Do Dietary Antioxidants Prevent Alzheimer’s Disease?

Abstract & Commentary

Sources: Engelhart MJ, et al. Dietary intake of antioxidants and risk of Alzheimer disease. JAMA. 2002;287:3223-3229; Morris MC, et al. Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study. JAMA. 2002;287:3230-3237; Morris MC, et al. Vitamin E and cognitive decline in older persons. Arch Neurol. 2002;59:1125-1132.

There is a large body of evidence that implicates oxidative damage as playing a role in the pathogenesis of Alzheimer’s disease (AD) and other neurodegenerative disorders. As yet, however, most of this evidence is correlative, and a strong case for a cause and effect relationship has not been established. Three recent studies have provided epidemiologic data that increased intake of antioxidants may be associated with a reduced risk of developing AD. The evidence has been most convincing for increased intake of vitamin E from dietary sources. The first study was that of Morris and colleagues, which studied the dietary intake of antioxidant nutrients in the Chicago Health and Aging project. Morris et al examined patients prospectively from 1993 to 2000. There were 815 residents 65 years and older who were free of AD at baseline and who were followed up for a mean of 3.9 years. They completed food frequency questionnaires at an average of 1.7 years after baseline examination. Morris et al made adjustments for numerous risk factors for AD including age, education, sex, race, ApoE4, and length of follow-up. The patients in the highest quintile of vitamin E intake from food were 70% less likely to develop AD than those in the lowest quintile of intake. This was a significant trend. The protective effect of vitamin E was observed only among patients who were ApoE4-negative. There appeared to be no association with dietary intake of vitamin C, beta-carotene, or intake from dietary supplements.

The second prospective study was that of Engelhart and colleagues. This is the Rotterdam Study, which is a population-based prospective cohort study conducted in The Netherlands. Engelhart et al examined a total of 5395 participants who at baseline were approximately 55 years of age. At that time, they were free of dementia, noninstitutionalized, and had reliable dietary assessment. They were subsequently reassessed at 2 further time points approximately 3 and 6 years after the initial evaluation. After a mean follow-up of 6 years, 197 participants developed dementia, of whom 146 were diagnosed as having AD. After an adjustment of multiple other risk factors, Engelhart et al found that vitamin E and C intake reduced the risk of AD to 0.82. The effect appeared to be largely confined to smokers in which the reduced incidence was much more profound being 0.58, and in this subpopulation, there was also a significant effect of beta-carotene being 0.49 relative risk and flavonoids being 0.54 relative risk.

The third study was again conducted in the Chicago cohort mentioned above. In this study, 2889 community residents age 65 and older were questioned 18 months after baseline. They were followed for an average of 3.2 years. They were examined with a number of cognitive tests, including the East Boston Memory test, the Mini-Mental State examination, and the Symbol Digit Modalities test, both at baseline and 3 years for all participants. Morris et al observed a 36% reduction in the rate of decline among patients in the highest quintile of vitamin E intake as compared to those from the lowest quintile. This was true of intake from both supplements or foods. They also observed an independent effect of vitamin E intake from foods.

Commentary

These studies are of considerable interest and provide "food for thought." There, however, are a number of caveats about these studies and their interpretation. In the initial 2 prospective studies, there was no identified association between incidence AD and the use of vitamin E and C supplements, although in the third, there did appear to be an association with vitamin E supplements. The fact that in the initial Chicago study there was no effect in ApoE-4 positive patients suggests that this genetic factor may override any potential protective effect of antioxidants. In that study, the dietary assessment occurred on average 1.7 years after the participant has been ascertained to be at risk, meaning that a number of the patients were studied essentially cross-sectionally, which has the potential for a number of biases that could have affected the results. The Rotterdam Study had a longer mean follow-up of 6 years. The patients were considerably younger by approximately 10 years than those in the Chicago Study. The effect in the Rotterdam Study, however, appeared to be largely confined to smokers. This is consistent with a number of other observations that smokers have a markedly increased risk of oxidative damage. This has been clearly demonstrated by measurement of a number of markers of oxidative damage in smokers. For instance, plasma markers of cholesterol hydroperoxides and urinary measurement of oxidative damage to DNA are significantly increased in smokers. In the Honolulu-Asia Aging Study, vitamin E and C supplements reduced the risk of vascular dementia, but not that of AD.1

Previous cross-sectional studies have suggested that increased plasma levels of vitamin E may also be associated with reduced risk of developing AD. Another epidemiological study suggests that increased dietary intake of flavonoids, another antioxidant, which is found in foods, is also associated with a reduced risk of developing AD.2 In contrast, increased plasma homocysteine levels, which may be associated with increased oxidative damage, are associated with an increased incidence of developing AD.3 When one assesses the evidence obtained thus far, it is both intriguing and worthy of further investigation. As yet, it cannot be said to be definitive. Prior studies have suggested that antioxidants might reduce the incidence of cancer and arthrosclerosis but the interventional studies thus far have not sustained these predictions. The present observation that dietary intake of vitamin E-rich foods may reduce the incidence of AD is similar to prior observations that foods rich in fruits and vegetables reduce the risk of cancer. Ultimately, the issue will have to be resolved with a well-designed primary prevention clinical trial. This is well justified considering the increasing age of the population and the increasing incidence of AD along with its consequent cost to society. 

M. Flint Beal, MD, Professor and Chairman, Department of Neurology, Cornell University Medical College, New York, NY, Editor, Neurology Alert.

References

1. Kraft E, Trenkwalder C, Auer DP. Neurology. 2000; 54:1265-1272.

2. Commenges D, et al. Eur J Epidemiol. 2000;16: 357-363.

3. Seshadri S, et al. N Engl J Med. 2002;346:476-483.