FNOA: Antioxidants (2011-2012)
Citation:
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:
To explore whether the associations between serum beta-carotene level and subsequent decline of cognitive function differed by APOE 4 genotype.
Inclusion Criteria:
- The MacArthur Research Network Study of Successful Aging:
- Aged 70 to 79 years old at its inception in 1988
- Met the criteria designed to identify persons functioning in the top third of the age group.
- Cognitive performance:
- A score of six or more correct on the nine-item Short Portable Mental Status Questionnaire (SPMSQ)
- The ability to remember three or more of six elements on a delayed recall of a short story
- Physical function:
- No reported disability on a seven-item scale of activities of daily living
- No more than one disability on eight items:
- Tapping gross mobility and range of motion
- Ability to hold a semi-tandem balance for at least 10 seconds
- Ability to stand from a seated position five times within 20 seconds without using the arms.
Exclusion Criteria:
Exclusion criteria for the MacArthur Research Network Study of Successful Aging, a subset of the Established Populations for Epidemiologic Studies of the Elderly (EPESE), were described elsewhere.
Description of Study Protocol:
Recruitment
The EPESE was a community-based cohort study of persons aged 65 years or older residing in Durham, North Carolina; East Boston, Massachusetts; and New Haven, Connecticut.
Design
Prospective cohort study.
Statistical Analysis
- For this analysis, high or low concentrations of beta-carotene were dichotomized based on the median of the distribution in the cohort (0.19μmol per L)
- The associations between serum beta-carotene level and other variables were first examined in bivariate analyses, stratified on APOE 4 status
- For continuous variables, the means and standard deviations (SD) were calculated for participants with high or low beta-carotene concentrations
- Because the distributions of some of the variables (such as CRP and IL-6) were right-skewed, the Wilcoxon rank sum test was used to test the significance of the difference
- For categorical variables, such as sex, the percentage of participants with certain characteristics was calculated for each category of beta-carotene level
- Statistical significance was determined by chi-square test
- The risk of SPMSQ score decline was calculated for participants with or without APOE 4 alleles
- The significance for the difference in the magnitude of SPMSQ score changes between the two groups was determined using two sample T-tests
- Because of previous findings that the effect of antioxidants on cognitive decline may be influenced by APOE 4 genotype (23), stratified logistic regression analysis was performed to examine the relationship between beta-carotene and change in cognitive functioning among individuals with or without APOE 4 alleles
- Adjusted odds ratios were used to estimate the protective effect of high beta-carotene level, while controlling for age, sex, race, baseline SPMSQ score, education, income, serum C-reactive protein (CRP) and Interleukin-6 (IL-6) levels, total and HDL-cholesterol levels, body mass index (BMI), smoking status and alcohol consumption
- The values of CPR and IL-6 were log transformed
- To further assess the modulating effect of APOE 4 genotype on serum beta-carotene level, multivariate logistic regression modeling was used to test the statistical significance of the interaction term between APOE 4 genotype and beta-carotene levels in the entire cohort.
Data Collection Summary:
Timing of Measurements
Baseline and seven-year follow-up.
Dependent Variables
Cognitive decline based on SPMSQ score.
Independent Variables
- Serum beta-carotene concentration
- APOE genotyping.
Control Variables
- Age
- Sex
- Race
- High school education
- Income less than $10K per year
- Current alcohol use
- Smoking (pack-years)
- CRP, IL-6, Total cholesterol, HDL-cholesterol
- BMI
- Baseline SPMSQ score.
Description of Actual Data Sample:
- Initial N:
- 1,313 participants met EPESE criteria and 1,189 agreed to participate
- 970 agreed to provide blood samples
- 47 refused follow-up visits
- 347 were excluded due to incomplete information
- 576 older persons had complete information on biomarkers and 121 died during follow-up
- Attrition (final N): 455 survivors were included in the final analysis
- Age: Average age was 74.1 years.
Ethnicity
| APOE 4 Positive | APOE 4 Negative | |||
| Low Serum Beta-Carotene Less Than 0.19μmol per L | High Serum Beta-carotene 0.19μmol per L or More | Serum Beta-carotene Less Than 0.19μmol per L | High Serum Beta-carotene 0.19μmol per L or More | |
| Percent White | 86% | 67% | 91% | 79% |
Other Relevant Demographics
| APOE 4 Positive | APOE 4 Negative | |||
| Low Serum Beta-carotene Less Than 0.19μmol per L | High Serum Beta-carotene 0.19μmol per L or More | Serum Beta-carotene Less Than 0.19μmol per L | High Serum Beta-carotene 0.19μmol per L or More | |
| Percent Male | 55% | 40% | 42% | 36% |
- Anthropometrics:
- 106 participants has at least one APOE 4 allele
- Nine participants were homozygous
- Mean serum beta-carotene level was 0.27μmol per L (SD 0.31μmol per L).
- Location
- Durham, North Carolina
- East Boston, Massachusetts
- New Haven, Connecticut.
