Neurochemical Research

, Volume 32, Issue 4–5, pp 775–781 | Cite as

Relation of Plasma Homocysteine to Plasma Amyloid Beta Levels

  • José A. Luchsinger
  • Ming-Xin Tang
  • Joshua Miller
  • Ralph Green
  • Pankash D. Mehta
  • Richard MayeuxEmail author
Original Paper



Elevated plasma homocysteine and amyloid β (Aβ) have been associated with Alzheimer’s disease (AD). We investigated the cross-sectional association between these biomarkers.


We used linear regression to relate plasma homocysteine and Aβ adjusting for age, gender, creatinine, APOE-ε4, and ethnic group in 327 persons aged 78 ± 6.6 years.


Plasma homocysteine correlated with age, serum creatinine, plasma Aβ40 and Aβ42, and was inversely correlated with serum vitamin B12, and folate. Aβ42, but not Aβ40, was related to later development of dementia. Homocysteine was related to higher Aβ40 levels (coefficient = 2.0; P < 0.0001) and this association was attenuated after adjustment for creatinine (coefficient = 1.0; P < 0.0001). The crude association between homocysteine and Aβ42 was weaker (coefficient = 0.5; P = 0.01) and became non-significant after adjustment for creatinine (coefficient = 0.4; P = 0.06). These associations were unrelated to ethnicity, the presence of APOE-ε4 or dementia. Analyses by quartiles of homocysteine showed that these association were driven primarily by the fourth quartile.


Plasma homocysteine is directly related to Aβ40. The association with Aβ42 is not significant. These results seem to indicate that homocysteine is related to aging but not specifically to AD.


Homocysteine Plasma Amyloid beta Alzheimer’s disease 



Support for this work was provided by grants from the National Institutes of Health AG15294, AG07232, AG07702, AG20856, RR00645 from the Charles S. Robertson Memorial Gift for research on Alzheimer’s disease, and from the Blanchette Hooker Rockefeller Foundation.


