RE: "MIDLIFE DIETARY INTAKE OF ANTIOXIDANTS AND RISK OF LATE-LIFE INCIDENT DEMENTIA: THE HONOLULU-ASIA AGING STUDY"

Kurt Hoffmann and Manuela M. Bergmann

German Institute of Human Nutrition, Potsdam-Rehbrücke, Germany

We read with interest the recent Journal paper on intake of antioxidants and risk of dementia. In that paper, Laurin et al. (1) reported that midlife intake of antioxidants does not modify the risk of late-life dementia or its most prevalent subtypes.

However, we have several concerns about the assessment of dietary intake and the statistical analysis of the data. First, assessing dietary intake by using a single 24-hour recall is unusual in nutritional epidemiology because the recall covers a very short time period that cannot reflect individual long-term intake. Although the authors addressed this problem in the Discussion section and excluded subjects who stated that the 24-hour recall was atypical, the bias due to the short time period of exposure assessment remains serious. The exclusion criterion referred to under- or overeating in general and not to micronutrient intake, so that participants who were not excluded (93.6 percent) may have had an atypical intake of antioxidants on the sampling day. A number of researchers have demonstrated a day-to-day variability in vitamin intake and have shown that this intraindividual variation tends to be even higher than the variation between individuals (2). Thus, misclassification will take place when subjects are assigned to quartiles of dietary intake according to a single 24-hour recall compared with long-term or repeated short-term intake measurements. Consequently, estimates of relative risks by quartiles of vitamin intake will be biased (3).

To illustrate this issue, we estimated the intra- and interindividual variance components for beta-carotene, vitamin C, and vitamin E by using data from the 1995–1996 European Prospective Investigation into Cancer and Nutrition–Potsdam validation study. In this study, twelve 24-hour dietary recall interviews were conducted, three interviews per season (4). About 80 percent of the total variance for each antioxidant could be attributed to day-to-day variation in individual intake. To ensure that our estimates were compatible with those of Laurin et al. (1), we categorized the exposure by quartiles of log-transformed energy-adjusted antioxidant intakes. If we did so for intake regarding the first sampling day and for mean intake of the twelve recalls, a misclassification rate of 59.7–62.7 percent would occur if the first 24-hour dietary recall was used instead of all twelve recalls (table 1).


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TABLE 1. Relative contributions (%) of intra- and interindividual variance in antioxidant intake assessed by 24-hour dietary recalls*
 
Second, the relative risks of late-life dementia were adjusted for coronary heart disease and stroke events that occurred after dietary assessment and before dementia. However, cardiovascular diseases themselves may be due to insufficient intake of antioxidants (5, 6) so that adjustment was made for factors causally subsequent to exposure. These intermediate variables cannot be considered confounders, and adjustment for variables that are possibly in the causal pathway between the exposure and the outcome may lead to bias and to invalid relative risks (7).

Third, levels of antioxidants in the diet are highly correlated. Thus, the combined effect of antioxidants on dementia may be quite different from the effects of single antioxidants. The regression models applied by Laurin et al. (1), with only one antioxidant as predictor adjusting for some covariates, are neither appropriate to model the combined effect nor to get unbiased estimates of single effects. To adjust each antioxidant for the other ones, all antioxidants should be included in the same regression model.

In conclusion, careful attention should be given to the very short time period covered by the dietary assessment method and the insufficient adjustment of antioxidant intake before a conclusive statement can be made about midlife dietary intake of antioxidants not being associated with late-life dementia.

REFERENCES

  1. Laurin D, Masaki KH, Foley DJ, et al. Midlife dietary intake of antioxidants and risk of late-life incident dementia: the Honolulu-Asia Aging Study. Am J Epidemiol 2004;159:959–67.[Abstract/Free Full Text]
  2. Ogawa K, Tsubono Y, Nishino Y, et al. Inter- and intra-individual variation of food and nutrient consumption in a rural Japanese population. Eur J Clin Nutr 1999;52:781–5.[CrossRef]
  3. Hartman AM, Brown CC, Palmgren J, et al. Variability in nutrient and food intakes among older middle-aged men: implications for design of epidemiologic and validation studies using food recording. Am J Epidemiol 1990;132:999–1012.[Abstract]
  4. Kroke A, Klipstein-Grobusch K, Voss S, et al. Validation of a self-administered food-frequency questionnaire administered in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study: comparison of energy, protein, and macronutrient intakes estimated with the doubly labeled water, urinary nitrogen, and repeated 24-h dietary recall methods. Am J Clin Nutr 1999;70:439–47.[Abstract/Free Full Text]
  5. Clarke R, Armitage J. Antioxidant vitamins and risk of cardiovascular disease. Review of large-scale randomized trials. Cardiovasc Drugs Ther 2002;16:411–15.[CrossRef][ISI][Medline]
  6. Voko Z, Hollander M, Hofman A, et al. Dietary antioxidants and the risk of ischemic stroke: the Rotterdam Study. Neurology 2003;61:1273–5.[Abstract/Free Full Text]
  7. Hernán MA, Hernández-Diaz S, Werler MW, et al. Causal knowledge as a prerequisite for confounding evaluation: an application to birth defects epidemiology. Am J Epidemiol 2002;155:176–84.[Abstract/Free Full Text]