Efficacy of a Vitamin/Nutriceutical Formulation for Early-stage Alzheimer's Disease: A 1-year,Open-label Pilot Study With an 16-Month Caregiver Extension
Free accessResearch articleFirst published online December, 2009
Efficacy of a Vitamin/Nutriceutical Formulation for Early-stage Alzheimer's Disease: A 1-year,Open-label Pilot Study With an 16-Month Caregiver Extension
We examined the efficacy of a vitamin/nutriceutical formulation (folate, vitamin B6, alpha-tocopherol, S-adenosyl methionine, N-acetyl cysteine, and acetyl-L-carnitine) in a 12-month, open-label trial with 14 community-dwelling individuals with early-stage Alzheimer's disease. Participants improved in the Dementia Rating Scale and Clock-drawing tests (Clox 1 and 2). Family caregivers reported improvement in multiple domains of the Neuropsychiatric Inventory (NPI) and maintenance of performance in the Alzheimer's Disease Cooperative Study—Activities of Daily Living (ADL). Sustained performance was reported by caregivers for those participants who continued in an 16-month extension. Performance on the NPI was equivalent to published findings at 3 to 6 months for donepezil and exceeded that of galantamine and their historical placebos. Participants demonstrated superior performance for more than 12 months in NPI and ADL versus those receiving naproxen and rofecoxib or their placebo group. This formulation holds promise for treatment of early-stage Alzheimer's disease prior to and/or as a supplement for pharmacological approaches. A larger, placebo-controlled trial is warranted.
Swerdlow RHPathogenesis of Alzheimer's disease. Clin Interv Aging. 2007;2:347-359.
2.
Shah S., Reichman WETreatment of Alzheimer's disease across the spectrum of severity. Clin Interv Aging. 2006;1: 131-142.
3.
Burns A., Gauthier S., Perdomo C.Efficacy and safety of donepezil over 3 years: an open-label, multicentre study in patients with Alzheimer's disease. Int J Geriatr Psychiatry. 2007;22:806-812.
4.
Feldman HH, Schmitt FA, Olin JT; Memantine MEM-MD-02 Study Group.Activities of daily living in moderate-to-severe Alzheimer disease: an analysis of the treatment effects of memantine in patients receiving stable donepezil treatment . Alzheimer Dis Assoc Disord. 2006;20:263-268.
5.
Johannsen P.Medical treatment of Alzheimer's disease. Ugeskr Laeger. 2006;168:3424-3429.
6.
Reisberg B., Doody R., Stoffler A., Schmitt F., Ferris S., Mobius HJA 24-week open-label extension study of memantine in moderate to severe Alzheimer disease. Arch Neurol. 2006;63:49-54.
7.
Seow D., Gauthier S.Pharmacotherapy of Alzheimer disease. Can J Psychiatry. 2007;52:620-629.
8.
McGeer PL , Schulzer M., McGeer EGArthritis and antiinflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiological studies. Neurology. 1996;47:425-432.
9.
Beier MTTreatment strategies for the behavioral symptoms of Alzheimer's disease: focus on early pharmacologic intervention. Pharmacotherapy. 2007;27:399-411.
10.
Park KW, Pavlik VN, Rountree SD, Darby EJ, Doody RSIs functional decline necessary for a diagnosis of Alzheimer's disease? Dement Geriatr Cogn Disord. 2007;24: 375-379.
11.
Touchon J., Portet F., Gauthier S.Prevention trials in Alzheimer disease: one step forward?Neurology. 2006;67(9 suppl 3):S21-S22.
12.
Fusco D., Colloca G., Lo Monaco MR, Cesari M.Effects of antioxidant supplementation on the aging process. Clin Interv Aging. 2007;2:377-387.
13.
Mattson MM, Shea TBFolate and homocysteine in neural plasticity and neurodegenerative disorders . Trends Neurosci. 2002;26:137-146.
14.
Burgener SC , Buettner L., Coen Buckwlater K., et al. Evidence supporting nutritional interventions for persons in early-stage Alzheimer's disease. J Nutr Health Aging. 2008;12:18-21.
15.
Panza F., Solfrizzi V., Colacicco AM, et al. Mediterranean diet and cognitive decline. Public Health Nutr. 2004;7: 959-963.
16.