  1. 1.
    Seshadri S, Beiser A, Selhub J et al (2002) Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med 346:476–483PubMedCrossRefGoogle Scholar
  2. 2.
    Luchsinger JA, Tang M-X, Shea S, Miller J, Green R, Mayeux R (2004) Plasma homocysteine levels and risk of Alzheimer disease. Neurology 62:1972–1976PubMedGoogle Scholar
  3. 3.
    Budge MM, de Jager C, Hogervorst E, Smith AD, Oxford Project To Investigate Memory and Ageing (2002) Total plasma homocysteine, age, systolic blood pressure, and cognitive performance in older people. J Am Geriatr Soc 50:2014–2018Google Scholar
  4. 4.
    Miller JW, Green R, Mungas DM, Reed BR, Jagust WJ (2002) Homocysteine, vitamin B6, and vascular disease in AD patients. Neurology.58:1471–1475PubMedGoogle Scholar
  5. 5.
    Seshadri S, Wolf PA (2003) Homocysteine and the brain: vascular risk factor or neurotoxin? Lancet Neurol 2:11PubMedCrossRefGoogle Scholar
  6. 6.
    Ritchie K, Lovestone S (2002) The dementias. Lancet 360:1759–1766PubMedCrossRefGoogle Scholar
  7. 7.
    Petersen RC, Doody R, Kurz A et al (2001) Current concepts in mild cognitive impairment. Arch Neurol 58:1985–1992PubMedCrossRefGoogle Scholar
  8. 8.
    Cummings JL (2004) Alzheimer’s disease. N Engl J Med 351:56–67PubMedCrossRefGoogle Scholar
  9. 9.
    Selkoe DJ (2000) The origins of Alzheimer disease: a is for amyloid. JAMA 283:1615–1617PubMedCrossRefGoogle Scholar
  10. 10.
    Frank RA, Galasko D, Hampel H et al (2003) Biological markers for therapeutic trials in Alzheimer’s disease. Proceedings of the biological markers working group; NIA initiative on neuroimaging in Alzheimer’s disease. Neurobiol Aging 24:521–536PubMedCrossRefGoogle Scholar
  11. 11.
    Schupf N, Patel B, Silverman W et al (2001) Elevated plasma amyloid beta-peptide 1–42 and onset of dementia in adults with Down syndrome. Neurosci Lett 301:199–203PubMedCrossRefGoogle Scholar
  12. 12.
    Scheuner D, Eckman C, Jensen M et al (1996) Secreted amyloid beta-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 2:864–870PubMedCrossRefGoogle Scholar
  13. 13.
    Mayeux R, Tang MX, Jacobs DM et al (1999) Plasma amyloid beta-peptide 1–42 and incipient Alzheimer’s disease. Ann Neurol 46:412–416PubMedCrossRefGoogle Scholar
  14. 14.
    Mayeux R, Honig LS, Tang M-X et al (2003) Plasma A{beta}40 and A{beta}42 and Alzheimer’s disease: relation to age, mortality, and risk. Neurology 61:1185–1190PubMedGoogle Scholar
  15. 15.
    Assini A, Cammarata S, Vitali A et al (2004) Plasma levels of amyloid {beta}-protein 42 are increased in women with mild cognitive impairment. Neurology 63:828–831PubMedGoogle Scholar
  16. 16.
    Tang MX, Stern Y, Marder K et al (1998) The APOE-epsilon4 allele and the risk of Alzheimer disease among African Americans, whites, and Hispanics. JAMA 279:751–755PubMedCrossRefGoogle Scholar
  17. 17.
    Stern Y, Andrews H, Pittman J et al (1992) Diagnosis of dementia in a heterogeneous population. development of a neuropsychological paradigm-based diagnosis of dementia and quantified correction for the effects of education. Arch Neurol 49:453–460PubMedGoogle Scholar
  18. 18.
    Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (1994) American Psychiatric Association, Washington, DC, pp 143–147Google Scholar
  19. 19.
    Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL (1982) A new clinical scale for the staging of dementia. Br J Psychiatry 140:566–572PubMedCrossRefGoogle Scholar
  20. 20.
    McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) 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 34:939–944PubMedGoogle Scholar
  21. 21.
    Honig LS, Tang MX, Albert S et al (2003) Stroke and the risk of Alzheimer disease. Arch Neurol 60:1707–1712PubMedCrossRefGoogle Scholar
  22. 22.
    Mayeux R, Honig LS, Tang MX et al (2003) Plasma A[beta]40 and A[beta]42 and Alzheimer’s disease: relation to age, mortality, and risk. Neurology 61:1185–1190PubMedGoogle Scholar
  23. 23.
    Luchsinger JA, Tang MX, Shea S, Miller J, Green R, Mayeux R (2004) Plasma homocysteine levels and risk of Alzheimer disease. Neurology 62:1972–1976PubMedGoogle Scholar
  24. 24.
    Gilfix BM, Blank DW, Rosenblatt DS (1997) Novel reductant for determination of total plasma homocysteine. Clin Chem 43:687–688PubMedGoogle Scholar
  25. 25.
    Fleiss JL (1981) Statistical methods for rates and proportions, 2nd edn. Joseph Wiley and SonsGoogle Scholar
  26. 26.
    Hofman A, Ott A, Breteler MM et al (1997) Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer’s disease in the Rotterdam study. Lancet 349:151–154PubMedCrossRefGoogle Scholar
  27. 27.
    Luchsinger J, Mayeux R (2004) Cardiovascular risk factors and Alzheimer’s disease. Curr Atheroscler Rep 6:261–266PubMedGoogle Scholar
  28. 28.
    Aisen PS, Egelko S, Andrews H et al (2003) A pilot study of vitamins to lower plasma homocysteine levels in Alzheimer disease. Am J Geriatr Psychiatry 11:246–249PubMedCrossRefGoogle Scholar
  29. 29.
