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Abstract & Commentary
Synopsis: The present results on the Cache County study provide some of the strongest evidence to date that intake of antioxidant vitamin supplements may be beneficial.
Sources: Zandi PP, et al. Arch Neurol. 2004;61:82-88; Kalmijn S, et al. Neurology. 2004;62:275-280; Longstreth WT, et al. Arch Neurol. 2004;61:67-72.
There is increasing evidence that a number of dietary manipulations may significantly affect the risk of dementia and Alzheimer’s disease (AD). Three studies in 2002 indicated that dietary intake of vitamins E and C lowered the risk of getting AD. However, there appeared to be no association with intake from dietary supplements. This is an important point since it is much easier to take dietary supplements than to increase one’s dietary intake of antioxidant vitamins. The previous prospective study in the Chicago Health and Aging Project suggested that patients in the highest quintile of vitamin E intake from food were 70% less likely to develop AD. The present study, which is known as the Cache County Study, has further examined the risk of AD prospectively and in a cross-sectional study of dementia. Zandi and associates examined patients 65 or older who were initially assessed from 1995 to 1997 for prevalent dementia in AD and again in 1998 to 2000 for incident illness. Supplement use was ascertained on the first contact. In the initial cross-sectional analysis, 4740 respondents were assessed, and there were 200 prevalent cases of AD. In the patients studied prospectively, there were 3227 survivors at risk, and 104 instant AD cases were identified at follow-up. A diagnosis of AD was established by an examination including a medical history, a chronologic history of cognitive symptoms, and a structured neurologic examination. There was also a battery of neuropsychological tests administered by psychometric technicians. The diagnosis of AD was established using standard criteria. The findings were that the analyses of prevalent and incident AD yielded similar results.
Use of vitamin E and C supplements in combination was associated with a reduced AD prevalence, with an adjusted odds ratio of 0.22. The incidence-adjusted hazard ratio was 0.36. A trend toward lowered AD risk was also evident in users of vitamin E and multivitamins containing vitamin C, but there was no protective effect for the use of vitamin E or C supplements alone or with multivitamins alone.
It has also been recently suggested that higher intake of fish and omega-3 fatty acids lowers the incidence of AD and dementia. Kalmijn and associates carried out a cross-sectional study on a population of 1613, ranging from 45 to 70 years old. The patients were administered an extensive cognitive battery, and compound scores were constructed for memory, psychomotor speed, cognitive flexibility, and overall cognition. Kalmijn et al administered a food-frequency questionnaire. Kalmijn et al found that the intake of marine omega-3 polyunsaturated fatty acids was inversely correlated to the risk of impaired overall cognitive function and speed. Results for fatty fish consumption were similarly inverse, while higher dietary intake of cholesterol was associated with an increased risk of impaired memory and flexibility.
Lastly, another study has examined the role of homocysteine levels using cranial magnetic resonance imaging in elderly persons. Longstreth and colleagues studied 622 elderly patients without a history of strokes or transient ischemic attacks. They had total homocysteine levels performed, as well as cranial MRIs. A number of other factors were controlled for. They examined white matter grade and infarcts, as well as ventricular grade and sulcal grade. In this study, there was no association of total homocysteine levels with individual MRI findings. There was a finding of a linear trend across quintiles of total homocysteine levels and a pattern of MRI findings combining infarcts and high white matter grade. This trend was significant.
Comment by M. Flint Beal, MD
The present results on the Cache County study provide some of the strongest evidence to date that intake of antioxidant vitamin supplements may be beneficial. It is of interest that only a combination of vitamin E with C was effective. This is because the 2 vitamins may interact in their antioxidant functions. Vitamin C is typically active in the aqueous phase and in the cytoplasm, whereas vitamin E tends to have its antioxidant effects in lipid bilayer membranes. Vitamin C may therefore be able to reduce the oxidized alpha-tocopherol quinone radical.
These studies are supportive of 3 other previous studies. The present study has the strength of being population-based, with a large sample and prospective design. The prevalence data, however, were cross sectional. The period of follow-up was also relatively short—an average of 3 years. The results may be confounded by a tendency toward a healthy lifestyle among supplement users. There, however, appear to be little evidence of such confounding when other nutritional supplements, such as multivitamins, calcium supplements, and B vitamin formulations, were considered.
The study on the intake of fish and omega-3 fatty acids also confirms other recent observations. This study was again cross sectional. It nevertheless provides further evidence that intake of fish, as well as omega-3 fatty acids, has protective effects against both vascular disease and impaired cognitive performance.
Lastly, the study of total homocysteine levels did show a linear trend toward an increased risk of stroke and white-matter damage. This also is consistent with some other recent findings suggesting that MRI imaging identifies more damage in patients with high homocysteine levels. The study, however, did not confirm the results of 2 other studies in which there was a much stronger association between total homocysteine levels and the degree of white matter damage assessed by MRI imaging. In addition, one of the previous studies had shown that there was a linear relationship between higher total plasma homocysteine levels and cortical atrophy, as well as hippocampal atrophy, which was not identified in the above-mentioned study.
Where does this leave us in the year 2004? I believe the evidence that dietary supplements of vitamin E and C may prevent dementia and AD is becoming increasingly strong. The data suggesting that intake of omega-3 fatty acids as well as fish are also quite strong. These findings, however, need to be confirmed in a prospective, primary prevention trial to determine whether intake of either antioxidant vitamins or omega-3 fatty acids will indeed prevent AD. Due to the increasing prevalence of AD in the population, this would be a valuable study to carry out.
Dr. Beal is Professor and Chairman, Department of Neurology, Cornell University Medical College, New York, NY.