Omega-3 index of 6 to 7 associated with best cognition in this study – Nov 2019

Omega-3 polyunsaturated fatty acids status and cognitive function in young women

Lipids in Health and Disease

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Rebecca L. Cook1, Helen M. Parker1,2, Cheyne E. Donges3, Nicholas J. O'Dwyer1,3, Hoi Lun Cheng4,5, Katharine S. Steinbeck4,5, Eka P. Cox1, Janet L. Franklin6, Manohar L. Garg7 and Helen T. O'Connor1,2*

Background: Research indicates that low omega-3 polyunsaturated fatty acid (n-3 PUFA) may be associated with decreased cognitive function. This study examined the association between n-3 PUFA status and cognitive function in young Australian women.

Methods: This was a secondary outcome analysis of a cross-sectional study that recruited 300 healthy women (IB- 35 y) of normal weight (NW: BMI 18.5-24.9 kg/m2) or obese weight (OB: BMI >30.0 kg/m2). Participants completed a computer-based cognition testing battery (IntegNeuro™) evaluating the domains of impulsivity, attention, information processing, memory and executive function. The Omega-3 Index (O3I) was used to determine n-3 PUFA status (percentage of EPA (20:5n-3) plus DHA (22:6n3) in the red cell membrane) and the participants were divided into O3I tertile groups: T1 < 5.47%, T2 = 5.47-6.75%, T3 > 6.75%. Potential confounding factors of BMI, inflammatory status (C-reactive Protein), physical activity (total MET-min/wk), alphal-acid glycoprotein, serum ferritin and hemoglobin, were assessed. Data reported as z-scores (mean ± SD), analyses via ANOVA and ANCOVA.

Results: Two hundred ninety-nine women (26.9 ± 5.4 y) completed the study (O3I data, n = 288). The ANOVA showed no overall group differences but a significant group x cognition domain interaction (p <0.01). Post hoc tests showed that participants in the low O3I tertile group scored significantly lower on attention than the middle group (p = 0.01; ES = 0.45 [0.15-0.74]), while the difference with the high group was borderline significant (p = 0.052; ES = 0.38 [0.09-0.68]). After confounder adjustments, the low group had lower attention scores than both the middle (p = 0.01) and high (p = 0.048) groups. These findings were supported by univariate analyses which found significant group differences for the attention domain only (p = 0.004).

Conclusions: Cognitive function in the attention domain was lower in women with lower O3I, but still within normal range. This reduced but normal level of cognition potentially provides a lower baseline from which cognition would decline with age. Further investigation of individuals with low n-3 PUFA status is warranted.

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Results

The screening and recruitment of participants are summarized in Fig. 1. Although 299 women completed the study, blood samples could not be assayed in 11 cases, hence the analysis was based on 288 participants.
The demographic characteristics of the tertile groups, as well as their biochemical markers, are shown in Table 1. Years of education varied significantly across the groups (p = 0.02), the post hoc tests showing that the lowest O3I tertile group had about 1 year less education than the highest group (p = 0.02) while the difference from the middle group was not significant (p = 0.10). Of the five covariates, the O3I groups did not differ significantly on PA, SF or Hb, but there were significant group differences in BMI (and weight), CRP and a1GP levels. Post hoc pairwise comparisons showed that the lowest O3I group differed significantly from the highest group on these three variables (p < 0.02) but differed significantly from the middle group only on a1GP levels (p = 0.03). There were proportionately more participants with normal weight in the highest tertile group and more participants with obesity in the lowest tertile group (p < 0.0001).
The cognitive function of the three groups was assessed across the five domains. The mean z-scores for each domain across all O3I tertile groups were in the normal range (Fig. 2). The ANOVA showed no significant overall difference between the groups (p = 0.22) but there was a significant interaction between groups and cognitive domains (p <0.01). Examination of the mean values in Fig. 2 shows that the locus of this interaction was the attention domain, with the lowest tertile group having a lower score than the other two groups. Post hoc tests on this interaction confirmed that the lowest tertile group scored significantly lower on attention than the middle group (p = 0.01; ES = 0.45 [0.15-0.74]), while the difference with the highest group was borderline significant (p = 0.052; ES = 0.38 [0.09-0.68]). The middle and highest O3I groups had similar attention scores. Univariate analyses on each domain across the three groups confirmed a significant group effect only for attention (p = 0.004).
Of the five covariates, only BMI and CRP showed significant (weak) correlations with cognition domains, specifically attention and memory (r = - 0.14 to - 0.22, p < 0.02). BMI and CRP were also found to be positively correlated with each other (r = 0.67, p < 0.0001). Consequently, only the analyses of covariance with these two covariates had any effect relative to the unadjusted model and so only they will be reported. Similar to the unadjusted model, there were no significant overall group effects after adjusting individually for BMI (p = 0.28) and CRP (p = 0.23). The group x domain interaction was still significant for CRP (p = 0.013) but now borderline for BMI (p = 0.053), the locus again being the attention domain. Given these p values, post hoc tests were carried out in both cases and showed that for BMI, the lowest O3I group scored significantly lower on attention than both the middle (p = 0.01) and highest (p = 0.047) O3I groups, while for CRP, the lowest group scored significantly lower on attention than the middle group (p = 0.01) and was borderline significant with the highest group (p = 0.050). The middle and highest O3I groups again had similar performance scores. The univariate analyses on each domain across the three groups again confirmed significant effects for attention only (p < 0.029).
When these two covariates were combined in one ANCOVA model, the pattern of results mirrored that found after adjusting for BMI alone (the lack of further effect of CRP can be attributed to the degree of collin- earity between these covariates). There was no significant group effect (p = 0.27) and the group x domain interaction was again borderline (p = 0.054). Given this p value, post hoc pairwise comparisons were carried out and again showed that the lowest O3I group had significantly lower performance on attention than both the middle (p = 0.01) and highest (p = 0.048) O3I groups. The middle and highest O3I groups had similar attention scores. The univariate analyses were again significant for the attention domain (p = 0.029).
In summary, no overall group effect was observed with either the ANOVA or ANCOVA models but in each case, post hoc tests on significant group x domain interactions revealed a pattern whereby the lowest O3I tertile group scored significantly lower than the middle and highest tertile groups in the
Table 1 Demographics and biochemical markers (mean ±SD)

