Abstract
Background
Observational epidemiological data suggest that habitual consumption in later life of oily fish, rich in n-3 long-chain polyunsaturated fatty acids (n-3 LCPs), is associated with better cognitive function, slower rates of cognitive decline and a lower risk of dementia. In this paper we present data on baseline fish consumption and cognitive function in cognitively healthy older people randomised onto the Older People And n-3 Long-chain polyunsaturated fatty acid (OPAL) study.
Methods
In total, 867 older people were recruited to join the OPAL study from 20 general practices in England and Wales. Participants were aged 70–79 years at baseline were free of dementia and diabetes, had a Mini-Mental State Examination score of 24 or greater and did not report daily fish oil supplement consumption. Self-reported habitual fish consumption was assessed at baseline via questions on frequency and type of fish consumption. Cognitive function at baseline was assessed via validated cognitive tests assessing memory, executive function, psychomotor speed and attention, including the Californian Verbal Learning Test (CVLT), the primary outcome of the OPAL study. Reported age at leaving full time education was recorded as a measure of educational achievement and psychological health was measured using the GHQ-30 questionnaire.
Results
Unadjusted analysis revealed significant positive associations between reported fish consumption and the CVLT scores with a mean increase of approximately 0.24 words remembered for each increase in level of reported fish consumption. These associations were noticeably attenuated on adjustment for age, gender and reported age at leaving full-time education and did not remain significant on further adjustment for GHQ-30 score. Similar associations were also observed between fish consumption and the global cognitive z-score, memory score, executive function score and delay scores in unadjusted analysis with the associations again attenuated on adjustment.
Conclusions
Baseline data from participants randomised into the OPAL study provide support for the hypothesis that higher fish consumption is associated with better cognitive function in later life. However, although in the main associations remain after adjusting for education and psychological health, the data do not allow us to rule out the possibility of residual confounding e.g. from socioeconomic status or other health behaviours. Evidence is needed from randomised clinical trials to clarify the role of n-3 LCPs in cognitive health in later life in the normal older person population.
Key words: Dementia, Fish Consumption, Oily Fish, Californian Verbal Learn Test, Good Cognitive Function
Introduction
Cognitive impairment in later life is a recognised risk factor for the development of dementia (1). Currently available pharmacological treatments for dementia are only modestly effective and very expensive (2), and there is considerable interest in lifestyle and dietary interventions for the primary prevention of dementia. Recent reviews of epidemiological data have identified n-3 long-chain polyunsaturated fatty acids (n-3 LCPs – most commonly found in oily fish) as potentially important candidate nutrients for the prevention of cognitive decline (3) and Alzheimer’s disease (4), although data from randomised controlled trials (RCTs) among healthy adults are extremely limited (5).
Strong mechanistic data support the roles of two of the most important n-3 LCPs, namely eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), for vascular and neuronal health respectively (6). The high levels of DHA found in the brain (7) and the recently discovered functions of docosanoids, metabolic products of DHA, in neuronal protection (8) suggest an important role for n-3 LCPs in cognitive health.
Epidemiological observational studies reporting associations of fish or n-3 LCP consumption with cognitive function have shown mixed results; some studies have reported a positive association with higher fish consumption (9, 10, 11, 12, 13, 14, 15), while others have found no association (16, 17). Studies evaluating the associations of serum levels of n-3 LCP with cognitive function have tended to report a positive association with high blood n-3 LCP concentrations (18, 19, 20, 21), although again there is some disagreement (22). To date, one RCT has been published to investigate the effect of n-3 LCP supplementation on cognitive function among healthy older people (23). This 6 month intervention study randomised 302 adults aged 65 years and over to either a low dose supplement (400mg n-3 LCP), a high dose supplement (1800mg n-3 LCP) or a placebo, and did not detect an effect of n-3 LCP supplementation on cognitive function.
The current paper reports information on baseline fish consumption and cognitive function in cognitively healthy older people randomised onto the Older People And n-3 Long-chain polyunsaturated fatty acid (OPAL) study. The OPAL study is a UK-based RCT providing 700mg n-3 LCPs or placebo daily to older people for 24 months (24).
