Clinical Briefs: Antioxidants and Alzheimer’s Disease: The Rotterdam Study

With Comments from John La Puma, MD, FACP

Engelhart MJ et al. Dietary intake of antioxidants and risk of Alzheimer disease. JAMA 2002;287:3223-3229.

Laboratory findings have suggested that oxidative stress may contribute to the pathogenesis of Alzheimer’s disease (AD). The risk of AD might be reduced by intake of antioxidants that counteract the detrimental effects of oxidative stress.

To determine whether dietary intake of antioxidants is related to risk of AD, The Rotterdam Study, a population-based, prospective cohort study was conducted in the Netherlands. The subjects totaled 5,395 participants who, at baseline (1990-1993), were age 55 or older, free of dementia, and noninstitutionalized and had reliable dietary assessment. Participants were reexamined in 1993-1994 and 1997-1999 and were continuously monitored for incident dementia.

The primary outcome was incidence of AD, based on Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R) criteria and National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer Disease and Related Disorders Association (NINCDS-ADRDA) criteria, associated with dietary intake of beta-carotene, flavonoids, vitamin C, and vitamin E.

After a mean follow-up of six years, 197 participants developed dementia, of whom 146 had AD. When adjustments were made for age, sex, baseline Mini-Mental State Examination score, alcohol intake, education, smoking habits, pack-years of smoking, body mass index, total energy intake, presence of carotid plaques, and use of antioxidative supplements, high intake of vitamin C and vitamin E was associated with lower risk of AD (rate ratio [RR] per 1-SD increase in intake were 0.82, 95% confidence interval [CI] 0.68-0.99 and 0.82, 95% CI 0.66-1.00, respectively). Among current smokers, this relationship was most pronounced (RR 0.65, 95% CI 0.37-1.14 and 0.58, 95% CI 0.30-1.12, respectively) and also was present for intake of beta-carotene (RR 0.49, 95% CI 0.27-0.92) and flavonoids (RR 0.54, 95% CI 0.31-0.96). The associations did not vary by education or apolipoprotein E genotype. High dietary intake of vitamin C and vitamin E may lower the risk of AD.


Oxidative processes appear to contribute to Alzheimer’s disease—the free radicals the body produces exacerbate the disruption of lipid membranes and damage to DNA. The brain is especially susceptible to oxidative stress—so much cholesterol and oxygen, so few antioxidants.

The Rotterdam study, based in Erasmus University in Rotterdam, is a well-known, population-based, prospective cohort study of the frequency and determinants of neurological, cardiovascular, locomotor, and ophthalmologic diseases in elderly persons. Nearly 80% of the inhabitants of Rotterdam participated.

Like the Rush study, the Rotterdam study examined protein E (from APOE*e4) and antioxidant intake. Also like the Rush study, it found that food was the key—at baseline, flavonoid intake, but not beta-carotene, vitamin C, or vitamin E intake, was significantly associated with higher Mini-Mental Status Examination scores. A high intake of foods rich in vitamins C and E (but not vitamin supplements) was associated with reduced risk of AD. Flavonoids, beta-carotene, and supplements were not related to the risk of AD at follow-up.

Smokers, as expected, had less risk of AD with higher intake of beta-carotene and flavonoids. What was the difference reported for those with at least one APOE*e4 allele? More anti-oxidants (except flavonoids) were better and associated with a lower risk of AD.

The Rotterdam study differs from the Rush study—in subject age, number, demographics, tobacco use, follow-up, and of course genetics. Only one dietary recall session was used—again, an unfortunate way to assess intake accurately and comprehensively. But this study too is best-of-its-kind-so-far data.

How antioxidants—of any type—act to prevent AD is uncertain. Antioxidants may decrease the level of neural oxidative stress, and in the same way diminish neural DNA damage and cell death. Oxidative stress in brains of Alzheimer patients is indicated by elevated cerebral levels of endogenous antioxidants that scavenge free radicals. Lab and animal studies show that exogenous antioxidants reduce the toxicity of beta-amyloid protein and the immune cells which combine to make amyloid plaques in the brains of patients with AD.


Foods that are rich in flavonoids include cranberries, green and black tea, strawberries, apples, grapes and red wine, onions, tomatoes, and citrus fruit. Foods rich in vitamin C include kiwis, red and green bell peppers, papayas, strawberries, oranges, and mangos. Foods that are rich in vitamin A include pumpkin, sweet potato, cantaloupe, carrots, spinach, and mango—and fortified breakfast cereal, which is an excellent source. Smokers who want to try to avoid AD should get their fill.