aOne-way ANOVA on all variables except Chi-square test for weight category distributions. Abbreviations: O3I omega-3 index, BMI body mass index, CRP C-reactive Protein, aiGP alpha1-acid glycoprotein, MET metabolic equivalent of task, min minute, wk. week, SF serum ferritin, Hb hemoglobin. Missing data: a1GP (n = 10),
Hb (n = 2)

cognitive domain of attention, with the latter groups showing similar scores. These findings were supported in each case by the univariate analyses, which found significant group differences for the attention domain (Fig. 2). When these ANOVA models were repeated on quartile (n = 72) and quintile (n = 57)

Fig. 2
O3I groups, a similar pattern of results was observed. There were no overall group effects but there were significant group x domain interactions (p < 0.02) on which post hoc tests revealed that the lowest quartile and quintile groups scored lowest in the domain of attention. Again, significant group differences in the attention domain were observed on univariate analyses (p < 0.01).

Discussion

This cross-sectional study examined the association of O3I with cognitive function in young, healthy, normal weight and obese women. While the cognitive performance of the participants was within the normal range, the study provides evidence for decreased performance in the attention domain in women with a lower Omega-3 Index. The major significant group differences remained after adjustment for known con- founders, with the post hoc tests still significant. Of the five confounders, BMI appeared to be most strongly linked to cognition. While a cut-off for n-3 PUFA intake for optimal brain health in young adults cannot be suggested at this stage, the lowest O3I tertile range (< 5.47%) may be sub-optimal for cognitive function. The reduced but normal level of cognition associated with lower n-3 PUFA potentially provides a lower baseline from which cognition would continue to decline with age.
There are a relatively small number of studies examining the effects of n-3 PUFA on cognitive function in young adults, ranging from randomized controlled trials to observational studies [1, 7, 38-45]. The majority of studies include psychometric tests measuring attention, memory and information processing, with memory tests more heavily represented in the literature. Overall, the evidence in healthy young adults suggests that dietary supplementation with n-3 PUFA does not enhance cognitive function, with only a handful of studies showing clear significant benefits on memory [40], information processing [44] and attention [43]. Importantly, none of the above-mentioned studies adjusted for confounders, which is a strength of our study. There is evidence however that a threshold effect of low n-3 PUFA on cognition may explain nonsignificant findings [38, 46, 47]; hence the effects of n- 3 PUFA supplementation in healthy participants may only be evident when cognitive performance is below average at baseline, or when n-3 PUFA status falls below a certain level (low or inadequate) [38]. Baseline or inadequate O3I levels has also been investigated in elderly cohorts, with O3I cut-off values suggested to define targets for future dementia trials. A study in dementia-free adults (70 years and over) reported an optimal cut-off of 5.3% for predicting notable cognitive decline and/or polyunsaturated fatty acid supplementation treatment response [48]. This cut-off is close to that for the lowest O3I tertile group in the current study (< 5.47%).
Several mechanisms of action have been proposed to explain the relationship between n-3 PUFA and cognitive function. First, PUFAs are known to facilitate effects on gene expression, especially in the central nervous system [1, 50-52]. One genetic factor that is attracting increasing attention is the Apolipo- protein E (APOE) genotype, which has been linked to Alzheimer's disease. There is some evidence that this gene variant is also linked to cognitive performance in healthy young adults, but at present studies are conflicting and there is no consensus in the literature [49, 53, 54]. Secondly, it is known that n-3 PUFA has an important role in maintaining membrane integrity and fluidity, and neuronal functioning has been shown to be influenced by n-3 PUFA through a decrease in inflammatory pathways [1, 55, 56]. In support of the published reports, [57] C-reactive protein, an indicator of low-grade sustained inflammation, was lowest in women with the higher O3I in the present study, supporting a possible role of inflammation in determination of the attention domain of cognitive function.
