Journal Mobile Options
Table of Contents
Vol. 65, No. 5, 2011
Issue release date: May 2011
Eur Neurol 2011;65:270–278

Folate and Homocysteine in the Cerebrospinal Fluid of Patients with Alzheimer’s Disease or Dementia: A Case Control Study

Smach M.A. · Jacob N. · Golmard J.-L. · Charfeddine B. · Lammouchi T. · Ben Othman L. · Dridi H. · Bennamou S. · Limem K.
aDepartment of Biochemistry, Faculty of Medicine of Sousse, and bDepartment of Neurology, Sahloul Hospital, Sousse,Tunisia; cLaboratoire de Biochimie Métabolique et dDépartement de Biostatistique, Groupe Hospitalier Pitié-Salpêtrière, AP-HP, Paris, France

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


Background: Amyloid deposition in the brain is an early event in Alzheimer’s disease (AD), but a dysfunction of the blood-brain barrier or a disturbance in the metabolism of folate and homocysteine (Hcy) may affect the development of dementia. We investigated if the concentrations of folate and Hcy would be modified in cerebrospinal fluid (CSF) of clinically diagnosed AD patients. Methods: We included 70 AD patients, 33 patients with another type of dementia (nAD) and 30 age-matched control subjects. Plasma Hcy was assayed as well as Hcy, folate, Aβ1-42 and T-tau in CSF. We used ANOVAs for comparison between groups, and then pairwise comparisons by Wilcoxon tests with Bonferroni-corrected p values. Correlations were tested with the Spearman’s rank test. Results: Levels of Aβ1-42, T-tau and folates in CSF were significantly different between groups, but not Hcy. In addition, the average folate in CSF was lower in AD patients compared with controls (18.7 ± 2.4 vs. 20.3 ± 1.7 nmol/l, Bonferroni-corrected p value < 0.02). There was no correlation between Aβ1-42 or T-tau and folate or Hcy in CSF, regardless of the group. In the AD group, there was a significant inverse correlation between Hcy and folate in CSF (ρ = –0.63, p < 0.0001), whereas in the nAD group, a significant correlation was found for Hcy between plasma and CSF (ρ = 0.59, p < 0.0005). Conclusion: The concentration of folate in CSF was found to be decreased in AD patients. These findings support the hypothesis of a possible role of folate in the onset or worsening of AD.

