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1 From the Rush Institute for Healthy Aging (MCM, DAE, JLB, RSW, and NTA), the Department of Internal Medicine (MCM, DAE, and JLB), the Department of Preventive Medicine (MCM), the Rush Alzheimer's Disease Center (DAE, RSW, and NTA), the Department of Clinical Nutrition (CCT), the Department of Neurological Sciences (RSW and NTA), and the Department of Psychology (RSW and PAS), Rush University Medical Center, Chicago, and the Division of Adult and Community Health, Centers for Disease Control and Prevention, Atlanta (PAS).
2 Supported by grants AG11101 and AG13170 from the National Institute on Aging. 3 Address reprint requests to MC Morris, Rush Institute for Healthy Aging, 1645 West Jackson, Suite 675, Chicago, IL 60612. E-mail: martha_c_morris{at}rush.edu.
ABSTRACT
Background: High intake of vitamin E from food (tocopherol), but not from supplements (which usually contain -tocopherol), is inversely associated with Alzheimer disease.
Objective: We examined whether food intakes of vitamin E, -tocopherol equivalents (a measure of the relative biologic activity of tocopherols and tocotrienols), or individual tocopherols would protect against incident Alzheimer disease and cognitive decline over 6 y in participants of the Chicago Health and Aging Project.
Design: The 1993–2002 study of community residents aged 65 y included the administration of 4 cognitive tests and clinical evaluations for Alzheimer disease. Dietary assessment was by food-frequency questionnaire.
Results: Tocopherol intake from food was related to the 4-y incidence of Alzheimer disease determined by logistic regression in 1041 participants who were clinically evaluated (n = 162 incident cases) and to change in a global cognitive score determined by mixed models in 3718 participants. Higher intakes of vitamin E (relative risk: 0.74 per 5 mg/d increase; 95% CI: 0.62, 0.88) and -tocopherol equivalents (relative risk: 0.56 per 5 mg/d increase; 95% CI: 0.32, 0.98) were associated with a reduced incidence of Alzheimer disease in separate multiple-adjusted models that included intakes of saturated and trans fats and docosahexaenoic acid. - and -Tocopherol had independent associations. In separate mixed models, a slower rate of cognitive decline was associated with intakes of vitamin E, -tocopherol equivalents, and - and -tocopherols.
Conclusion: The results suggest that various tocopherol forms rather than - tocopherol alone may be important in the vitamin E protective association with Alzheimer disease.
Key Words: Vitamin E • -tocopherol • -tocopherol • ß-tocopherol • -tocopherol • antioxidant nutrients • Alzheimer disease • cognitive function • Chicago Health and Aging Project
INTRODUCTION
In previous studies, we (1) and others (2) reported an association between Alzheimer disease and vitamin E from food sources but not from vitamin E supplements. Because vitamin E is composed of 4 different tocopherol forms (-, , , and ß-tocopherols) and 4 corresponding tocotrienols, and because vitamin E supplements usually consist of -tocopherol only, one possible explanation for the seeming inconsistency is that the effect is not due to -tocopherol alone but to another tocopherol form or to a combination of tocopherol forms.
In this report we examined the roles of the different tocopherol forms in the protective vitamin E association with Alzheimer disease and cognitive decline in the Chicago Health and Aging Project (CHAP). We also reexamined earlier findings of a vitamin E association with 3-y cognitive change and with incident Alzheimer disease after 3 additional years of follow-up of the CHAP study population.
SUBJECTS AND METHODS
Study population
The Chicago Health and Aging Project is an ongoing study (3) that began in 1993 with a door-to-door census of 3 neighborhoods on the south side of Chicago: Morgan Park, Beverly, and Washington Heights. A total of 8501 residents aged 65 y were identified, of whom 439 died, 249 moved before contact, 1655 declined to be studied, and 6158 participated; the overall response rate was 78.9%. The study population was 62% white, 38% black, and 0.4% of another race. Baseline in-home interviews that included cognitive testing were conducted from 1993 to 1997 and were repeated in 2 follow-up interviews. In addition, stratified random samples were selected for clinical evaluation of prevalent disease at baseline and of incident disease at each of the follow-up assessment periods (Figure 1). Each cycle of population interviews and clinical evaluations occurred at 3-y intervals over a 6-y period. All study participants completed a self-administered food-frequency questionnaire (FFQ) at a median of 1.2 y from the baseline cognitive interview and from the date that disease-free status was determined in the clinical evaluation samples. A total of 4390 of the 6158 study participants had 2 periods of cognitive assessment (1298 died before follow-up); of these participants, we eliminated 213 persons who had an invalid FFQ (see below) and 460 who completed the FFQ >2.5 y after baseline, which left 3718 persons for analysis of cognitive change. A total of 1141 persons (1041 with complete data for analysis) were clinically evaluated for incident Alzheimer disease, of whom 815 were analyzed in our previous study of vitamin E intake and incident Alzheimer disease. More detailed descriptions of the CHAP study design were published previously (3, 4). The Institutional Review Board of Rush University Medical Center approved the study, and all participants gave written informed consent.
