The journal of nutrition, health & aging

, Volume 20, Issue 8, pp 825–834 | Cite as

Novel therapy of hyperhomocysteinemia in mild cognitive impairment, Alzheimer’s disease, and other dementing disorders

  • Junko HaraEmail author
  • W. R. Shankle
  • L. W. Barrentine
  • M. V. Curole



Studies have produced conflicting results assessing hyperhomocysteinemia (HYH) treatment with B vitamins in patients with normal cognition, Alzheimer’s disease and related disorders (ADRD). This study examined the effect of HYH management with L-methylfolate (LMF), methylcobalamin (MeCbl; B12), and N-acetyl-cysteine (CFLN: Cerefolin®/Cerefolin-NAC®) on cognitive decline.


Prospective, case-control study of subjects followed longitudinally.


Outpatient clinic for cognitive disorders.


116 ADRD patients (34 with HYH, 82 with No-HYH) met inclusion and exclusion criteria to participate. No study participant took B vitamins.


HYH patients received CFLN, and No-HYH patients did not.


Cognitive outcome measures included MCI Screen (memory), CERAD Drawings (constructional praxis), Ishihara Number Naming (object recognition), Trails A and B (executive function), and F-A-S test (verbal fluency). Dependent or predictor measures included demographics, functional severity, CFLN and no CFLN treatment duration, ADRD diagnosis, memantine and cholinesterase inhibitor treatment. Linear mixed effects models with covariate adjustment were used to evaluate rate of change on cognitive outcomes.


The duration of CFLN treatment, compared to an equivalent duration without CFLN treatment, significantly slowed decline in learning and memory, constructional praxis, and visual-spatial executive function (Trails B). CFLN treatment slowed cognitive decline significantly more for patients with milder baseline severity. CFLN treatment effect increased as baseline functional severity decreased. The analytical model showed that treatment duration must exceed some minimum period of at least one year to slow the rate of cognitive decline.


After covariate adjustment, HYH+CFLN significantly slowed cognitive decline compared to No-HYH+No-CFLN. Longer CFLN treatment duration, milder baseline severity, and magnitude of homocysteine reduction from baseline were all significant predictors. There are a number of factors that could account for disagreement with other clinical trials of B vitamin treatment of HYH. Moreover, CFLN is chemically distinct from commonly used B vitamins as both LMF and MeCbl are the fully reduced and bioactive functional forms; CLFN also contains the glutathione precursor, N-acetyl-cysteine. The findings of other B vitamin trials of HYH can, therefore, only partly account for treatment effects of CFLN. These findings warrant further evaluation with a randomized, placebo-controlled trial.

Key words

Homocysteine cognitive impairment N-acetyl-cysteine L-methylfolate methylcobalamin B vitamins 


