Antioxidants for Dementia: The Case for Vitamin E


By Barak Gaster, MD

Alzheimer’s dementia (AD) is one of the most tragic diseases of advancing age. In the course of my busy, geriatrics-filled practice, I make new diagnoses of AD several times a month. Treatment is never an easy subject, but in the past year it has become more difficult as families arrive carrying magazine advertisements and Internet reports of breakthroughs in the treatment of AD. The increasing popularity of these direct-to-consumer information campaigns puts even more pressure on primary care physicians to be familiar with the latest literature on purported "breakthroughs."


During the past 20 years, vitamin E has been evaluated as a treatment for a wide range of conditions. The studies have shown vitamin E to be everything from probably helpful (secondary prevention of coronary artery disease) to possibly helpful (treating tardive dyskinesia, lower extremity claudication, premenstrual syndrome), to probably not helpful (treating Parkinson’s disease and preventing cataracts).1-6 Only recently has it been tested in AD.

Despite hopes that vitamin E may be the long-awaited breakthrough in the treatment of AD, current evidence suggests that it is likely to have only minimal benefit in delaying disease progression. Its low cost and excellent safety profile, however, make it a reasonable option for those who wish to take it.

Mechanism of Action

Vitamin E is one of the most powerful antioxidants. It is essential for protecting cell lipid membranes from attack by free radicals, acting as a scavenger of these highly reactive molecules. Although much about the pathophysiology of AD remains unknown, there is mounting evidence that oxidative stress plays an important role in the neuronal death characteristic of AD.7 Thus, it is postulated that vitamin E may have a neuroprotective effect.


Vitamin E is a fat-soluble essential vitamin. As a result, the bioavailability of vitamin E is dependent on the absorption of fat. Vitamin E is metabolized primarily in the liver and excreted in the bile. Its half-life is long, varying from 50 to 250 hours depending on its route of administration. Plasma levels remain elevated for days following a large dose. It does not appear to cross the blood-brain barrier easily.8

Efficacy Data

Vitamin E intake and serum levels have consistently been associated with a lower incidence and a slower rate of progression of AD in epidemiological studies. In one well-designed study from Austria, low serum levels of vitamin E (alpha-tocopherol) were significantly associated with a decline in cognitive function (P = 0.019), while those of nine other common antioxidants were not.9

In the only randomized controlled trial to date, Sano and colleagues randomized 169 patients with AD of moderate severity to either two years of dl-alpha-tocopherol (synthetic vitamin E) 1000 IU bid or to placebo.10 The four primary end points of the study were death, institutionalization, loss of the ability to perform basic activities of daily living (ADLs), or the development of severe dementia by a standardized clinical dementia rating.

At the end of two years, the only outcome to be statistically different between the two groups was rate of institutionalization (26% in the vitamin E group vs 39% in the placebo group; P = 0.003). There were no significant differences in the rate of death, onset of severe dementia, or loss of ADLs.

The vitamin E group took 71 days longer, on average, to reach one of these primary end points compared to the placebo group (597 days vs 526 days), although this difference did not reach statistical significance (P = 0.077). The deck may have been stacked against vitamin E, however, as the vitamin E group started out with a significantly lower baseline score on the Mini-Mental State Examination despite careful randomization.

When Sano et al adjusted their data for this difference in baseline cognitive function, the difference in time to reach one of the end points was statistically significant (670 days vs 440 days; P = 0.001). Although this type of adjustment adds uncertainty to the study’s conclusion, the fact that the unadjusted result missed statistical significance by only a small margin adds some credence to a cautiously positive interpretation of the finding.

Cognitive function as measured by the Alzheimer’s Dementia Assessment Scale was a secondary outcome in this study. Oddly enough, patients given vitamin E did not fare better on cognitive testing than those given placebo, in contrast to studies of the other three publicized treatments for dementia. In fact, there was a non-significant worsening in cognitive function in the vitamin E group as compared to the placebo group, possibly attributable to that group’s poorer function at baseline.

The lack of a significant effect on cognitive function, global dementia severity, and ability to perform ADLs in this study makes the finding of the slower rate of institutionalization somewhat difficult to explain. Some have speculated that this finding may be attributable to a cardioprotective effect of vitamin E, although no significant difference was found in the incidence of major cardiovascular events between the two groups.

This trial also examined the effect of combining vitamin E with selegiline, which is a selective MAO inhibitor. Combination therapy in this case had no advantage over vitamin E monotherapy. Vitamin E has never been tested as therapy for dementia other than the Alzheimer’s type or directly compared to a cholinesterase inhibitor such as donepezil.

Adverse Effects

Vitamin E appears to be very safe. In contrast to other fat-soluble vitamins such as vitamin A, which can cause serious hepatotoxicity in high doses, no serious adverse effects have been reliably linked to vitamin E. Rarely, patients may experience mild nausea, diarrhea, or fatigue.11

In the randomized trial by Sano et al,10 the only adverse events that occurred more often in patients taking vitamin E were falls (14% vs 5%) and syncope (7% vs 3%). The mechanism for such events is unclear and may have been related to the difference in rates of institutionalization between the two groups.

Drug Interactions

Vitamin E interacts with components of the clotting cascade and has been shown to potentiate bleeding in patients taking oral anticoagulants. As a result, vitamin E supplementation should be avoided in patients taking oral anticoagulants.12 Vitamin E does not appear to have antiplatelet action in vitro, so no drug interactions would be expected on this basis.13


Eight naturally occurring compounds have been shown to have vitamin E activity, including tocopherols (alpha, beta, gamma, and delta) and tocotrienols. Because these substances are ubiquitous in many foods, dietary deficiency is almost unheard of except in rare inherited conditions. The highest concentrations of vitamin E are found in fruits, vegetables, whole grains (especially wheat germ), seed oils, and vegetable oils.

Of the eight naturally occurring compounds, d-alpha-tocopherol has the most potent antioxidant activity. Synthetic forms of vitamin E are primarily a racemic mixture of d-alpha-tocopherol, designated as dl-alpha-tocopherol. It is this formulation that was used in the clinical trial by Sano et al.10 Some have questioned whether better results might be attainable using a natural form of vitamin E, containing a full mix of the eight compounds.14 No data are available to support this hypothesis. Depending on the formulation of vitamin E, there are between 0.6 and 1.4 mg of vitamin E per IU.


In the trial by Sano et al, the vitamin E group received 1000 IU bid.10 This is significantly higher than the doses used in the trial of high-dose vitamin E for coronary disease in which patients received 800 IU or 400 IU daily.1 Whether a higher dose is needed to treat CNS disease because vitamin E crosses the blood-brain barrier poorly is unknown.8 Vitamin E is probably better absorbed if taken with food that contains some amount of fat. The RDI for vitamin E is 15 IU for men and 12 IU for women daily.


Given the mixed results of a single randomized trial, it is premature to recommend vitamin E for the treatment of AD. There is, however, consistent indirect evidence that it may be mildly effective, especially in slowing the rate of institutionalization, and there is no evidence that it is harmful. This is in contrast to the antioxidant provitamin beta-carotene, which has been shown to increase the rate of certain cancers in smokers.15


Given vitamin E’s low cost and safety profile, it is a reasonable treatment option for those who wish to take it to attempt to delay progression of disease. (Dr. Gaster is an Acting Assistant Professor of Medicine at the University of Washington in Seattle.)


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    2. Lohr JB, Caligiuri MP. J Clin Psychiatry 1996;57: 167-173.

    3. Kleijnen J, et al. Vitamin E for the treatment of intermittent claudication. Available in The Cochrane Library [disk and CD-ROM]. The Cochrane Collaboration; Issue 4. Oxford: Update Software; 1998.

    4. London RS, et al. J Reprod Med 1987;32:400-404.

    5. The Parkinson Study Group. N Engl J Med 1993; 328:176-183.

    6. Teikari JM, et al. Acta Ophthalmol Scand 1997; 75:634-640.

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    8. Pappert EJ, et al. Neurology 1996;47:1037-1042.

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    11. Meydani SN, et al. Am J Clin Nutr 1994;60:704-709.

    12. Kim JM, White RH. Am J Cardiol 1996;77:545-546.

    13. Stampfer MJ, et al. Am J Clin Nutr 1988;47:700-706.

    14. Herbert V. J Am Diet Assoc 1997;97:375-376.

    15. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 1994;330:1029-1035.

Which of the following drugs should not be taken in combination with vitamin E?

    a. Warfarin
    b. Phenytoin
    c. Cimetidine
    d. Erythromycin