FIGURE 1.. Longitudinal study design of the Chicago Health and Aging Project, 1993–2002, showing the number of clinical evaluations and incident cases of Alzheimer disease (AD) at baseline (cycle 1) and at 2 follow-up cycles (cycles 2 and 3). FFQ, food-frequency questionnaire.
Dietary assessment
Dietary intake was assessed with the use of a modified version of the self-administered Harvard FFQ (5–7) that ascertained usual frequency of intake over the past year of 139 different foods, vitamin supplements, and dietary behaviors. The FFQs were optically scanned and analyzed for nutrient intake at the Harvard University Department of Nutrition, which uses the US Department of Agriculture (8) and other sources for nutrient composition of food items. Food composition of vitamin E and the individual tocopherols in the Harvard database were based on data from the laboratories of Ronald Eitenmiller (University of Georgia) and V Piironen (Finland) (personal communication, 2003). Daily nutrient intake was computed by multiplying the nutrient content of specified foods by frequency of consumption and summing over all food items. Because we found no association with vitamin E supplements, the analysis was restricted to food sources only. The nutrient composition of foods was modified on the basis of specified types of oil used at home and of brand name products of margarine and cereal. Vitamin E intake includes the total intake of all 8 vitamin E forms from food. -Tocopherol equivalents (-TE) were based on the current conversion factors of biologic activity of the different vitamin E forms: 1.0 for -tocopherol, 0.5 for ß-tocopherol, 0.1 for -tocopherol, and 0.3 for -tocotrienol. All nutrients were energy-adjusted separately for males and females with the use of the residual regression method (9). We eliminated from the analysis potentially invalid FFQs, including those with implausible daily caloric intakes (women: <500 kcal or >3800 kcal; men: <700 kcal or >4000 kcal) or with entire pages or >50% of the items unanswered. FFQs were also considered invalid if the Mini-Mental State Examination score was 10 at the baseline population interview.
In a validity study of 232 randomly selected CHAP participants, Pearson's correlations between food intakes on the FFQ and multiple 24-h dietary recalls over 12 mo were as follows: 0.42 for -tocopherol, 0.31 for -tocopherol, 0.31 for -tocopherol, and 0.03 for ß-tocopherol. Spearman's correlations for reproducibility were as follows: 0.49 for -tocopherol, 0.40 for -tocopherol, 0.34 for -tocopherol, and 0.47 for ß-tocopherol.
Sampling for clinical evaluation
For the baseline clinical evaluation (cycle 1), participants were randomly selected within categories of age, sex, race, and cognitive score (good, intermediate, and poor). Evaluations for prevalent Alzheimer disease were completed for 729 participants (75.9% response) and were used to identify a disease-free cohort of 3838 persons that included 312 clinically evaluated participants who were unaffected by disease and 3526 participants who had good cognitive performance at the baseline population interview (only 3% of this group was affected by prevalent Alzheimer disease at the clinical evaluation).
After the third year (cycle 2) population interviews, a second stratified random sample was selected for clinical evaluation of incident disease. Participants were randomly selected from the disease-free cohort with different probabilities of selection applied within categories of age, sex, race, and change in cognitive score between the population cycle 1 and cycle 2 interviews (no decline, intermediate, or large). A total of 842 persons (74.8% response) were evaluated for incident disease after a median 3.9 y of follow-up. A new disease-free cohort of 2594 persons was identified at cycle 2, from which a sample was drawn for evaluation at cycle 3. In the current analyses, we included data from 299 persons who were evaluated for incident Alzheimer disease for the first time from among those selected for this new sample. Combining this new sample of persons (n = 299) with the first sample evaluated for incident disease (n = 842) thus yielded a total sample size of 1141 persons, all of whom were clinically evaluated for incident Alzheimer disease after 4 y of follow-up. Of the 1141 clinically evaluated persons, we eliminated 32 who did not complete a valid FFQ and 68 who had missing data on important variables, which left 1041 persons for analysis. More detailed descriptions of the design and a combination of the incidence samples were published previously (4, 10).
