Antioxidants and Alzheimer’s Disease: The Rush Study

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.

Oxidative processes have been suggested as elements in the development of Alzheimer’s disease (AD), but whether dietary intake of vitamin E and other antioxidant nutrients prevents its development is unknown.

To examine whether intake of antioxidant nutrients, vitamin E, vitamin C, and beta-carotene, is associated with incident AD, a prospective study was conducted from 1993 to 2000, of individuals selected in a stratified random sample of community-dwelling residents in Chicago. The 815 residents ages 65 years and older were free of AD at baseline and were followed for a mean of 3.9 years. They completed food frequency questionnaires an average of 1.7 years after baseline.

The primary outcome studied included incident AD diagnosed in clinical evaluations with standardized criteria.

Increasing vitamin E intake from foods was associated with decreased risk of developing AD after adjustment for age, education, sex, race, APOE*e4, and length of follow-up. Relative risks (95% confidence intervals [CIs) from lowest to highest quintiles of intake were 1.00, 0.71 (0.24-2.07), 0.62 (0.26-1.45), 0.71 (0.27-1.88), and 0.30 (0.10-0.92) (P for trend = 0.05). The protective association of vitamin E was observed only among persons who were APOE 4 negative. Adjustment for other dietary factors reduced the protective association.

After adjustment for baseline memory score, the risk was 0.36 (95% CI 0.11-1.17). Intake of vitamin C, beta-carotene, and vitamin E from supplements was not significantly associated with risk of AD. This study suggests that vitamin E from food, but not other antioxidants, may be associated with a reduced risk of AD. Unexpectedly, this association was observed only among individuals without the APOE*e4 allele.


This study, by Rush University investigators, found that a vitamin E rich diet, but not vitamin E supplements, reduced the risk of AD in older adults with the apolipoprotein E*e4 (APOE*e4) allele. A previous randomized controlled trial found that very high doses of vitamin E (2,000 IU daily) did not affect the mental status examination results of patients with advanced AD, but did delay ADL loss and death.

Apolipoprotein E is encoded by the APOE*e4 gene on chromosome 19, and is one of the major lipid transport proteins in the brain. Individuals have an APOE genotype, with the presence or absence of the APOE*e4 allele. Some 34-65% of individuals with AD carry the APOE*e4 allele, but it is present in only 24-31% of the general population: just 28% in the Rotterdam study, below. With a greater number of APOE*e4 alleles, a patient’s risk of AD increases and the age of AD onset decreases. Having an allele roughly triples the risk of the disease, but it is not 100%: Most people with the gene don’t get AD.

This may be the clue to why family history seems to be important in AD: the presence of the genotype APOE*e4 and its alleles, and perhaps the protein it encodes. Prospective studies of food’s affects on people who carry those alleles are unlikely to be conducted, but not a far-fetched concept. The new science of nutrigenomics can, it promises, target dietary advice based on your genome. It suggests that what you should eat depends on your own DNA, and not the latest and most general rule.

For example, vitamin E protected only those who were APOE*e4 negative. But this finding contradicts in part what’s known about APOE*e4 and heart disease: Those with APOE*e4 alleles who are therefore at risk for heart disease can leverage their genes with a heart-healthy diet more effectively than can those people other genotypes. The same gene may code for a protein that acts differently in different diseases.

The investigators found that subjects with greater intake of vitamin E from food tended to be men and to have a higher intake of fat and beta-carotene and lower intake of vitamin C. Subjects with high food intake of vitamin C tended to be women and to have a lower intake of vitamin E and total fat. The study did not include flavonoid analysis, and subjects completed the nutrition questionnaire just two years before their AD diagnosis. So, the inability to record all foods may have been due, in some cases, to undetected early onset.

Taking food as medicine, for many Americans, is not as appealing as taking pills for what ails them. But an emerging literature suggests that there’s more to food than flavor, texture, color—and reward, companionship, and comfort. There’s medicine.


Good food sources of vitamin E include whole grains, nuts, milk, and egg yolks. As a fat-soluble vitamin, it is better absorbed in the presence of a little (dietary) fat. Recommend that patients eat these foods, though additional modest doses of vitamin E from supplements will probably do no harm. Advanced AD patients should still receive 2,000 IU daily of supplemental vitamin E.