Methods
The OPAL study is designed to test the hypothesis that daily supplementation with 700mg n-3 LCP (500mg DHA and 200mg EPA) will slow the rate of cognitive decline in cognitively healthy individuals aged 70-79 years at baseline (ISRCTN72331636). Ethical approval for the trial was provided by the NHS multi-centre research ethics committee and the LSHTM ethics committee.
Study sample
All adults aged 70-79 years registered at twenty general practices in England and Wales were screened for physician-diagnosed pre-existing dementia and/or diabetes and remaining individuals were invited to attend a baseline appointment at their local clinic. Potential participants reporting daily fish oil supplement consumption, and individuals scoring less than 24 out 30 in the Mini-Mental State Examination (MMSE) at the baseline appointment were excluded. On receipt of full informed written consent, eligible individuals were randomised onto the OPAL study. In total, 5166 potentially eligible individuals were invited to take part in the OPAL study and 867 were randomised onto the study.
Fish consumption
All study participants were asked two questions about their habitual fish consumption. The first question on consumption frequency asked: “How often do you eat fish?”, with the following response options: more than once a week, once a week, once a fortnight, once a month, rarely or never. Participants were then asked to list the three fish they most commonly consumed, and these were categorised into white (e.g. cod, haddock, plaice) or oily (e.g. salmon, mackerel, trout) fish according to UK Food Standard Agency guidelines (25).
For the purpose of the current paper, these data were used to construct a fish consumption variable that took into account both frequency and type of fish consumption. Five distinct categories were constructed: 1. reported fish consumption once a month or less; 2. reported fish consumption once a week or once a fortnight and two out of the three most commonly consumed fish were white; 3. reported fish consumption more than once a week and two out of the three most commonly consumed fish were white; 4. reported fish consumption once a week or once a fortnight and two out of the three most commonly consumed fish were oily; 5. reported fish consumption more than once a week and two out of the three most commonly consumed fish were oily.
Cognitive function
A standardised battery of cognitive tests was administered to all study participants at the baseline appointment which consisted of the following tests: Californian Verbal Learning Test (CVLT); subjective memory assessment; three tests of prospective memory; story recall (immediate and delayed); verbal fluency; letter cancellation; location memory (immediate and delayed); symbol-letter substitution; digit span forwards and backwards; simple and choice reaction time (24).
The CVLT is the primary outcome of the OPAL study and the baseline data are analysed here on CVLT scores (sum of words recalled at three immediate recalls, and words recalled at long-delayed recall) by fish consumption category. To avoid multiple statistical testing, data on all secondary cognitive outcomes of the OPAL study are presented but not analysed. Cognitive outcomes were also transformed into z-scores, grouped into the following cognitive domains and standardised for further statistical analysis:
Global cognitive function = ZCVLT sum of words recalled + ZCVLT delayed recall + Zprospective memory-test1 + Zprospective memory-test2 + Zprospective memory-test3-item + Zprospective memory-test3-location + Zstory recall + Zstory recall-delayed + Zverbal fluency + Zletter cancellation + Zlocation memory + Zlocation memory-delayed + Zsymbol-letter substitution + Zdigit span forwards + Zdigit span backwards + Zsimple reaction time + Zchoice reaction time)/17
Memory = (ZCVLT sum of words recalled + ZCVLT delayed recall + Zlocation memory + Zlocation memory-delayed +Zstory recall + Zstory recall-delayed) /16
Processing speed = (Zlgetter cancellation + Zsimple reaction time + Zchoice reaction time + Zsymbol-letter substitution)/4
Executive function = (Zdigit span backwards + Zverbal fluency)/2
Global delay score = ZCVLT delayed recall + Zlocation memory delayed recall + Zstory recall delayed)/3
Covariates
At the baseline interview, data collected by study nurses included information on age, sex and age at leaving full-time education. Weight (kg) and height (m) were measured to enable the calculation of body mass index (BMI kg/m2). Participants completed the 30-item General Health Questionnaire (GHQ-30) as a measure of psychological health (26).