Alzheimer disease
A neuropsychiatric team, blinded to dietary information, conducted clinical evaluations in participants' homes using structured forms and procedures. The 2.5-h evaluations included a complete medical history and neurologic examination, laboratory testing, and neuropsychological testing with the use of the tests of Consortium Established for Research on Alzheimer's Disease (11) and others (12–19). A board-certified neuropsychologist reviewed all test scores and rendered a decision of impairment in the different cognitive domains. A board-certified neurologist examined every participant and reviewed all clinical data. Diagnostic use of magnetic resonance imaging was restricted to persons with evidence of dementia and uncertainty as to whether a stroke had occurred or was related to the dementia. A diagnosis of probable Alzheimer disease was made on the basis of criteria of the National Institute of Neurological Communicative Disorders and Stroke and the Alzheimer's Disease and Associated Disorders Association (NINCDS-ADRDA Disorders) (20), except that we included all cases of Alzheimer disease, regardless of whether another dementing disease was present (19 cases had a coexisting dementing disease). Apolipoprotein E genotyping was conducted with the use of the methods of Hixson and Vernier (21) and the primers described by Wenham et al (22).
Cognitive testing
The population interviews included the administration of 4 cognitive tests: the East Boston Tests of Immediate and Delayed Recall (12, 23), the Mini-Mental State Examination (24), and the Symbol Digit Modalities Test (25). Standardized scores were computed for each test by using the baseline population means and SDs (z scores) and then the results on the 4 tests were averaged to provide a single global measure of cognitive function. The global measure had the advantage of being more normally distributed than any of the individual cognitive tests and had reduced problems of measurement error, including floor and ceiling effects.
Statistical analysis
Logistic regression in SAS (26) was used to estimate the odds of developing Alzheimer disease by tocopherol intake. All models were weighted by the inverse of the stratified sampling probabilities. Data from the 2 incident samples were combined for analysis. Variance estimation for the odds ratios was based on jackknife repeated replication (10, 27, 28). Given that the incidence of disease in the study population is low, the odds ratios estimated from the model are considered to be estimates of the relative risk (RR).
Change in cognitive function over 6 y was examined in the entire study population with random coefficients mixed models (29) in SAS. This model estimates the average initial level of cognitive score over time and the rate of change (fixed effect) while also accounting for within-person variation in the initial level and the rate of change (random effects).
The multiple-adjusted models were determined from previous studies of dietary and other important risk factors for Alzheimer disease (3, 30–32) and cognitive change (33). The adjusted model for incident Alzheimer disease included terms for age (y), sex, race (black or nonblack), education (y), APOE-4 allele (any 4 allele or none), interaction between APOE-4 and race, time from the determination of disease-free status to the time of clinical evaluation of incident disease, frequency of participation in cognitive activities, and intakes of saturated fat (g/d), trans unsaturated fat (g/d), and docosahexaenoic acid (22:6n–3). Frequency of participation in cognitive activities was based on a previously established composite measure representing the average frequency score for 7 cognitive activities (32, 34). The adjusted model for change in cognitive score included terms for age (y), sex, race, education (y), total intake of vitamin C (mg/d), time since baseline, and the interaction between time and each covariate. The interaction terms with time represented the effects of variables on the rate of change in cognitive score.
For both sets of analyses, tocopherol intakes were measured as continuous variables. The nonlinearity of associations was investigated by the inclusion of polynomial terms (with a significance level of = 0.05). In no case was the association with the tocopherol variables nonlinear. Results are presented in 5 mg/d increments, except for - and ß-tocopherols, which are presented in 1 mg/d increments because of the small range of intakes.
RESULTS
The distribution of important potential confounders by quintiles of food intake of - and -tocopherols in 3718 CHAP participants is provided in Table 1. Persons with a high intake of -tocopherol tended to have a favorable risk profile for dementia, with greater years of education, and higher intakes of vitamin C and the n–3 fatty acid docosahexaenoic acid. By contrast, persons with a high intake of -tocopherol tended to have a less favorable risk profile, with lower intakes of total vitamin C and higher intakes of saturated and trans unsaturated fats.