    McIlroy SP, Dynan KB, Lawson JT, Patterson CC, Passmore AP (2002) Moderately elevated plasma homocysteine, methylenetetrahydrofolate reductase genotype, and risk for stroke, vascular dementia, and Alzheimer disease in Northern Ireland. Stroke 33:2351–2356PubMedCrossRefGoogle Scholar
  30. 30.
    McCaddon A, Hudson P, Davies G, Hughes A, Williams JH, Wilkinson C (2001) Homocysteine and cognitive decline in healthy elderly. Dement Geriatr Cogn Disord 12:309–313PubMedCrossRefGoogle Scholar
  31. 31.
    Prins ND, Den Heijer T, Hofman A et al (2002) Homocysteine and cognitive function in the elderly: the Rotterdam scan study. Neurology 59:1375–1380PubMedGoogle Scholar
  32. 32.
    Sachdev PS, Valenzuela MJ, Brodaty H et al (2003) Homocysteine as a risk factor for cognitive impairment in stroke patients. Dement Geriatr Cogn Disord 15:155–162PubMedCrossRefGoogle Scholar
  33. 33.
    den Heijer T, Vermeer SE, Clarke R et al (2003) Homocysteine and brain atrophy on MRI of non-demented elderly. Brain 126:170–175CrossRefGoogle Scholar
  34. 34.
    Bostom AG, Rosenberg IH, Silbershatz H et al (1999) Nonfasting plasma total homocysteine levels and stroke incidence in elderly persons: the Framingham study. Ann Intern Med 131:352–355PubMedGoogle Scholar
  35. 35.
    Perry IJ, Refsum H, Morris RW, Ebrahim SB, Ueland PM, Shaper AG (1995) Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. Lancet 346:1395–1398PubMedCrossRefGoogle Scholar
  36. 36.
    Vermeer SE, van Dijk EJ, Koudstaal PJ et al (2002) Homocysteine, silent brain infarcts, and white matter lesions: the Rotterdam scan study. Ann Neurol 51:285–289PubMedCrossRefGoogle Scholar
  37. 37.
    Honig LS, Tang MX, Albert S et al (2003) Stroke and the risk of Alzheimer disease. Arch Neurol 60:1707–1712PubMedCrossRefGoogle Scholar
  38. 38.
    Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM (2003) Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 348:1215–1222PubMedCrossRefGoogle Scholar
  39. 39.
    He K, Merchant A, Rimm EB et al (2004) Folate, vitamin B6, and B12 intakes in relation to risk of stroke among men. Stroke 35:169–174PubMedCrossRefGoogle Scholar
  40. 40.
    Toole JF, Malinow MR, Chambless LE et al (2004) Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: The Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 291:565–575PubMedCrossRefGoogle Scholar
  41. 41.
    Ho PI, Collins SC, Dhitavat S et al (2001) Homocysteine potentiates beta-amyloid neurotoxicity: role of oxidative stress. J Neurochem 78:249–253PubMedCrossRefGoogle Scholar
  42. 42.
    Mok SS, Turner BJ, Beyreuther K, Masters CL, Barrow CJ, Small DH (2002) Toxicity of substrate-bound amyloid peptides on vascular smooth muscle cells is enhanced by homocysteine. Eur J Biochem 269:3014–3022PubMedCrossRefGoogle Scholar
  43. 43.
    Kruman II, Culmsee C, Chan SL et al (2000) Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J Neurosci 20:6920–6926PubMedGoogle Scholar
  44. 44.
    Kruman II, Kumaravel TS, Lohani A et al (2002) Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer’s disease. J Neurosci 22:1752–1762PubMedGoogle Scholar
  45. 45.
    Selkoe DJ (1997) Alzheimer’s disease: genotypes, phenotypes, and treatments. Science 275:630–631PubMedCrossRefGoogle Scholar
  46. 46.
    Pak KJ, Chan SL, Mattson MP (2003) Homocysteine and folate deficiency sensitize oligodendrocytes to the cell death-promoting effects of a presenilin-1 mutation and amyloid beta-peptide. Neuromol Med 3:119–128CrossRefGoogle Scholar
  47. 47.
    Pacheco-Quinto J, Rodriguez de Turco EB, DeRosa S et al (2006) Hyperhomocysteinemic Alzheimer’s mouse model of amyloidosis shows increased brain amyloid [beta] peptide levels. Neurobiol Dis 22:651–656PubMedCrossRefGoogle Scholar
  48. 48.
    Irizarry MC, Gurol ME, Raju S et al (2005) Association of homocysteine with plasma amyloid {beta} protein in aging and neurodegenerative disease. Neurology 65:1402–1408PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • José A. Luchsinger
    • 1
    • 2
  • Ming-Xin Tang
    • 1
    • 3
  • Joshua Miller
    • 5
  • Ralph Green
    • 5
  • Pankash D. Mehta
    • 9
  • Richard Mayeux
    • 1
    • 4
    • 6
    • 7
    • 8
    Email author
  1. 1.Taub Institute for Research of Alzheimer’s Disease and the Aging BrainColumbia UniversityNew YorkUSA
  2. 2.Division of General Medicine, Department of MedicineColumbia University College of Physicians and SurgeonsNew YorkUSA
  3. 3.Division of Biostatistics, Joseph P. Mailman School of Public HealthColumbia UniversityNew YorkUSA
  4. 4.Division of Epidemiology, Joseph P. Mailman School of Public HealthColumbia UniversityNew YorkUSA
  5. 5.Department of Medical Pathology, School of MedicineUniversity of CaliforniaDavisUSA
  6. 6.Gertrude H. Sergievsky CenterColumbia UniversityNew YorkUSA
  7. 7.Department of NeurologyColumbia University College of Physicians and SurgeonsNew YorkUSA
  8. 8.Department of PsychiatryColumbia University College of Physicians and SurgeonsNew YorkUSA
  9. 9.Department of ImmunologyInstitute for Basic Research in Developmental DisabilitiesStaten IslandUSA

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