Zhu X., Su B., Wang X., Smith MA, Perry G.Causes of oxidative stress in Alzheimer disease. Cell Mol Life Sci. 2007;64:2202-2210.
17.
Joseph JA, Denisova NA, Bielinski D., Fisher DR, Shukitt-Hale. Oxidative stress protection and vulnerability in aging: putative nutritional implications for intervention. Mech Ageing Dev . 2000;116:141-153.
18.
Berman K., Brodaty H.Tocopherol (vitamin E) in Alzheimer's disease and other neurodegenerative disorders. CNS Drugs. 2004;18:807-825.
19.
Esposito E.,Rotilio D.,DiMatteo V.,DiGuilio C.,Cacchio M.,Algeri S.A reiew of specific dietary antioxidants and the effects on biochemical mechanisms related to neurodegenerative processes. Neurobiol Aging. 2002;23:719-735.
20.
Morris MC, Evans DA, Tangey CC, Bienas JL, Wilson RS, Aggarwal NTRelation of the tocopherol forms to incident Alzheimer's disease and to cognitive change. Am J Clin Nutr. 2005;82:508-514.
21.
Dhitavat S. , Rivera E., Shea TBDifferential efficacy of lipophilic and cytosolic antioxidants on generation of reactive oxygen species by amyloid-beta. J Alz Dis. 2001;3:525-529.
22.
Liu H., Wang H., Shenvi S., Hagen TM, Liu RMGlutathione metabolism during aging and in Alzheimer disease. Ann N Y Acad Sci. 2004;1019:346-349.
23.
Lovell MA, Xie C., Markesbery WRDecreased glutathione transferase activity in brain and ventricular fluid in Alzheimer's disease. Neurology. 1998;51:1562-1566.
24.
Bernardini S., Bellincampi L., Ballerini S., et al. Glutathione S-transferase P1 *C allelic variant increases susceptibility for late-onset Alzheimer disease: association study and relationship with apolipoprotein E epsilon4 allele. Clin Chem.2005;51:944-951.
25.
Spalletta G. , Bernardini S., Bellincampi L., et al. Glutathione S-transferase P1 and T1 gene polymorphisms predict longitudinal course and age at onset of Alzheimer disease. Am J Geriatr Psychiatry. 2007;15: 879-887.
26.
Adair JC, Knoefel JE, Morgan N.Controlled trial of N-acetylcysteine for patients with probable Alzheimer's disease. Neurology. 2001;57:1515-1517.
27.
St George-Hyslop PHGenetic factors in the genesis of Alzheimer's disease. Ann N Y Acad Sci. 2000;924:1-7.
28.
Reyes-EngelA,Munoz E., Gaitan MJ, et al. Implications on human fertility of the 677C->T and 1298A->C polymorphisms of the MTHFR gene: consequences of a possible genetic selection . Mol Hum Reprod. 2002;8:952-957.
29.
Tchantchou F., Graves M., Ortiz D., Shea TBS-adenosyl methionine: a link between nutritional and genetic risk factors in Alzheimer's disease. J Nutri Health Aging. 2006;10:541-544.
30.
Connelly PJ , Prentice NP, Cousland G., Bonham J.A randomised double-blind placebo-controlled trial of folic acid supplementation of cholinesterase inhibitors in Alzheimer's disease. Int J Geriatr Psychiatry. 2008;23: 155-160.
31.
Ellinson M. , Thomas J., Patterson A.A critical evaluation of the relationship between serum vitamin B12, folate and total homocystein with cognitive impairment in the elderly. J Hum Nutr Diet. 2004;17:371-383.
32.
Salerno-Kennedy R., Cashman KDRelationship between dementia and nutrition-related factors and disorders: an overview. Int J Vitam Nutr Res. 2005;75:83-95.
Malouf R., Grimley Evans J.The effect of vitamin B6 on cognition. Cochrane Database Syst Rev.2003;(4): CD004393.
35.
Malouf M., Grimley EJ, Areosa SAFolic acid with or without vitamin B12 for cognition and dementia. Cochrane Database Syst Rev.2003;(4):CD004514.
36.
Kennedy BP, Bottiglieri T., Arning E., Ziegler MG, Hansen LA, Masliah E.Elevated S-adenosylhomocysteine in Alzheimer brain: influence on methyltransferases and cognitive function. J Neural Transm. 2004 ;111:547-567.
37.