Effects have also been found on dopaminergic neurotransmission, in particular, the mesocortical pathway has been implicated in attention, memory and executive function [56, 58, 59]. If these dopaminergic systems are altered via low n-3 PUFA, deficiency in this nutrient may contribute to reduced cognitive function. A recent study in diabetic rodents showed that administration of low doses of n-3 PUFAs could protect against neuronal damage in the hippocampus in type 2 diabetes and was associated with improved cognitive-behavioral performance and reduced inflammatory markers [55]. Furthermore, animal studies have reported evidence that n-3 PUFA (more specifically DHA) accumulates in areas of the brain involved in attention and memory, including the cerebral cortex and hippocampus [60, 61]. This observation is of interest, given that the current study found evidence of reduced cognitive function in the attention domain with lower O3I, albeit with no evidence of an effect on memory. There is limited information on the impact of short-term versus chronic inadequacy of n-3 PUFA or low O3I on cognition. However, in maternal and infant studies, there is evidence that there are crucial periods for adequate n-3 PUFA which may impact neurocognitive development [1, 3-5].
A major strength of this study is the recruitment of a large, healthy cohort, free of comorbidities. This study is one of the first to comprehensively exclude and/or adjust for a broad range of confounding variables when examining the influence of n-3 PUFA status on cognitive function in young women. Additionally, the use of erythrocyte n-3 PUFA (allowing for the calculation of the Omega-3 Index) provided an accurate and validated measure of longer-term n-3 PUFA status. Another major strength is the use of well-validated tools (IPAQ, Integ- Neuro™) to assess outcome measures.
A limitation of this study is that it is not possible to deduce causal effects due to the cross-sectional study design. Limitations more generally in the examination of the effect of n-3 PUFA on cognitive function include use of plasma or serum n-3 PUFA to classify status. The long-term measure of erythrocyte n-3 PUFA may be more precise but is less accessible. A major limitation in the literature, particularly in the studies conducted in young adults, is that confounder adjustment for factors that may potentially influence cognition, including inflammation, obesity and physical activity, is rarely conducted. Previous systematic reviews assessing the effect of n-3 PUFA supplementation on cognitive function have also cited large heterogeneity in supplement interventions (the type of supplement, EPA/DHA content, duration of intervention, etc.) and variability in cognition assessment, as major limitations in this field [3, 10, 42]. There is also currently no consensus regarding the classification of cognitive tests and domains [16] and this lack may explain some of the discrepancies in results between studies.

Conclusions

This study found reduced cognitive performance in the attention domain in young women with lower overall n- 3 PUFA, although cognition scores were still within the normal range. Thus, the clinical significance of these findings warrants further investigation. Cognition testing pre- and post-intervention to rectify low n-3 PUFA status and assessment of genetic factors (particularly APOE4 and dopamine receptor genes) may help to further identify the relationship and mechanisms of action between n-3 PUFA status and cognitive performance.

Abbreviations

ANCOVA: Analysis of covariance;
ANOVA: Analysis of variance;
APOE: Apolipoprotein E;
BMI: Body mass index;
CRP: C-reactive protein;
DHA: Docosahexaenoic acid;
EPA: Eicosapentaenoic acid;
ES: Effect size;
Hb: Hemoglobin;
IPAQ: International Physical Activity Questionnaire;
MET: Metabolic equivalent of the task;
n-3 PUFA: Omega-3 polyunsaturated fatty acid;
NATA: National Association of Testing Authorities;
NW: Normal weight;
O3I: Omega-3 Index;
OB: Obese;
PA: Physical activity;
PUFA: Polyunsaturated fatty acid;
SD: Standard deviation;
SDT: Suggested dietary target;
SE: Standard error;
SF: Serum ferritin;
a1GP: Alpha1-acid glycoprotein

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