EAL

FNOA: Antioxidants (2011-2012)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To examine whether use of vitamin C or E alone or in a combination was associated with lower incidence of dementia or Alzheimer's disease (AD).

Inclusion Criteria:

Study participants, aged 65 years and older, were randomly sampled from the Seattle area members of the Group Health Cooperative (GHC).

Exclusion Criteria:

Participants without at least one study follow-up visit.

Description of Study Protocol:

Recruitment

The Adult Changes in Thought (ACT) study is a population-based prospective cohort study of incident dementia and AD.

Design

Prospective cohort study.

Intervention

Vitamin C and vitamin E use.

Statistical Analysis

Differences in participation characteristics between antioxidant supplement users, multivitamin (MVI) users and nonusers were examined using chi-square test and analysis of variance models for categorical and continuous variables
Cox proportional hazards regression models were used to examine the association between baseline antioxidant supplement use and risk of dementia or AD using age as the time scale
Dementia onset was defined by convention as occurring halfway between the date of diagnosis and the date of the prior examination
Follow-up time was censored at age of death or last follow-up
To improve the precision of estimated exposure effects and control for potential confounding, all multivariate models adjusted variables that were significantly related to both the exposure and outcomes in these data or varied by type of supplement use.

Data Collection Summary:

Timing of Measurements

Subjects followed from 1994 to 2002.

Dependent Variables

Any dementia
Possible AD
Probable AD
As diagnosed by using the Cognitive Abilities Screening Instrument (CASI), which was performed at baseline and every two years to assess changes in cognitive function. Participants whose CASI scores fell below 86 underwent a standardized dementia diagnostic evaluation including a physical and neurological examination by a study neurologist, geriatrician or internist and a one-hour battery of neuropsychological testing. Relevant laboratory tests and brain computed tomography or magnetic resonance imaging studies were performed or results were obtained from GHC records.

Independent Variables

Use of supplements broken down as:

No vitamins E or C or MVI
Any vitamin E
Any vitamin C
Any MVI
MVI only
Vitamin C only
Vitamin E only
Vitamin C and MVI
Vitamin E and MVI
Vitamins E and C with or without MVI.

Control Variables

Demographic factors, including age, sex, ethnicity, years of education and income
Self-reported medical history, including diagnosis of angina pectoris, congestive heart failure, heart attack, stroke or cerebral hemorrhage, small strokes or transient ischemic attack, hypertension, diabetes mellitus, coronary bypass surgery or balloon angioplasty
Health and lifestyle characteristics, including body mass index (BMI), self-assessed health, physical activity, smoking and alcohol use
Apolipoprotein E (APOE) genotype
Family history of dementia.

Description of Actual Data Sample:

Initial N: 3,392
Attrition (final N): 2,969

Age

	Vitamin C or E Supplement	Multivitamin Use	No Supplement
Age at baseline, mean ± SD	75.4±6.2	76.1±6.6	75.4±6.2

Ethnicity

	Vitamin C or E Supplement	Multivitamin Use	No supplement
Percent Caucasian	92.8	89.8	87.4

Other Relevant Demographics

Characteristic	Vitamin C or E Supplement	Multivitamin	No Supplement
BMI
Less than 25	34	30.3	31
25 to 29.0	40.5	37	43.4
30 or more	25.5	23.7	25.5
Presence of apolipoprotein E ε4 allele (percent)	27.3	21.8	25.5
Family history of dementia (percent)	31.7	32.6	30.7

Location

Seattle, Washington.

Summary of Results:

Key Findings

At baseline, 32.5% of participants reported use of vitamin E and 37.8% reported use of vitamin C. One quarter of participants taking any antioxidant took vitamin E and vitamin C concurrently.
Of baseline supplement users who survived to the next follow-up visit, 73% of vitamin C users and 75% of vitamin E users and 66% of concurrent vitamin E and vitamin C users remained users
Of those not using vitamin C and E at baseline, 10% to 16% reported use of both supplements at one of the next three follow-up visits
Users of vitamin C or E were more likely to be female and Caucasian, have higher levels of formal education, exercise regularly and have higher CASI scores than those reporting no supplement use
Similar covariates were associated with vitamin E and vitamin C use when examined separately with the exception that users of vitamin E had a significantly higher prevalence of coronary heart disease than nonusers of vitamin C
Over a mean follow up of 5.5±2.7 years, 405 subjects developed dementia (289 developed AD).