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


  1. Ferri CP, Prince M, Brayne C, Brodaly H, Fratiglioni L, Ganguli M, et al: Global prevalence of dementia: a Delphi consensus study. Lancet 2005;366:2112–2117.
  2. Blennow K, de Léon MJ, Zetterberg H: Alzheimer’s disease. Lancet 2006;368:387–403.
  3. McKann G, Drachman DA, Folstein M, Katzman R, Price DL, Stadlan EM: Clinical diagnosis of Alzheimer’s disease – report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task force on Alzheimer’s disease. Neurology 1984;34:939–944.
  4. Glenner GG, Wong CW: Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984;120:885–890.
  5. Brion J, Passareiro E, Nunez J, Flament-Durand J: Mise en évidence immunologique de la protéine tau au niveau des lésions de dégénérescence neurofibrillaire de la maladie d’Alzheimer. Arch Biol 1985;95:229–235.
  6. Andreasen N, Minthon L, Davidsson P, Vanmechelen E, Vanderstichele H, Winblad B, et al: Evaluation of CSF-τ and CSF-Aβ42 as diagnostic markers for Alzheimer disease in clinical practice. Arch Neurol 2001;58:373–379.
  7. Hampel H, Teipel SJ, Fuchsberger T, Andreasen N, Wiltfang J, Otto M, et al: Value of CSF β-amyloid-42 and tau as predictors of Alzheimer’s disease in mild cognitive impairment. Mol Psychiatry 2004;9:705–710.
  8. Gómez-Tortosa E, Gonzalo I, Fanjul S, Sainz MJ, Canterero S, Cemillan C, et al: Cerebrospinal fluid markers in dementia with Lewy bodies compared with Alzheimer disease. Arch Neurol 2003;60:1218–1222.
  9. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L: Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 2006;5:228–234.
  10. Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, et al: Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 2007;6:734–746.
  11. Selkoe DJ: Toward a comprehensive theory for Alzheimer’s disease. Hypothesis: Alzheimer’s disease is caused by cerebral accumulation and cytotoxicity of amyloid β-protein. Ann N Y Acad Sci 2000;924:17–25.
  12. Rubenstein E: Relationship of senescence of cerebrospinal fluid circulatory system to dementias of the age. Lancet 1998;351:283–285.
  13. Corder EH, Saunders AM, Strittmatter WJ, Schechel DE, Gaskelle PC, Small GW, et al: Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late-onset families. Science 1993;261:921–923.
  14. Cavalieri M, Enzinger C, Petrovic K, Fuerst AP, Homayoon N, Schmidt H, et al: Vascular dementia and Alzheimer’s disease – are we in a dead-end road? Neurodegener Dis 2010;7:122–126.
  15. Dickstein DL, Walsh J, Brautigam H, Stocklon SD Jr, Gandy S, Hof PR: Role of vascular risk factors and vascular dysfunction in Alzheimer’s disease. Mt Sinai J Med 2010;77:82–102.
  16. Bowman GL, Quinn JF: Alzheimer’s disease and the blood-brain barrier: past, present and future. Aging Health 2008;4:47–55.
  17. Weir DG, Scott JM: Brain function in the elderly: role of vitamin B12 and folate. Br Med Bull 1999;55:669–682.
  18. Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM: Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 1998;55:1449–1455.
  19. Ramos MI, Allen LH, Mungas DM, Jagust WJ, Haan MN, Green R, Miller JW: Low folate status is associated with impaired cognitive function and dementia in the Sacramento Area Latino Study on Aging. Am J Clin Nutr 2005;82:1346–1352.
  20. De Lau LM, Refsum H, Smith AD, Johnston C, Breteler MM: Plasma folate concentration and cognitive performance: Rotterdam Scan Study. Am J Clin Nutr 2007;86:728–734.
  21. 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 2002;346:476–483.
  22. Sérot JM, Christmann D, Dubost T, Béné MC, Faure GC: CSF-folate levels are decreased in late-onset AD patients. J Neural Transm 2001;108:93–99.
  23. Mulder C, Schoonenboom NS, Jansen EEW, Verhoeven NM, van Kamp GJ, Jakobs C, et al: The transmethylation cycle in the brain of Alzheimer patients. Neurosci Lett 2005;386:69–71.
  24. Hagnelius NO, Wahlund LO, Nilsson TK: CSF/serum folate gradient: physiology and determinants with special reference to dementia. Dement Geriatr Cogn Disord 2008;25:516–523.
  25. Popp J, Lewczuk P, Linnebank M, Cvetanovska G, Smulders Y, Kölsch H, et al: Homocysteine metabolism and cerebrospinal fluid markers for Alzheimer’s disease. J Alzheimers Dis 2009;18:819–828.
  26. Sérot JM, Barbé F, Arning E, Bottiglieri T, Franck P, Montagne P, Nicolas JP: Homocysteine and methylmalonic acid concentrations in cerebrospinal fluid: relation with age and Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2005;76:1585–1587.
  27. Isobe C, Murata T, Sato C, Terayama Y: Increase of total homocysteine concentration in cerebrospinal fluid in patients with Alzheimer’s disease and Parkinson’s disease. Life Sci 2005;77:1836–1843.
  28. Folstein MF, Folstein SE, McHugh PR: ‘Mini-Mental State’: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–198.
  29. Bellaj T: Dysfonctionnement de la mémoire de travail dans la maladie d’Alzheimer; thesis, Faculté des Sciences Humaines et Sociales de Tunis, 1999.
  30. Snowdon DA, Tully CL, Smith CD, Riley KP, Markesbery WR: Serum folate and the severity of atrophy of the neocortex in Alzheimer disease: findings from the Nun study. Am J Clin Nutr 2000;71:993–998.
  31. Kim SR, Choi SH, Ha CK, Park SG, Pyun HW, Yoon DH: Plasma total homocysteine levels are not associated with medial temporal lobe atrophy, but with white matter changes in Alzheimer’s disease. J Clin Neurol 2009;5:85–90.
  32. Selley ML, Close DR, Stern SE: The effect of increased concentration of homocysteine on the concentration of (E)-4-hydroxy-2-nonenal in the plasma and cerebrospinal fluid of patients with Alzheimer’s disease. Neurobiol Aging 2002;23:383–388.
  33. Linnebank M, Popp J, Smulders Y, Smith D, Semmler A, Farkas M, et al: S-adenosylmethionine is decreased in the cerebrospinal fluid of patients with Alzheimer’s disease. Neurodegener Dis 2010;7:373–378.
  34. Spector R: Nutrient transport systems in brain: 40 years of progress. J Neurochem 2009;111:315–320.
  35. Blom HJ, Wevers RA, Verrips A, TePoele-Pothoff MT, Trijbels JM: Cerebrospinal homocysteine and the cobalamin status of the brain. J Inherit Metab Dis 1993;16:517–519.
  36. Obeid R, Kostopoulos P, Knapp JP, Kasoha M, Becker G, Fasbender K, Hermann W: Biomarkers of folate and vitamin B12 are related in blood and cerebrospinal fluid. Clin Chem 2007;53:326–333.
  37. Obeid R, Kasoha M, Knapp JP, Kostopoulos P, Becher G, Fasbender K, Hermann W: Folate and methylation status in relation to phosphorylated tau protein (181p) and β-amyloid (1-42) in cerebrospinal fluid. Clin Chem 2007;53:1129–1136.
  38. Bottiglieri T, Reynolds EH, Laundy M: Folate in CSF and age. J Neurol Neurosurg Psychiatry 2000;69;562–567.
  39. Ormazabal A, Garcia-Cazorla A, Pérez- Dueñas B, Gonzalez V, Ferńandez-Álvarez E, Pineda M, et al: Determination of 5-methyltetrahydrofolate in cerebrospinal fluid of paediatric patients: reference values for a paediatric population. Clin Chim Acta 2006;371:159–162.
  40. Stabler SP, Allen RH, Barrett RE, Savage DG, Lindenbaum J: Cerebrospinal fluid methylmalonic acid levels in normal subjects and patients with cobalamin deficiency. Neurology 1991;41:1627–1632.
  41. Hyland K, Bottiglieri T: Measurement of total plasma and cerebrospinal fluid homocysteine by fluorescence following high-performance liquid chromatography and precolumn derivatization with o-phtaldialdehyde. J Chromatogr 1992;579:55–62.
  42. Jack CR, Knopman DS, Jagust WJ, Shaw LM, Aisen PA, Weiner MW, et al: Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol 2010;9:119–128.
  43. Alexopoulos P, Günther F, Popp J, Jessen F, Peters O, Wolf S, et al: Plasma homocysteine and cerebrospinal fluid neurodegeneration biomarkers in mild cognitive impairment and dementia. J Am Geriatr Soc 2009;57:737–739.
  44. Malouf R, Grimley Evans J: Folic acid with or without vitamin B12 for the prevention and treatment of healthy elderly and demented people. Cochrane Database Syst Rev 2008;4:CD004514.

Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50