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Editorials represent the opinions of the authors and JAMA and not those of the American Medical Association.
Vitamin E, Memantine, and Alzheimer DiseaseDenis A. Evans, MD; Martha Clare Morris, ScD; Kumar Bharat Rajan, PhD The report by Dysken et al1 in this issue of JAMA raises inter-
to support its use because the comparison of the group esting issues about drug therapy for Alzheimer disease (AD) assigned to memantine with the group assigned to placebo and emphasizes the importance of closely following this rap- suggested no differences in either the primary ADCS-ADL outcome or in the secondary cognitive outcomes. The nega- tive interaction between alpha tocopherol treatment, which was significantly beneficial alone, and memantine treatment in predicting the primary trial outcome is of concern and nation (MMSE) scores of 12 to 26 who were receiving acetyl- deserves further investigation. No formal comparison of the cholinesterase inhibitors were assigned to 1 of 4 treatment primary outcome was reported between the group assigned groups: receiving synthetic vitamin E (alpha tocopherol, 2000 to alpha tocopherol alone and the group assigned to the com- IU/d); memantine, 20 mg/d; both agents; or placebo.
bination of alpha tocopherol and memantine; the statement As in almost all trials of therapy in AD, death was fre- in the “Discussion” that “… the combination of alpha tocoph- quent (128 of 613 study participants), medication adherence erol and memantine had less effect than either alpha tocoph- was moderate, and loss to follow-up was greater than opti- erol alone or memantine alone” is difficult to support in the mal, reflecting the practical challenges in conducting random- absence of such a comparison with significance testing.
ized trials among people with this disease of older age.
For vitamin E, the results of this trial are more encourag- The primary trial outcome was score on the Alzheimer’s ing because of the significant difference from the placebo group Disease Cooperative Study/Activities of Daily Living (ADCS- observed for the primary outcome and the absence of severe ADL) Inventory; secondary outcomes included scores on the adverse effects. A previous trial4 among individuals with mod- MMSE and the Alzheimer’s Disease Assessment Scale– erate to severe AD found delayed disease progression with 2000 Cognitive subscale (ADAS-cog). Compared with individuals as- IU/d of alpha tocopherol both alone and in combination with signed to placebo, those assigned to vitamin E alone experi- selegiline. The results of a trial5 of vitamin E therapy among enced 3.15 units less decline on the ADCS-ADL Inventory, a people with mild cognitive impairment were null; however, so fairly modest 19% reduction that was statistically significant were the results of trials6,7 examining the effects of vitamin E (P = .03) and may well be meaningful as the authors suggest.
on cognitive function among people with normal cognition.
The groups assigned to memantine or the combination did not These null results emphasize that the findings of these 2 trials differ significantly from those assigned to placebo on the pri- should not be extrapolated to use of vitamin E at different dos- mary outcome, and none of the groups assigned to active in- ages, among people with different AD severity levels, or in com- terventions differed from the placebo group on the cognitive bination with different agents than the ones examined in either of these 2 trials1,4 reporting beneficial results. Different situ- The results seem especially pertinent to the use of com- ations will require future direct empirical testing. Caution that binations of agents to treat AD. Combination therapy for AD the adverse effect profile of vitamin E may be greater than seen has substantial appeal because agents currently available for in these 2 trials is also warranted in view of the findings of a treating AD offer on average only modest therapeutic ben- meta-analysis8 of 19 randomized trials that vitamin E in doses efits, and some have bothersome adverse effects. Achieving greater than 400 IU/d was associated with increased all- greater benefit without more adverse effects by using medi- cause mortality. Other possibly productive directions for fu- cations in combinations, especially agents with different ture AD trials to explore include other dosage levels of alpha presumed mechanisms of action, is a reasonable goal. In this tocopherol and use of other tocopherols or combinations of to- trial, differences among the randomly assigned groups were assessed among study participants receiving nonrandomly Major AD treatment trials like this one use functional abil- assigned acetylcholinesterase inhibitor therapy at entry ity, especially as assessed by the ADCS-ADL Inventory, as an (donepezil, 65%; galantamine, 32%; or rivastigmine, 3%).
outcome with increasing frequency. The use of functional abil- For memantine therapy in this context, the trial results ity measures for this purpose overtly or tacitly uses impair- are not encouraging. Memantine is approved by the US Food ment in functional ability as though it were solely a conse- and Drug Administration for use in moderate to severe AD.