Tchantchou F. , Graves M., Ashline D., et al. Increased transcription and activity of glutathione synthase in response to deficiencies in folate, vitamin E and apolipoprotein E. J Neurosci Res. 2004;75:508-515.
38.
Fuso A., Seminara L., Cavallaro RA, D'Anselmi F., Scarpa S.S-adenosylmethionine/homocysteine cycle alterations modify DNA methylation status with consequent deregulation of PS1 and BACE and beta-amyloid production . Mol Cell Neurosci.2005;28:195-204.
39.
Scarpa S., Fuso A., D'Anselmi F., Cavallaro RAPresenilin 1 gene silencing by S-adenosylmethionine: a treatment for Alzheimer disease?FEBS Lett. 2003;541:145-148.
40.
Bottiglieri T.S-Adenosyl-L-methionine (SAMe): from the bench to the bedside-molecular basis of a pleiotrophic molecule. Am J Clin Nutr.2002;76: 1151S-1157S.
41.
Di Rocco A. , Rogers JD, Brown R., Werner P., Bottiglieri T.S-adenosyl-methionine improves depression in patients with Parkinson's disease in an open-label clinical trial. Mov Disord. 2000;15:1225-1229.
42.
Mischoulon D., Fava M.Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence. Am J Clin Nutr.2002;76:1158S-1161S.
43.
Aureli T., Puccetti C., Di Cocco ME, et al. Entry of [(1,2-13C2) acetyl]-L-carnitine in liver tricarboxylic acid cycle and lipogenesis: a study by 13C NMR spectroscopy in conscious, freely moving rats. Eur J Biochem. 1999;263:287-293.
44.
Thaj LJ, Carta A., Clarke WR, et al. A 1-year multicenter placebo-controlled study of acetyl-L-carnitine in patients with Alzheimer's disease. Neurology. 1996;47: 705-711.
45.
Barnes CA, Markowska AL, Ingram DK, et al. Acetyl-1-carnitine. 2: Effects on learning and memory performance of aged rats in simple and complex mazes. Neurobiol Aging.1990;11:499-506.
46.
Chan A., Shea TBDietary and genetically-induced oxidative stress alter tau phosphorylation: influence of folate and apolipoprotein E deficiency. J Alzheimers Dis. 2006;9:399-405.
47.
Chan A., Shea TBFolate deprivation increases presenilin expression, gamma-secretase activity and Abeta levels in murine brain: potentiation by Apoe deficiency and alleviation by dietary S-adenosyl methionine. J Neurochem. 2007;102:753-760.
48.
Chan A., Tchantchou F., Graves V., Rozen R., Shea TBDietary and genetic compromise in folate availability reduces acetylcholine and cognitive performance: critical role of S-adenosylmethionine. J Health Nutr Aging. 2008;12:252-261.
49.
De La Cruz JP, Pavia J., Gonzalez-Correa JA, Ortiz P., Sanchez de la Cuesta F.Effects of chronic administration of S-adenosyl-L-methionine on brain oxidative stress in rats. Naunyn Schmiedebergs Arch Pharmacol. 2000;361:47-52.
50.
De La Cruz JP, Villalobos MA, Cuerda MA, Guerrero A., González-Correa JA, Sánchez D.e La Cuesta F.Effects of S-adenosyl-L-methionine on lipid peroxidation and glutathione levels in rat brain slices exposed to reoxygenation after oxygen-glucose deprivation. Neurosci Lett.2002;318:103-107.
51.
Dhitavat S. , Ortiz D., Rogers E., Rivera E., Shea TBFolate, vitamin E and acetyl-L-carnitine provide synergistic protection against oxidative stress resulting from exposure of human neuroblastoma cells to amyloid beta. Brain Res. 2005;9:114-117.
52.
Fu AL, Dong ZH, Sun MJProtective effect of N-acetyl-L-cysteine on amyloid beta-peptide-induced learning and memory deficits in mice. Brain Res. 2006 ;1109: 201-206.
53.
Markowska AL , Olton DSDietary acetyl-L-carnitine improves spatial behaviour of old rats. Int J Clin Pharmacol Res. 1990;10:65-68.
54.
Shea TB, Chan A.S-adenosyl methionine: a natural therapeutic agent effective against multiple hallmarks and risk factors associated with Alzheimer's disease. J Alzheimers Dis. 2008;13:67-70.
