degen D, Muller T, Kuhn W, Gerlach M, Przuntek H, Riederer P. Interleukin-1β and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer’s and de novo Parkinson’s disease patients.Neurosci Lett 202: 17–20, 1995.

    PubMed  CAS  Google Scholar 

  106. Angelis P, Scharf S, Mander A, Vajda F, Christophidis N. Serum interleukin-6 and interleukin-6 soluble receptor in Alzheimer’s disease.Neurosci Lett 244: 106–108, 1998.

    PubMed  CAS  Google Scholar 

  107. Chao CC, Ala TA, Hu S, Crossley KB, Sherman RE, Peterson PK, et al. Serum cytokine levels in patients with Alzheimer’s disease.Clin Diagn Lab Immunol 1: 433–436, 1994.

    PubMed  CAS  Google Scholar 

  108. van Duijn CM, Hofman A, Nagelkerken L. Serum levels of interleukin-6 are not elevated in patients with Alzheimer’s disease.Neurosci Lett 108: 350–354, 1990.

    PubMed  Google Scholar 

  109. Ershler WB, Sun WH, Binkley N, Gravenstein S, Volk MJ, Kamoske G, et al. Interleukin-6 and aging: blood levels and mononuclear cell production increase with advancing age and in vitro production is modifiable by dietary restriction.Lymphokine Cytokine Res 12: 225–230, 1993.

    PubMed  CAS  Google Scholar 

  110. Teunissen CE, Lutjohann D, von Bergmann K, Verhey F, Vreeling F, Wauters A et al. Combination of serum markers related to several mechanisms in Alzheimer’s disease.Neurobiol Aging 24: 893–902, 2003.

    PubMed  CAS  Google Scholar 

  111. Butterfield DA, Boyd-Kimball D, Castegna A. Proteomics in Alzheimer’s disease: insights into potential mechanisms of neurodegeneration.J Neurochem 86: 1313–1327, 2003.

    PubMed  CAS  Google Scholar 

  112. Carrette O, Demalte I, Scherl A, Yalkinoglu O, Corthals G, Burkhard P et al. A panel of cerebrospinal fluid potential biomarkers for the diagnosis of Alzheimer’s disease.Proteomics 3: 1486–1494, 2003.

    PubMed  CAS  Google Scholar 

  113. Ueno I, Sakai T, Yamaoka M, Yoshida R, Tsugita A. Analysis of blood plasma proteins in patients with Alzheimer’s disease by two-dimensional electrophoresis, sequence homology and immunodetection.Electrophoresis 21: 1832–1845, 2000.

    PubMed  CAS  Google Scholar 

  114. Frank R, Hargreaves R. Clinical biomarkers in drug discovery and development.Nat Rev Drug Discov 2: 566–580, 2003.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Alzheimer Disease Research Unit, Department of Neurology, Massachusetts General Hospital, 02129, Charlestown, Massachusetts

    Michael C. Irizarry

Authors
  1. Michael C. Irizarry
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael C. Irizarry.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Irizarry, M.C. Biomarkers of Alzheimer disease in plasma. Neurotherapeutics 1, 226–234 (2004). https://doi.org/10.1602/neurorx.1.2.226

Download citation

  • Issue Date: April 2004

  • DOI: https://doi.org/10.1602/neurorx.1.2.226

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

Key Words

  • Biomarkers
  • amyloid β-protein
  • isoprostanes
  • homocysteine
  • 24S-hydroxycholesterol
  • cytokines
  • proteomics
Use our pre-submission checklist

Avoid common mistakes on your manuscript.

Advertisement

Search

Navigation

  • Find a journal
  • Publish with us
  • Track your research

Discover content

  • Journals A-Z
  • Books A-Z

Publish with us

  • Journal finder
  • Publish your research
  • Open access publishing

Products and services

  • Our products
  • Librarians
  • Societies
  • Partners and advertisers

Our imprints

  • Springer
  • Nature Portfolio
  • BMC
  • Palgrave Macmillan
  • Apress
  • Your US state privacy rights
  • Accessibility statement
  • Terms and conditions
  • Privacy policy
  • Help and support
  • Cancel contracts here

149.56.12.38

Not affiliated

Springer Nature

© 2025 Springer Nature