Statistical analysis
To avoid loss of information, the z-scores were created by summing all available answers and then by weighting the total by the number of questions answered. For tests in which lower scores represented better performance, reciprocals of test results were used. Regression analysis was carried out to examine the association between fish consumption and the pre-specified cognitive outcomes. In all analyses, the five-level fish consumption variable was treated as a continuous measure; this approach was supported by examination of the mean cognitive scores in each category and statistical tests for linear trend. We report unadjusted coefficients with 95% confidence intervals and the results from two adjusted analyses. The first analysis was adjusted for age, sex and age at leaving full-time education, and the second adjusted further for GHQ-30 score; this two-stage approach was used to guard against the remote possibility that mood might confound the association between fish consumption and cognitive function.
Results
Fish consumption among OPAL study participants was moderate. Only 8% of participants reported eating fish less than once a month or never, while 46.5% of participants reported consumption of fish on two or more occasions a week. Oily fish consumption was less common than white fish consumption. Examination of the data suggests that individuals reporting frequent oily fish consumption were more likely to be female, were a little younger, and had a slightly higher age at leaving full-time education than individuals in other fish consumption categories (Table 1).
Table 1.
Descriptive information on OPAL sample at baseline by fish consumption category
| Fish consumption category | |||||
|---|---|---|---|---|---|
| Once a month or less | Once a week/fortnight, mainly white | More than once a week, mainly white | Once a week/fortnight, mainly oily | More than once a week, mainly oily | |
| n | 71 | 290 | 258 | 101 | 144 |
| Sex; n(%) | |||||
| Male (n=474) | 36 (7.6) | 176 (37.1) | 143 (30.2) | 53 (11.2) | 66 (13.9) |
| Female (n=390) | 35 (9.0) | 114 (29.2) | 115 (29.5) | 48 (12.3) | 78 (36.9) |
| Age (years) | |||||
| Mean (sd) | 74.7 (2.7) | 75.1 (2.5) | 74.6 (2.7) | 74.6 (2.8) | 74.0 (2.6) |
| Education status (years) | |||||
| Age at leaving full-time education: | |||||
| Mean (sd) | 16.1 (2.9) | 15.9 (2.5) | 15.9 (2.6) | 16.5 (3.2) | 16.7 (3.1) |
| Body Mass Index (kg/m2) | |||||
| Mean (sd) | 27.6 (4.7) | 27.7 (4.6) | 27.4 (4.4) | 26.9 (3.7) | 27.1 (3.9) |
| Male; Mean (sd) | 27.5 (4.5) | 27.4(4.1) | 27.6 (3.7) | 26.7 (3.1) | 26.6 (3.3) |
| Female; Mean (sd) | 27.8 (5.0) | 28.2 (5.3) | 27.2 (5.1) | 27.2 (4.3) | 27.6 (4.3) |
| GHQ-30; n(%) | |||||
| Depression (GHQ > 5) | 24 (33.8) | 53 (18.3) | 41 (15.9) | 17 (16.8) | 24 (16.7) |
| Male | 9 (25.0) | 26 (14.8) | 19 (13.3) | 8 (15.1) | 8 (12.1) |
| Female |
15 (42.9) |
27 (23.7) |
22 (19.1) |
9 (18.8) |
16 (20.5) |
Individuals reporting regular consumption of oily fish performed consistently better on most cognitive function tests than individuals in other fish consumption categories (Table 2). For the CVLT (the OPAL study primary outcome), and for all of the constructed z-scores, there appeared to be a steady increase in cognitive scores across fish consumption categories, with lowest scores in individuals reporting infrequent fish consumption, intermediate scores in individuals reporting occasional or frequent white fish consumption, and highest scores in individuals reporting occasional or frequent oily fish consumption.
Table 2.