55.
Shea TB, Ortiz D., Rogers E.Differential susceptibity of transgenic mice lacking one or both apolipoprotein alleles to folate and vitamin E deprivation. J Alzheimers. Dis.2004;6:269-273.
56.
Tchantchou F., Graves M., Rogers E., Ortiz D., Shea TBN-acetyl cysteine alleviates neurodegeneration and increased glutathione expression in normal and ApoEdeficient mice. J Alzheimers Dis. 2005;7:135-138.
57.
Tchantchou F., Graves M., Rogers E., Ortiz D., Shea TBDietary supplementation with 3-deaza adenosine, N-acetyl cysteine and S-adenosyl methionine provide neuroprotection against multiple consequences of vitamin deficiency and oxidative challenge: relevance to age-related neurodegeneration. Neuromol Med. 2005;6: 93-104.
58.
Villalobos MA, De La Cruz JP, Cuerda MA, Ortiz P., Smith-Agreda JM, Sanchez De La Cuesta F.Effect of S-adenosyl-L-methionine on rat brain oxidative stress damage in a combined model of permanent focal ischemia and global ischemia-reperfusion . Brain Res. 2000;883:31-40.
59.
Chan A., Shea TBImproved cognitive performance and decreased aggression in normal and ApoE4 mice following dietary supplementation with N-acetyl cysteine, acetyl-L-carnitine and S-adenosyl methionine. Neuromol Med. 2007 ;9:264-269.
60.
Shea TB, Rogers E.Folate quenches oxidative damage in brains of apolipoprotein E-deficient mice: augmentation by vitamin E. Brain Res Mol Brain Res. 2002;108:1-6.
61.
Mckhann G., Drachman D., Folstein M., Katzman R., Price D., Stadlan EMClinical diagnosis of Alzheimer's disease report of the NINCDS-ADRDA Work Group under the auspices of the Department of Health and Human Services Task Force on Alzheimer's disease. Neurology. 1984 ;34:939-944.
62.
Lucas JA, Ivnik RJ, Smith GE, et al. Normative data for the Mattis Dementia Rating Scale. J Clin Exp Neuropsychol. 1993;20:536-547.
63.
Monsch AU, Bondi MW, Salmon DP, et al. Clinical validity of the Mattis Dementia Rating Scale in detecting Dementia of the Alzheimer type. A double cross-validation and application to a community-dwelling sample. Arch Neurol.1995;52:899-904.
64.
Royall DR, Cordes JA, Polk M.CLOX: an executive clock drawing test. J Neurol Neurosurg Psychiatry. 1998;64: 588-594.
65.
Paskavitz JF , Gunstad JJ, Samuel JEClock drawing and frontal lobe behavioral effects of memantine in Alzheimer's disease: a rater-blinded study. Am J Alzheimers Dis Other Demen. 2006;21:454-459.
Galasko D., Bennett D., Sano M., et al. An inventory to assess activities of daily living for clinical trials in Alzheimer's disease. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord. 1997;11(suppl 2): S33-S39.
68.
Potkin SGThe ABC of Alzheimer's disease: ADL and improving day-to-day functioning of patients. Int Psycho-geriatr. 2002;14(suppl 1):7-26.
69.
Cohen J.Statistical PowerAnalysis for the Behavioral Sciences. 2nd ed. Hillsdale, NJ: Lawrence Erlbaum; 1988.
70.
Erkinjuntti T., Kurz A., Gauthier S., Bullock R., Lilienfeld S., Damaraju CVEfficacy of galantamine in probable vascular dementia and Alzheimer's disease combined with cerebrovascular disease: a randomised trial. Lancet. 2002;359:1283-1290.
71.
Feldman H., Gauthier S., Hecker J., Vellas B., Subbiah P., Whalen E.A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer's disease. Neurology. 2001;57:613-620.
72.
Aisen PS, Schafer KA, Grundman M., et al. Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA. 2003;289:2819-2826.
73.
Bouchard RW, Rossor M.Typical clinical features. Clinical Diagnosis and Management of Alzheimer's Disease. In: Gauthier S, ed. London: Martin Dunitz Ltd; 1996: 35-51.
74.
Conn D., Thorpe L.Assessment of behavioural and psychological symptoms associated with dementia . Can J Neurol Sci. 2007;34(suppl 1):S67-S71.