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TABLE 1. Baseline characteristics of 3718 participants aged 65 y in the Chicago Health and Aging Project (1993–1997) by intakes of -tocopherol and -tocopherol1
Of the 1041 clinically evaluated persons in the analysis, 162 developed incident Alzheimer disease after a median follow-up of 3.9 y. The correlations between food intakes of total vitamin E and of each tocopherol form were as follows: 0.68 for -tocopherol, 0.90 for -tocopherol, 0.86 for -tocopherol, 0.56 for ß-tocopherol, and 0.42 for -tocopherol equivalents.
Vitamin E intake from food was linearly and inversely associated with 4-y risk of developing Alzheimer disease in the model adjusted for age, sex, race, APOE-4, education, frequency of participation in cognitive activities, and fat intake (Table 2) There was a statistically significant 26% reduction in risk per 5 mg/d increase in vitamin E intake. We next examined the associations between Alzheimer disease and intake of the individual tocopherol forms. -, -, and -Tocopherols were significantly and inversely associated with incident Alzheimer disease, with reductions in risk of 34% per 5 mg/d increase in -tocopherol, 40% per 5 mg/d increase in -tocopherol, and 25% per 1 mg/d increase in -tocopherol. There was no evidence of an association between intake of ß-tocopherol and Alzheimer disease risk. Intake of -tocopherol equivalents was associated with a 44% reduction in risk of Alzheimer disease per 5 mg/d increase in intake. In further analyses, we modeled ß-, -, and - tocopherols simultaneously in the multiple-adjusted model. -Tocopherol was not included because of collinearity with -tocopherol (r = 0.96). Both -tocopherol (RR: 0.66 per 5 mg/d increase; 95% CI: 0.43, 1.03) and -tocopherol (RR: 0.60 per 5 mg/d increase; 95% CI: 0.41, 0.88) were independently associated (P = 0.07 and P = 0.009, respectively) with incident Alzheimer disease.
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TABLE 2. Adjusted relative risks of incident Alzheimer disease per designated increases in food intakes of vitamin E; -, -, -, and ß-tocopherols; and -tocopherol equivalents in 1041 persons with 162 incident cases during 4.0 y of follow-up in the Chicago Health and Aging Project (1993–2003)1
In further analyses, we examined whether the interaction effect observed between the APOE-4 allele and vitamin E intake in the previous study remained with the additional cases of Alzheimer disease and also whether there were interaction effects with the different tocopherol forms. As in the previous report, the protective association of vitamin E was observed only in persons who were APOE-4 negative (multiple-adjusted RR: 0.76 per 5 mg/d; P = 0.01). In addition, there was a suggestion that the inverse association with intake of -tocopherol equivalents was also restricted to this group, with a multiple-adjusted RR of 0.47 (P = 0.08) per 5 mg/d increase in intake.
Tocopherols and cognitive change
Of the 3718 participants from the study population who had 2 cognitive assessments over 6 y, the mean cognitive score at baseline was 0.18 standardized units (SU) (range: –3.5 to 1.6), and the overall annual rate of change in cognitive score was a decrease of 0.04 SU/y.
High intake of vitamin E from food was significantly associated with a slower decline in cognitive score over 6 y of follow-up. (Table 3) When expressed per 5 mg/d increase in vitamin E intake, the rate of cognitive decline was significantly slower by 0.0049 SU/y. Of the 4 tocopherol forms, higher food intakes of - and -tocopherols were each significantly associated with slower rates of cognitive decline. Neither - nor ß-tocopherols were associated with cognitive change. High intake of -tocopherol equivalents was also strongly associated with a slower rate of cognitive decline. On the basis of these models, compared with the rate of cognitive decline in a 75-y-old white woman with 12 y of education and median intakes of vitamin C and vitamin E from food, the rate for a similar woman who consumed a 5 mg/d higher intake of vitamin E would have a slower rate of cognitive decline, by 8.7% per year. In similar computations for other tocopherols, per 5 mg/d increase in -tocopherol, the annual rate of decline would be reduced by 14.7%, for -tocopherol by 11.7%, and for -tocopherol equivalents by 19.6%.
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TABLE 3. Adjusted differences in the rate of cognitive change per designated increases in food intakes of vitamin E; -, -, -, and ß-tocopherols; and -tocopherol equivalents in the total cohort of 3718 participants during 6 y of follow-up in the Chicago Health and Aging Project (1993–2002)1
Because commercially baked products are commonly prepared with vegetable oils that are high in
DISCUSSION
Longer follow-up of the CHAP study population corroborated earlier findings of an inverse association between vitamin E and Alzheimer disease and cognitive decline. Of the different tocopherol forms, - and -tocopherols had inverse associations with both Alzheimer disease and cognitive decline that were similar in magnitude. Intake of -tocopherol equivalents also had a strong inverse association with both Alzheimer disease and cognitive change. The association between intake of -tocopherol and cognitive change was most likely due to its correlation with -tocopherol intake.