Primary and secondary cognitive function outcomes by fish consumption category
| Fish consumption category | |||||
|---|---|---|---|---|---|
| Once a month or less | Once a week/fortnight, mainly white | More than once a week, mainly white | Once a week/fortnight, mainly oily | More than once a week, mainly oily | |
| n | 71 | 290 | 258 | 101 | 144 |
| Primary outcomes | |||||
| CVLT1 : Words recalled at long-delayed recall, Mean (sd) | 6.6 (2.8) | 7.2 (2.9) | 7.5 (3.0) | 7.5 (2.6) | 7.8 (3.0) |
| CVLT2: Sum of words recalled (3 immediate trials), Mean (sd) | 22.8 (5.8) | 23.3 (6.1) | 23.9 (6.0) | 24.6 (5.2) | 25.2 (6.0) |
| z-scores | |||||
| Global cognitive function; Mean (sd) | -0.26 (1.03) | -0.12 (1.02) | 0.00 (0.96) | 0.09 (0.95) | 0.29 (0.99) |
| Memory; Mean (sd) | -0.23 (1.15) | -0.11 (1.02) | 0.05 (0.94) | 0.01 (0.90) | 0.23 (1.00) |
| Processing speed; Mean (sd) | -0.22 (1.09) | -0.06 (0.98) | -0.02 (1.01) | 0.10 (1.00) | 0.20 (0.95) |
| Executive function; Mean (sd) | -0.18 (0.85) | -0.07 (0.99) | -0.05 (1.01) | 0.13 (0.92) | 0.23 (1.09) |
| Global “delay”; Mean (sd) | -0.22 (1.16) | -0.11 (1.01) | 0.06 (0.94) | 0.03 (0.89) | 0.21 (1.03) |
| Secondary outcomes | |||||
| Subjective assessment of memory; n. (%) | |||||
| No problems | 20 (28) | 82 (28) | 49 (19) | 15 (15) | 35 (24) |
| Occasional | 40 (56) | 146 (51) | 169 (66) | 70 (69) | 83 (58) |
| Often | 8 (11) | 48 (17) | 34 (13) | 14 (14) | 22 (15) |
| Very often | 3 (4) | 13 (5) | 5 (2) | 2 (2) | 4 (3) |
| Prospective memory; Mean (sd) | |||||
| Test 1 | 2.1 (1.0) | 2.0 (1.2) | 2.2 (1.1) | 2.1 (1.1) | 2.3 (1.0) |
| Test 2 | 2.0 (1.2) | 1.9 (1.2) | 1.9 (1.3) | 2.1 (1.1) | 2.2 (1.1) |
| Test 3 item | 2.4 (0.9) | 2.3 (1.0) | 2.3 (1.0) | 2.5 (0.8) | 2.4 (0.9) |
| Test 3 location | 2.3 (1.0) | 2.4 (1.0) | 2.4 (1.0) | 2.4 (0.9) | 2.5 (0.9) |
| Story recall; Mean (sd) | |||||
| Immediate | 10.3 (4.0) | 10.3 (3.9) | 10.7 (3.9) | 11.2 (3.6) | 11.5 (4.0) |
| Delayed | 8.4 (4.2) | 8.3 (3.8) | 8.7 (3.7) | 9.3 (3.5) | 9.5 (3.9) |
| Verbal fluency; Mean (sd) | 18.7 (4.7) | 19.6 (5.3) | 19.6 (5.1) | 20.2 (4.6) | 20.0 (5.4) |
| Visual search task; Mean (sd) | 74.8 (15.2) | 78.2 (12.8) | 80.0 (12.4) | 78.0 (14.2) | 79.3 (12.5) |
| Location memory; Mean (sd) | |||||
| Immediate | 4.8 (2.6) | 5.2 (2.5) | 5.5 (2.5) | 4.7 (2.5) | 5.5 (2.4) |
| Delayed | 4.1 (2.6) | 4.4 (2.5) | 4.8 (2.5) | 4.1 (2.5) | 4.9 (2.4) |
| Symbol-letter substitution; Mean (sd) | 41.1 (10.3) | 42.4 (9.8) | 42.9 (9.9) | 44.7 (9.8) | 45.3 (9.8) |
| Digit span; Mean (sd) | |||||
| Forwards | 7.4 (2.0) | 8.1 (2.4) | 8.0 (2.4) | 8.3 (2.3) | 8.6 (2.4) |
| Backwards | 6.3 (1.8) | 6.3 (2.0) | 6.3 (2.0) | 6.6 (2.2) | 7.0 (2.3) |
| Reaction time; Mean (sd) | |||||
| Simple | 0.30 (0.09) | 0.31 (0.20) | 0.31 (0.19) | 0.29 (0.11) | 0.29 (0.09) |
| Choice |
0.71 (0.11) |
0.75 (0.58) |
0.77 (0.69) |
0.69 (0.10) |
0.67 (0.09) |
Crude regression coefficients suggest a statistically significant relationship between fish consumption and cognitive function based on CVLT (Table 3). Adjustment for age, sex and age at leaving full-time education considerably reduced the strength of the associations, which were further attenuated when also adjusted for GHQ-30 score. The adjusted regression coefficients from the final model (Table 4) demonstrate that in this sample, younger age, female sex, greater age at leaving full-time education and lower GHQ-30 score were each associated with better cognitive function.