  1. 1.
    Wong YY, Almeida OP, McCaul KA et al. Homocysteine, Frailty, and All-Cause Mortality in Older Men: The Health in Men Study. J Gerontol A Biol Sci Med Sci. 2013;68(5):590–598.CrossRefPubMedGoogle Scholar
  2. 2.
    MacFarlane AJ, Greene-Finestone LS, Shi Y. Vitamin B-12 and homocysteine status in a folate-replete population: results from the Canadian Health Measures Survey. Am J Clin Nutr. 2011;94(4):1079–1087.CrossRefPubMedGoogle Scholar
  3. 3.
    Selhub J, Jacques PF, Bostom AG et al. Relationship between plasma homocysteine and vitamin status in the Framingham study population. Impact of folic acid fortification. Public Health Rev. 2000;28(1–4):117–145.PubMedGoogle Scholar
  4. 4.
    Sachdev PS, Lipnicki DM, Crawford J et al. Sydney Memory and Ageing Study Team. Risk profiles for mild cognitive impairment vary by age and sex: the sydney memory and ageing study. Am J Geriatr Psychiatry. 2012;20(10):854–865.CrossRefPubMedGoogle Scholar
  5. 5.
    Nie T, Lu T, Xie L, Huang P, Lu Y, Jiang M. Hyperhomocysteinemia and risk of cognitive decline: a meta-analysis of prospective cohort studies. Eur Neurol. 2014;72(3–4):241–248.PubMedGoogle Scholar
  6. 6.
    Shea TB, Rogers E. Lifetime requirement of the methionine cycle for neuronal development and maintenance. Curr Opin Psychiatry. 2014;27(2):138–142.CrossRefPubMedGoogle Scholar
  7. 7.
    Krupanidhi S, Sedimbi SK, Vaishnav G, Madhukar SS, Sanjeevi CB. Diabetes—role of epigenetics, genetics, and physiological factors. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2009;34(9):837–845.PubMedGoogle Scholar
  8. 8.
    Bruce KD, Cagampang FR. Epigenetic priming of the metabolic syndrome. Toxicol Mech Methods. 2011;21(4):353–361.CrossRefPubMedGoogle Scholar
  9. 9.
    Ordovás JM, Smith CE. Epigenetics and cardiovascular disease. Nat Rev Cardiol. 2010;7(9):510–519.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Lavebratt C, Almgren M, Ekström TJ. Epigenetic regulation in obesity. Int J Obes (Lond). 2012;36(6):757–765.CrossRefGoogle Scholar
  11. 11.
    Shi F, Chen X, Fu A, Hansen J, Stevens R, Tjonneland A, Vogel UB, Zheng T, Zhu Y. Aberrant DNA methylation of miR-219 promoter in long-term night shiftworkers. Environ Mol Mutagen. 2013;54(6):406–413.CrossRefPubMedGoogle Scholar
  12. 12.
    Joska TM, Zaman R, Belden WJ. Regulated DNA methylation and the circadian clock: implications in cancer. Biology (Basel). 2014;3(3):560–577.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Liu HC, Hu CJ, Tang YC, Chang JG. A pilot study for circadian gene disturbance in dementia patients. Neurosci Lett. 2008;435(3):229–233.CrossRefPubMedGoogle Scholar
  14. 14.
    Lim AS, Srivastava GP, Yu L, Chibnik LB, Xu J, Buchman AS, Schneider JA, Myers AJ, Bennett DA, De Jager PL. 24-hour rhythms of DNA methylation and their relation with rhythms of RNA expression in the human dorsolateral prefrontal cortex. PLoS Genet. 2014;10(11):e1004792.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Robinson RA, Joshi G, Huang Q, Sultana R, Baker AS, Cai J, Pierce W, St Clair DK, Markesbery WR, Butterfield DA. Proteomic analysis of brain proteins in APP/ PS-1 human double mutant knock-in mice with increasing amyloid beta-peptide deposition: insights into the effects of in vivo treatment with N-acetylcysteine as a potential therapeutic intervention in mild cognitive impairment and Alzheimer’s disease. Proteomics. 2011;11(21):4243–4256.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Szucs TD, Käser A, Riesen WF. Economic impact of hyperhomocysteinemia in Switzerland. Cardiovasc Drugs Ther. 2005;19(5):365–369.CrossRefPubMedGoogle Scholar
  17. 17.
    Kwok T, Lee J, Law CB, Pan PC, Yung CY, Choi KC, Lam LC. A randomized placebo controlled trial of homocysteine lowering to reduce cognitive decline in older demented people. Clin Nutr. 2011;30(3):297–302.CrossRefPubMedGoogle Scholar