quence of AD progression. Such impairment, however, is not Use in individuals with milder AD may be widespread2 specific to AD but occurs frequently among older people as a despite little evidence suggesting the agent is beneficial at consequence of many conditions.9 Some aspects of this trial this level of disease severity.3 This trial by Dysken et al of highlight the nonspecificity of the link between AD and func- treating mild to moderate AD does not provide any new data tional decline. First, the results of the secondary cognitive out- JAMA January 1, 2014 Volume 311, Number 1
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comes, MMSE and ADAS-cog, were null for all treatment also supported by parallel improvements in the relevant sec- groups; this can be viewed both positively (functional ability ondary outcomes and by a vitamin E mechanism of action more may be a more sensitive measure of AD progression and non- significant trends in the same direction were seen for these sec- Many features of the trial by Dysken et al reflect the best ondary cognitive outcomes) or with concern (the lack of speci- in trials of AD therapy, especially its size, duration, and sepa- ficity of functional ability and the perception that cognitive ration from commercial motivation. However, as with almost decline is the essence of AD). Second, the significant differ- all previous AD trials, the therapeutic effect seen was modest ence in the primary outcome, ADCS-ADL score, was not con- and more relevant to AD symptoms and consequences than firmed by significant differences in the secondary outcomes to reversal of the disease process. The importance of treating that might reflect functional ability, such as scores on the Care- patients with AD is clear, but finding the best balance be- giver Activity Scale (CAS) and the Dependence Scale, al- tween treatment and prevention efforts is challenging for this though there was nonsignificant change in the same direc- grim disease affecting millions of people from all developed tion for CAS score. Third, the mechanism of action of vitamin countries.10 Few would doubt the wisdom inherent in Rose’s E in AD is uncertain. Much attention is focused on its antioxi- humanitarian justification11 for prevention: “It is better to be dant properties, but this mechanism is not specific for AD. Al- healthy than ill or dead.” Considering the difficulties inherent though these considerations do not lessen the significance of in trying to treat rather than prevent very high-prevalence dis- the difference found between the group randomized to vita- eases and the limitations thus far of the therapeutic efforts for min E and the group randomized to placebo for the primary people with AD, shifting to more emphasis on prevention seems outcome, this difference would have been more convincing if Alzheimer disease: the TEAM-AD VA Cooperative supplementation and cognitive function in women.
Author Affiliations: Department of Internal
randomized trial. JAMA. doi:10.1001 Arch Intern Med. 2006;166(22):2462-2468.
Medicine, Rush Institute for Healthy Aging, Rush 7. Kang JH, Cook NR, Manson JE, Buring JE, Albert
University Medical Center, Chicago, Illinois (Evans, 2. Schneider LS, Insel PS, Weiner MW; Alzheimer’s
CM, Grodstein F. Vitamin E, vitamin C, beta Rajan); Department of Internal Medicine, Section of Disease Neuroimaging Initiative. Treatment with carotene, and cognitive function among women Nutrition and Nutritional Epidemiology, Rush cholinesterase inhibitors and memantine of with or at risk of cardiovascular disease: the University Medical Center, Chicago, Illinois (Morris).
patients in the Alzheimer’s Disease Neuroimaging Women’s Antioxidant and Cardiovascular Study.
Corresponding Author: Denis A. Evans, MD, Rush
Initiative. Arch Neurol. 2011;68(1):58-66.
Circulation. 2009;119(21):2772-2780.
Institute for Healthy Aging, Rush University Medical 3. Schneider LS, Dagerman KS, Higgins JPT,
8. Miller ER III, Pastor-Barriuso R, Dalal D,
Center, 1645 W Jackson Blvd, Ste 675, Chicago, IL McShane R. Lack of evidence for the efficacy of Riemersma RA, Appel LJ, Guallar E. Meta-analysis: memantine in mild Alzheimer disease. Arch Neurol.
high-dosage vitamin E supplementation may Conflict of Interest Disclosures: All authors have
increase all-cause mortality. Ann Intern Med.
completed and submitted the ICMJE Form for 4. Sano M, Ernesto C, Thomas RG, et al. A
Disclosure of Potential Conflicts of Interest. Dr controlled trial of selegiline, alpha-tocopherol, or 9. Cohen RA, Van Nostrand JF. Trends in the health
Evans reported having received grants from the both as treatment for Alzheimer’s disease: the of older Americans: United States: National Center National Institutes of Health. Dr Morris reported Alzheimer’s Disease Cooperative Study. N Engl J for Health Statistics. Vital Health Stat 3. 1994;(30).
having received grants from the National Institutes 10. Ferri CP, Prince M, Brayne C, et al; Alzheimer’s
of Health and consultant fees from Nutrispective 5. Petersen RC, Thomas RG, Grundman M, et al;
Disease International. Global prevalence of and Abbott Nutrition. No other disclosures were Alzheimer’s Disease Cooperative Study Group.
dementia: a Delphi consensus study. Lancet.
Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med.
11. Rose G. The Strategy of Preventive Medicine.
Oxford, UK: Oxford University Press; 1992.
1. Dysken MW, Sano M, Asthana S, et al. Effect of
6. Kang JH, Cook N, Manson J, Buring JE,
vitamin E and memantine on functional decline in Grodstein F. A randomized trial of vitamin E JAMA January 1, 2014 Volume 311, Number 1
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