Table 3.
Regression analyses of fish consumption categories (treated as a continuous variable) with cognitive function outcomes (trial primary outcomes and z-scores)
| Unadjusted Coef (95% CI) | p-value | Adjusteda Coef (95% CI) | p-value | Adjustedb Coef (95% CI) | p-value | |
|---|---|---|---|---|---|---|
| Primary outcomes | ||||||
| CVLT1 : Words recalled at long-delayed recall | 0.24 (0.08,0.40) | 0.004 | 0.13 (-0.03,0.28) | 0.112 | 0.10 (-0.05,0.26) | 0.188 |
| CVLT2: Sum of words recalled (3 immediate trials) | 0.61 (0.28,0.94) | 0.000 | 0.34 (0.02,0.65) | 0.035 | 0.29 (-0.02,0.60) | 0.068 |
| z-scores | ||||||
| Global cognitive function | 0.13 (0.08,0.19) | 0.000 | 0.09 (0.03,0.14) | 0.001 | 0.07 (0.02,0.12) | 0.006 |
| Memory | 0.10 (0.05,0.16) | 0.000 | 0.06 (0.01,0.11) | 0.030 | 0.05 (-0.01,0.11) | 0.078 |
| Processing speed | 0.09 (0.04,0.15) | 0.001 | 0.06 (0.00,0.11) | 0.034 | 0.04 (-0.01,0.10) | 0.100 |
| Executive function | 0.10 (0.04,0.15) | 0.001 | 0.07 (0.01,0.12) | 0.015 | 0.06 (0.01,0.11) | 0.027 |
| Global “delay” |
0.10 (0.04,0.15) |
0.001 |
0.06 (0.00,0.11) |
0.034 |
0.05 (-0.01,0.10) |
0.084 |
a. adjusted for age, sex and age left education; b. adjusted for age, sex, age left education and GHQ-30 score
Table 4.