Results From Adjusted Models Relating Antioxidant Vitamins to Dementia and AD

No protective effect was found with vitamin E or C use for overall dementia or AD
Furthermore, when examining combinations of supplements, concomitant use of vitamins E and C offered no protective effect for either outcome
The following chart shows the hazard ratios (HR) and 95% confidence intervals (CI):

	Any Dementia		Possible or Probable AD
Vitamin Use	HR	95% CI	HR	95% CI
No vitamin E or C or MVI (reference group)	1	-	1	-
Any vitamin E	0.98	0.77 to 1.25	1.04	0.78 to 1.39
Any vitamin C	0.9	0.71 to 1.13	0.95	0.72 to 1.25
Any MVI	0.87	0.70 to 1.09	0.94	0.72 to 1.22
Combination of supplements
MVI only	0.91	0.69 to 1.19	0.97	0.7 to 1.34
Vitamin C only	0.91	0.59 to 1.41	0.87	0.52 to 1.48
Vitamin E only	1.17	0.65 to 2.11	1.31	0.66 to 2.6
Vitamin C and MVI	0.7	0.45 to 1.06	0.78	0.48 to 1.28
Vitamin E and MVI	1.02	0.6 to 1.74	0.89	0.51 to 1.9
Vitamin E and C (with or without MVI)	0.93	0.32 to 1.2	1	0.73 to 1.35

No difference was found in degree of association between supplement use and overall dementia or AD risk when stratified according to age
Furthermore, repeating the analyses to exclude those who scored lower than 91 on the CASI at baseline did not appreciably change the hazard ratios.

Author Conclusion:

This population-based, longitudinal study of persons aged 65 and older with more than five years of follow-up showed no effect of supplemental use of vitamins E or C on risk for overall dementia or AD after adjusting for several potential confounders, which is consistent with other epidemiological evaluations of supplement use. Furthermore, these analysis did not support the hypothesis that concurrent use of vitamins E and C would reduce dementia or AD risk.
A question that has not been addressed is whether antioxidant supplement use in midlife may prevent AD and other forms of dementia, but given the recent evidence that high-dose vitamin E may have adverse health consequences, it is unlikely that this line of research will be pursued. This current evidence does not support recommending use of antioxidant vitamin supplements for prevention of dementia in older adults.

Funding Source:

Government:

National Institute on Aging

Reviewer Comments:

The authors noted that the main limitation was imprecision in the exposure ascertainment, a limitation frequently encountered in research that has examined antioxidant supplement use and dementia outcomes, but note the following:
- Two factors that should be considered when defining supplement exposure are frequency of use and daily dose. With regard to frequency of use, participants in this study has to report use for at least one week during the previous month
- Other studies have not provided clear definitions for exposure based on frequency or required use to exceed a specified number of days per week
- Furthermore, most studies have not used a dose requirement for defining clinically meaningful vitamin E or C exposure
- Information about dose of vitamin E and C was not available, but assumptions were made about relative dose based on whether the source was a single supplement or MVI. To overcome the limitation of not having the exact dose, the analysis of separate combinations of vitamin E and C with or without MVI was performed.
- It is possible that an association was not found between antioxidant supplement use and dementia because the dose of antioxidants used by participants was too low or too infrequent to confer protection.
Other limitations noted by the authors include:
- This sample may not be a representative of other general populations, as evidenced by the generally high prevalence of several preventative health behaviors
- In this study, a higher amount of supplement usage was reported when compared to other studies
- In examining the effects of specific combinations of supplements, some combinations had a low number of incident cases, which resulted in lack of precision in the estimate of the effect, especially for vitamin E
- The current study, like most prior research, did not have information about antioxidant exposure before baseline
- Because these studies are primarily conducted in older populations, duration of exposure before baseline is important, given that the benefits of antioxidants are likely to precede AD onset by several years
The complete inclusion and exclusion criteria for the ACT study were described in detail elsewhere.

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		No
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	No
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	No
3.	Were study groups comparable?		Yes
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	Yes
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	No
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	N/A
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	Yes
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
4.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	Yes
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
5.	Was blinding used to prevent introduction of bias?		No
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	N/A
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	No
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	No
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		???
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	N/A
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	Yes
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	???
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	No
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	N/A
	6.6.	Were extra or unplanned treatments described?	N/A
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	Yes
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
7.	Were outcomes clearly defined and the measurements valid and reliable?		???
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	???
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	N/A
	7.5.	Was the measurement of effect at an appropriate level of precision?	???
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	N/A
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	N/A
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes