Antioxidants for Dementia: The Case for Vitamin E

February 1999; Volume 2: 17-19

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."

Background

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.

Pharmacokinetics

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 that of nine other common antioxidants were not.9

In the only randomized controlled trial to date, Sano et al 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 endpoints 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 endpoints 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 the authors adjusted their data for this difference in baseline cognitive function, the difference in time to reach one of the endpoints 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 anti-platelet action in vitro, so no drug interactions would be expected on this basis.13

Formulation

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.

Cost

Retail costs of common therapies for Alzheimer’s dementia are listed in Table 1.

Table 1
Retail cost of common therapies for Alzheimer’s dementia
Therapeutic Agent
Usual Dosage
Cost (30-day supply)*
Donepezil
5 mg qd
$135
Ginkgo biloba
40 mg tid
$14
Tacrine
10 mg qid
$172
Vitamin E
1000 IU bid
$16

*Average cost based on the author’s phone survey of nationalpharmacy chains, December 1998.
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Dosage

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.

Conclusion

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

Recommendation

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.

References

1. Stephens NG, et al. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study. Lancet 1996;347:781-786.

2. Lohr JB, Caligiuri MP. A double-blind placebo-controlled study of vitamin E treatment of tardive dyskinesia. 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. Efficacy of alpha-tocopherol in the treatment of the premenstrual syndrome. J Reprod Med 1987;32:400-404.

5. The Parkinson Study Group. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 1993;328:176-183.

6. Teikari JM, et al. Long-term supplementation with alpha-tocopherol and beta-carotene and age-related cataract. Acta Ophthalmol Scand 1997;75:634-640.

7. Vatassery GT. Vitamin E and other endogenous antioxidants in the central nervous system. Geriatrics 1998;53(suppl 1):S25-S27.

8. Pappert EJ, et al. Alpha-tocopherol in the ventricular cerebrospinal fluid of Parkinson’s disease patients: Dose-response study and correlations with plasma levels. Neurology 1996;47:1037-1042.

9. Schmidt R, et al. Plasma antioxidants and cognitive performance in middle-aged and older adults: Results of the Austrian Stroke Prevention Study. J Am Geriatr Soc 1998;46:1407-1410.

10. Sano M, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study. N Engl J Med 1997;336:1216-1222.

11. Meydani SN, et al. Assessment of the safety of high-dose, short-term supplementation with vitamin E in healthy older adults. Am J Clin Nutr 1994;60:704-709.

12. Kim JM, White RH. Effect of vitamin E on the anticoagulant response to warfarin. Am J Cardiol 1996;77:545-546.

13. Stampfer MJ, et al. Vitamin E supplementation effect on human platelet function, arachidonic acid metabolism, and plasma prostacyclin levels. Am J Clin Nutr 1988; 47:700-706.

14. Herbert V. The value of antioxidant supplements vs their natural counterparts. J Am Diet Assoc 1997;97:375-376.

15. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994;330:1029-1035.