  18. 18.
    Aisen PS, Schneider LS, Sano M, et al. Alzheimer Disease Cooperative Study. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA. 2008;300(15):1774–1783.PubMedGoogle Scholar
  19. 19.
    Shankle WR, Hara J, Rafii MS, Russell J. Impact of Hyperhomocysteinemia Treatment on Cognitive Decline due to Alzheimer’s Disease and Related Disorders. JARCP. 2013;2(4): 319–324.Google Scholar
  20. 20.
    Shankle WR, Mangrola T, Chan T, Hara J. Development and Validation of the Memory Performance Index: Reducing Measurement Error in Recall Tests. Alzheimer’s & Dementia. 2009;5:295–306.CrossRefGoogle Scholar
  21. 21.
    Shankle WR, Romney AK, Hara J, et al. Method to improve the detection of mild cognitive impairment. Proc Natl Acad Sci USA. 2005;102(13):4919–4924.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Rafii M, Taylor C, Coutinho A, Kim K, Galasko D. Comparison of the memory performance index with standard neuropsychological measures of cognition. Am J Alzheimers Dis Other Demen. 2011;26(3):235–239.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Reisberg B. Dementia: a systematic approach to identifying reversible causes. Geriatrics. 1986;41(4):30–46.PubMedGoogle Scholar
  24. 24.
    Blasko I, Hinterberger M, Kemmler G, Jungwirth S, Krampla W, Leitha T, Heinz Tragl K, Fischer P. Conversion from mild cognitive impairment to dementia: influence of folic acid and vitamin B12 use in the VITA cohort. J Nutr Health Aging 2012;16(8):687–694.CrossRefPubMedGoogle Scholar
  25. 25.
    de Jager CA, Oulhaj A, Jacoby R et al. Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: a randomized controlled trial. Int J Geriatr Psychiatry. 2012;27(6):592–600.CrossRefPubMedGoogle Scholar
  26. 26.
    Sassone-Corsi P. Physiology. When metabolism and epigenetics converge. Science. 2013;339(6116):148–150.PubMedGoogle Scholar
  27. 27.
    Moustafa AA, Hewedi DH, Eissa AM et al. The relationship between associative learning, transfer generalization, and homocysteine levels in mild cognitive impairment. PLoS One. 2012;7(9):e46496.Google Scholar
  28. 28.
    Sala I, Belén Sánchez-Saudinós M, Molina-Porcel L, Lázaro E, Gich I, Clarimón J, Blanco-Vaca F, Blesa R, Gómez-Isla T, Lleó A. Homocysteine and cognitive impairment. Relation with diagnosis and neuropsychological performance. Dement Geriatr Cogn Disord. 2008;26(6):506–512.CrossRefPubMedGoogle Scholar
  29. 29.
    Doets EL, Ueland PM, Tell GS, Vollset SE, Nygård OK, Van’t Veer P, de Groot LC, Nurk E, Refsum H, Smith AD, Eussen SJ. Interactions between plasma concentrations of folate and markers of vitamin B(12) status with cognitive performance in elderly people not exposed to folic acid fortification: the Hordaland Health Study. Br J Nutr. 2014;111(6):1085–1095CrossRefPubMedGoogle Scholar
  30. 30.
    Miller JW, Garrod MG, Allen LH, Haan MN, Green R. Metabolic evidence of vitamin B-12 deficiency, including high homocysteine and methylmalonic acid and low holotranscobalamin, is more pronounced in older adults with elevated plasma folate. Am J Clin Nutr. 2009 Dec;90(6):1586–92.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Vidal JS, Dufouil C, Ducros V, Tzourio C. Homocysteine, folate and cognition in a large community-based sample of elderly people—the 3C Dijon Study. Neuroepidemiology. 2008;30(4):207–214.CrossRefPubMedGoogle Scholar
  32. 32.
    Rabaneda LG, Carrasco M, Lopez-Toledano MA, Murillo-Carretero M, Ruiz FA, Estrada C, Castro C. Homocysteine inhibits proliferation of neuronal precursors in the mouse adult brain by impairing the basic fibroblast growth factor signaling cascade and reducing extracellular regulated kinase 1/2-dependent cyclin E expression. FASEB J. 2008;22(11):3823–3835.CrossRefPubMedGoogle Scholar
  33. 33.
    Kruman II, Fowler AK. Impaired one carbon metabolism and DNA methylation in alcohol toxicity. J Neurochem. 2014;129(5):770–780.CrossRefPubMedGoogle Scholar
  34. 34.
    Jayalakshmi K, Sairam M, Singh SB, Sharma SK, Ilavazhagan G, Banerjee PK. Neuroprotective effect of N-acetyl cysteine on hypoxia-induced oxidative stress in primary hippocampal culture. Brain Res. 2005;1046(1–2):97–104.CrossRefPubMedGoogle Scholar
  35. 35.
    Unnithan AS, Choi HJ, Titler AM, Posimo JM, Leak RK. Rescue from a two hit, high-throughput model of neurodegeneration with N-acetyl cysteine. Neurochem Int. 2012;61(3):356–368.CrossRefPubMedGoogle Scholar
  36. 36.
    Rideau Batista Novais A, Guiramand J, Cohen-Solal C, Crouzin N, de Jesus Ferreira MC, Vignes M, Barbanel G, Cambonie G. N-acetyl-cysteine prevents pyramidal cell disarray and reelin-immunoreactive neuron deficiency in CA3 after prenatal immune challenge in rats. Pediatr Res. 2013;73(6):750–755.CrossRefPubMedGoogle Scholar
  37. 37.
    Otte DM, Sommersberg B, Kudin A, Guerrero C, Albayram O, Filiou MD, Frisch P, Yilmaz O, Drews E, Turck CW, Bilkei-Gorzó A, Kunz WS, Beck H, Zimmer A. N-acetyl cysteine treatment rescues cognitive deficits induced by mitochondrial dysfunction in G72/G30 transgenic mice. Neuropsychopharmacology. 2011;36(11):2233–2243.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Cheng Y, Jin Y, Unverzagt FW, Su L, Yang L, Ma F, Hake AM, Kettler C, Chen C, Liu J, Bian J, Li P, Murrell JR, Hendrie HC, Gao S. The relationship between cholesterol and cognitive function is homocysteine-dependent. Clin Interv Aging. 2014;9:1823–1829.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Glushchenko AV, Jacobsen DW. Molecular targeting of proteins by L-homocysteine: mechanistic implications for vascular disease. Antioxid Redox Signal. 2007;9(11):1883–1898.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Hooshmand B, Polvikoski T, Kivipelto M, Tanskanen M, Myllykangas L, Erkinjuntti T, Mäkelä M, Oinas M, Paetau A, Scheltens P, van Straaten EC, Sulkava R, Solomon A. Plasma homocysteine, Alzheimer and cerebrovascular pathology: a populationbased autopsy study. Brain. 2013;136(Pt 9):2707–2716.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Fuso A, Nicolia V, Cavallaro RA, Ricceri L, D’Anselmi F, Coluccia P, Calamandrei G, Scarpa S. B-vitamin deprivation induces hyperhomocysteinemia and brain S-adenosylhomocysteine, depletes brain S-adenosylmethionine, and enhances PS1 and BACE expression and amyloid-beta deposition in mice.31. Mol Cell Neurosci. 2008;37(4):731–746.CrossRefPubMedGoogle Scholar
  42. 42.
    Schaub C, Uebachs M, Beck H, Linnebank M. Chronic homocysteine exposure causes changes in the intrinsic electrophysiological properties of cultured hippocampal neurons. Exp Brain Res. 2013;225(4):527–534.CrossRefPubMedGoogle Scholar
  43. 43.
    Görtz P, Hoinkes A, Fleischer W, Otto F, Schwahn B, Wendel U, Siebler M. Implications for hyperhomocysteinemia: not homocysteine but its oxidized forms strongly inhibit neuronal network activity. J Neurol Sci. 2004 Mar 15;218(1–2):109–14.CrossRefPubMedGoogle Scholar

Copyright information

© Serdi and Springer-Verlag France 2016

Authors and Affiliations

  • Junko Hara
    • 1
    • 2
    Email author
  • W. R. Shankle
    • 1
    • 2
    • 3
    • 4
  • L. W. Barrentine
    • 5
  • M. V. Curole
    • 5
  1. 1.Medical Care CorporationNewport BeachUSA
  2. 2.Shankle ClinicNewport BeachUSA
  3. 3.Memory and Cognitive Disorders Program, Neurosciences InstituteHoag Memorial Hospital PresbyterianNewport BeachUSA
  4. 4.Dept. of Cognitive SciencesUniversity of CaliforniaIrvineUSA
  5. 5.Nestlé Health Science - Pamlab, Inc.Newport BeachUSA

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