These findings suggest that the vitamin E protection of the brain may be due to the combined intake of the tocopherol forms. -Tocopherol is the most biologically active form of vitamin E and the most potent antioxidant (36). Even though all tocopherols are equally poorly absorbed, -tocopherol is preferentially secreted into the plasma from the liver by the -tocopherol transport protein and is the most abundant form in animal and human tissue. Vitamin E is also commonly expressed as -tocopherol equivalents, which represents the sum of the relative bioavailability of all of the tocopherol forms. Whereas the most recent dietary reference intakes for vitamin E issued by the Food and Nutrition Board of the Institute of Medicine are based on -tocopherol only (37), previous recommendations for dietary intake were based on all 8 naturally occurring forms of vitamin E.
Previous studies indicate that the tocopherols may act synergistically. In experimental studies a mixture of the different tocopherols resulted in a greater lowering of lipid peroxidation and increased synthesis of antioxidant proteins, such as superoxide dismutase, when compared with the effects of -tocopherol alone (38). The addition of increased amounts of -tocopherol to a diet in which -tocopherol was held constant increased -tocopherol concentration in the forebrain of experimental rats (39).
The major sources of vitamin E are vegetable and seed oils. -Tocopherol is more abundant in sunflower and wheat germ oils, whereas corn and soybean oils contain predominantly -tocopherol. Recent studies have begun to examine the biologic effects of -tocopherol more closely because it has become the major form of vitamin E in the North American diet (40) as a result of more widespread use of corn and soybean oils, especially in commercially prepared foods. Both - and -tocopherols reduced cerebral ischemic-induced brain damage when injected into rat brain (41). -Tocopherol was shown to have greater antiinflammatory properties than -tocopherol (42) and to be a major scavenger of reactive nitrogen species (43, 44), which were found in laboratory studies to be significant contributors to lipid oxidation in the brains of patients with Alzheimer disease.
The CHAP study has many strengths. The findings were based on a large prospective study of a diverse urban community. Dietary intake was assessed with the use of the well-validated Harvard FFQ that was also shown to be a valid and reliable tool in the CHAP study population (45). The outcome of Alzheimer disease was determined by structured clinical evaluations that used standardized criteria. Dietary associations with cognitive change were analyzed with the use of multiple outcome measures over multiple time periods, thus reducing random and nonrandom errors that occur in analyses that use a single test or 2-point change in score. As with any observational study, an alternative explanation of the observed associations is uncontrolled confounding. Arguments against this possibility rest in the consistency of the associations across 2 different but related outcomes and samples and statistical control of factors associated with a healthy lifestyle, including educational level, race, sex, and intakes of different types of fat. Of note, persons with higher intakes of -tocopherol tended to have unhealthy dietary behaviors, such as higher intakes of saturated and trans unsaturated fats. A limitation of the study is the questionable validity of intakes of some of the different tocopherol forms. The correlations between intakes measured with the FFQ and the 24-h dietary recalls were moderately low and near 0 for ß-tocopherol. This may call into question the null findings for ß-tocopherol. However, the validity study likely resulted in underestimates of the true correlations because of the different sources of tocopherol food composition used in the 2 dietary assessment methods.
These findings suggest that the combined intake of the tocopherol forms, particularly -tocopherol equivalents, may be more important than -tocopherol alone in the protective relations with Alzheimer disease and cognitive decline. This may explain the absence of association reported in some studies between Alzheimer disease and use of vitamin E supplements, which have traditionally contained only -tocopherol. Additional testing through randomized controlled clinical trials appears warranted to more firmly establish the effects of various tocopherol forms on the prevention of age-related cognitive decline and Alzheimer disease.
ACKNOWLEDGMENTS
We gratefully acknowledge the study coordination efforts of Cheryl Bibbs, Ann Marie Lane, Michelle Bos, Jennifer Tarpey, Holly Hadden, and Flavio Lamorticella and their staffs and the analytic programmers (Woojeong Bang and Hye-Jin Nicole Kim).
All authors contributed to the study design, data collection, data analysis, and writing of the manuscript. None of the authors had a conflict of interest.
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