Summary of Results:
Key Findings
- 67 participants with APOE 4 alleles (63%) and 182 participants without APOE alleles (52%) had a decline in SPMSQ score during the seven-year follow-up period (P=0.04). The magnitude of SPMSQ score decline in these two groups was 1.5 (SD 2.3) and 0.8 (SD 1.8), respectively (P=0.02)
- Bivariate analysis showed no significant associations between high serum beta-carotene level and risk of cognitive decline in the cohort
- Among participants who were APOE 4 negative, there was minimal change in the relationship between serum beta-carotene level and cognitive decline after adjustments for covariates. However, for participants with at least one APOE 4 allele, the odds ratio of high beta-carotene for SPMSQ score decline changed from 0.99 (95% CI: 0.45 to 2.17) to 0.63 (95% CI: 0.25 to 1.54) after controlling for age, sex and race.
- The adjusted odds ratio was 0.11 (95% CI: 0.02 to 0.57) after additional adjustments for baseline SPMSQ score, education, income, smoking status, alcohol consumption, serum levels of CRP, IL-6 and total and HDL-cholesterol and BMI
- Using two-point decline in SPMSQ to define cognitive decline, the adjusted odds ratio of low beta-carotene was 0.25 (95% CI: 0.06 to 0.99)
- Among participants who were APOE 4 positive, the odds ratio of higher beta-carotene for SPMSQ score decline was 0.2 (95% CI: 0.06 to 0.72) after adjusting for only these four covariates and sex
- In logistic regression models using information from the entire sample including participants with or without APOE 4 alleles, the P-value for the interaction term between low beta-carotene level and presence of APOE 4 allele was 0.04.
Author Conclusion:
- The findings from this population of high-functioning community-dwelling older persons suggest that APOE 4 genotype is not only an independent predictor for cognitive decline as previously shown, but also modifies the relation between serum beta-carotene concentrations and subsequent cognitive change. Higher serum beta-carotene level is associated with lower risk of cognitive decline only among participants who have at least one APOE 4 allele. This study and other studies have shown that APOE 4 genotype is associated with decline in cognitive functioning.
- This study was unique in that it was not only shown that the APOE 4 alleles to be a risk factor, but also to be a potential modifier for the association between serum beta-carotene level and cognitive decline. It suggests that high serum beta-carotene is protective against cognitive decline in persons who are APOE 4 positive, but not among those who do not have APOE 4 alleles. The findings from this study further support the importance of the relationship between genetic predisposition and antioxidants.
- It is possible that in persons with APOE 4 alleles, beta-carotene level may be more crucial in countering oxidative stress involved in the pathogenesis of AD. The potential modulation of APOE 4 on the effects of serum beta-carotene level could have contributed to the previous inconsistent findings in the literature on the relation between beta-carotene and cognitive decline. Although the results of antioxidant supplementation has generally been disappointing in trials, this analysis raises the possibility of a more beneficial role of increased dietary intake of antioxidant or supplementation in high-risk groups of cognitive impairment defined by APOE 4 genotype.
- Further research with larger cohorts is needed to explore the effects of interaction between antioxidants and APOE genotype on cognitive functions and risk of AD in older persons. If the current findings are confirmed, new clinical interventions (dietary intervention or antioxidant supplementation) to improve the cognitive functional status of older persons at high risk of dementia must be evaluated in formal clinical trials.
Funding Source:
| Government: | USC/UCLA Biodemography Center funded by the National Institute on Aging (AG-17265), Laboratory of Epidemiology Demography and Biometry Office and the Social Research Program of the National Institute on Aging | ||
| Industry: |
|
||
| University/Hospital: | UCLA Claude Pepper Older American Independence Center | ||
| Not-for-profit |
|
Reviewer Comments:
The authors note the following limitations:
- The sample size for participants with APOE 4 alleles was relatively small. Consequently, the CI for the estimated effect size of the relationship between high beta-carotene and cognitive decline was wide in this group
- The study was also not powered to examine the associations between beta-carotene and clinical outcomes, such as dementia. No dietary intake of beta-carotene was measured. However, previous research has shown that serum level of beta-carotene is correlated with both dietary intake measured by food frequency questionnaires and supplementation of beta-carotene.
- Only 576 participants had complete information on antioxidants, APOE 4 genotype and outcome measurements. The true magnitude of the possible selection bias cannot be assessed directly with the data. However, when comparing the participants who had complete information with those who were excluded, it was found that the two groups were not significantly different in the distribution of common risk factors for cognitive decline.
|
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) | N/A | |
| 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) | N/A | |
| 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? | Yes | |
| 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? | Yes | |
| 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? | Yes | |
| 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? | Yes | |
| 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? | Yes | |
| 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? | Yes | |
| 6.4. | Was the amount of exposure and, if relevant, subject/patient compliance measured? | N/A | |
| 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? | Yes | |
| 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? | Yes | |
| 7.4. | Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? | Yes | |
| 7.5. | Was the measurement of effect at an appropriate level of precision? | Yes | |
| 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 | |