75.
Craig D., Mirakhur A., Hart DJ, McIlroy SP, Passmore APA cross-sectional study of neuropsychiatric symptoms in 435 patients with Alzheimer's disease. Am J Geriatr Psychiatry. 2005;13:460-468.
76.
Hinchcliffe AC, Hyman IL, Blizard B., Livingston G.Behavioural complications of dementia-can they be treated? Int J Geriatr Psychiatry. 1995;10:839-847.
77.
Matsumoto N. , Ikeda M., Fukuhara R., et al. Caregiver burden associated with behavioral and psychological symptoms of dementia in elderly people in the local community . Dement Geriatr Cogn Disord. 2007;23: 219-224.
78.
de Vugt ME, Riedijk SR, Aalten P., Tibben A., van Swieten JC, Verhey FRImpact of behavioural problems on spousal caregivers: a comparison between Alzheimer's disease and frontotemporal dementia. Dement Geriatr Cogn Disord. 2006;22:35-41.
79.
Sachs GSA review of agitation in mental illness: burden of illness and underlying pathology. J Clin Psychiatry. 2006;67(suppl 10):5-12.
80.
Shin IS, Carter M., Masterman D., Fairbanks L., Cummings JLNeuropsychiatric symptoms and quality of life in Alzheimer disease. Am J Geriatr Psychiatry. 2005;13:469-474.
81.
Paton J., Johnston K., Katona C., Livingston G.What causes problems in Alzheimer's disease: attributions by caregivers. A qualitative study. Int J Geriatr Psychiatry.2004;19:527-532.
82.
Riello R., Geroldi C., Zanetti O., Frisoni GBCaregiver's distress is associated with delusions in Alzheimer's patients . Behav Med. 2002;28:92-98.
83.
Buhr GT, White HKDifficult behaviors in long-term care patients with dementia. J Am Med Dir Assoc. 2007;8(3 suppl 2):e101-e113.
84.
Sourial R., McCusker J., Cole M., Abrahamowicz M.Agitation in demented patients in an acute care hospital: prevalence, disruptiveness, and staff burden. Int Psycho-geriatr. 2001 ;13:183-197.
85.
Aalten P., Verhey FR, Boziki M., et al. Consistency of neuropsychiatric syndromes across dementias: results from the European Alzheimer Disease Consortium. Part II. Dement Geriatr Cogn Disord.2008;25:1-8.
86.
de Vugt ME, Riedijk SR, Aalten P., Tibben A., van Swieten JC, Verhey FRImpact of behavioural problems on spousal caregivers: a comparison between Alzheimer's disease and frontotemporal dementia. Dement Geriatr Cogn Disord. 2006;22:35-41.
87.
Cummings JL , Schneider L., Tariot PN, Kershaw PR, Yuan W.Reduction of behavioral disturbances and caregiver distress by galantamine in patients with Alzheimer's disease. Am J Psychiatry. 2004;161:532-538.
88.
De Jesus Moreno Moreno M.Cognitive improvement in mild to moderate Alzheimer's dementia after treatment with the acetylcholine precursor choline alfoscerate: a multicenter, double-blind, randomized, placebo-controlled trial . Clin Ther. 2003;25:178-193.
89.
Sun Y., Lu CJ, Chien KL, Chen ST, Chen RCEfficacy of multivitamin supplementation containing vitamins B6 and B12 and folic acid as adjunctive treatment with a cholinesterase inhibitor in Alzheimer's disease: a 26-week, randomized, double-blind, placebo-controlled study in Taiwanese patients. Clin Ther. 2007;29: 2204-2214.
90.
Connelly PJ, Prentice NP, Cousland G., Bonham J.A randomised double-blind placebo-controlled trial of folic acid supplementation of cholinesterase inhibitors in Alzheimer's disease. Int J Geriatr Psychiatry. 2008;23:155-160.
91.
Hager K., Kenklies M., McAfoose J., Engel J., Munch G.Alpha-lipoic acid as a new treatment option for Alzheimer's disease-a 48 months follow-up analysis. J Neural Transm Suppl. 2007;(72):189-193.
92.
Chan A., Paskvitz J., Shea TBA novel vitamin/nutriceutical formulation that delays cognitive decline and improves mood in early-stage Alzheimer's disease. Alzheimer's Dement.2007;3:S98.