Adjusted regression coefficients (95% confidence intervals) of covariates included in fully adjusted model
| Age Coef (95% CI) | Sex Coef (95% CI) | Age left education Coef (95% CI) | GHQ-30 score Coef (95% CI) | |
|---|---|---|---|---|
| Primary outcomes | ||||
| CVLT1 : Words recalled at long-delayed recall | -0.11 (-0.18,-0.04) | 1.36 (0.98,1.73) | 0.18 (0.11,0.25) | -0.08 (-0.14,-0.03) |
| CVLT2: Sum of words recalled (3 immediate trials) | -0.25 (-0.40,-0.11) | 3.20 (2.45,3.96) | 0.46 (0.32,0.59) | -0.17 (-0.28,-0.07) |
| z-scores | ||||
| Global cognitive function | -0.06 (-0.08,-0.03) | 0.22 (0.09,0.34) | 0.11 (0.08,0.13) | -0.05 (-0.07,-0.03) |
| Memory | -0.04 (-0.06,-0.01) | 0.47 (0.34,0.60) | 0.09 (-0.01,0.10) | -0.04 (-0.06,-0.03) |
| Processing speed | -0.05 (-0.07,-0.02) | 0.08 (-0.05,0.21) | 0.09 (0.06,0.11) | -0.02 (-0.04,-0.00) |
| Executive function | -0.03 (-0.05,-0.01) | -0.01 (-0.14,0.12) | 0.11 (0.09,0.13) | -0.02 (-0.04,-0.00) |
| Global “delay” |
-0.03 (-0.06,-0.01) |
0.45 (0.32,0.58) |
0.08 (0.06,0.10) |
-0.04 (-0.06,-0.02) |
Discussion
The results reported here provide added support to the published epidemiological studies suggesting that high levels of fish consumption are associated with better cognitive function in later life. Of particular interest is the apparent linear trend for increased cognitive function across the five-item fish consumption variable, with highest cognitive function levels found in those individuals who report eating the largest amount of oily, as opposed to white, fish. This concords with the biological hypothesis that the potentially protective active ingredients are the n-3 LCPs, since oily fish contains considerably greater amounts of n-3 LCPs than white fish (approximately 2g and 0.3g n-3 LCP per 100g average fish respectively) (25). In the fully adjusted model, cognitive function also varied in the expected manner (27) with age, sex, age at leaving full-time education and GHQ-30 score.
The construction of z-scores permitted determination of the strength of the association by cognitive domain. Fish consumption remained associated with all cognitive domains when adjusted for age, sex and age at leaving full-time education, although the adjusted coefficients were smaller than the crude coefficients, suggesting that the positive association with higher fish consumption was at least in part confounded by the higher education levels of regular oily fish consumers. Once psychological state (as measured by GHQ-30) was also incorporated in the analyses, fish consumption only remained associated with global cognitive z-score and the executive function z-score. While psychological state is known to be associated with cognitive performance (28, 29), the possibility that psychological state confounds the relationship between fish consumption and cognitive function requires further investigation in prospective studies.
The analysis presented here highlights the importance of adequate statistical adjustment for potential confounders in studies investigating the relationships between fish consumption and cognitive function. A similar attenuation was found in the PAQUID study (9), which reported a statistically significant relationship (adjusted for age and sex) between fish consumption and protection against dementia in a 7-year follow-up of 1416 older French people, that became statistically non-significant once also adjusted for education level. The association between fish consumption and cognitive function, further adjusted for psychological state, has to the best of our knowledge, not previously been reported.
In general, reported fish consumption in the current sample is moderate. Fewer than 10% of participants were not regular fish eaters, more than 45% of study participants reported consuming fish on two or more occasions a week, white fish was consumed more commonly than oily fish, and women reported greater oily fish consumption than men. Data from the National Diet and Nutrition Survey (NDNS) a nationally representative sample of older people (65 years and older) assessed in the UK in 1994/5 (30), suggested that only 36% and 32% of adults reported the consumption of white and oily fish respectively, white fish consumption was more common than oily fish, and men were more common consumers of oily fish. Average consumption of fish (260g/week) in the NDNS sample equates to less than two portions (140g) per week, suggesting that reported fish consumption in the current study was higher than the national average, although unknown changes in consumption patterns since the collection of the NDNS data may be relevant. The current study has distinct strengths such as the large population-based sample size, the homogeneity of the sample (all cognitively normal aged 70-79 years), and the large battery of cognitive tests assessing the most important cognitive domains using a standardised protocol. However, some weaknesses are also present in the study design. First, this is analysis of cross-sectional data and thus it is not possible to ascribe causality; second, our exposure variable (reported fish consumption) may be subject to reporting bias with participants over-reporting consumption of a food item known to have possible health benefits; third, we have used reported fish consumption rather than a biological measure of n-3 LCP status; and finally, the possibility of residual confounding e.g. from socio-economic status and other health behaviours cannot be excluded.
In conclusion, we have demonstrated a positive association between reported fish consumption and cognitive function in a large sample of healthy older people in the UK. This finding supports previous mechanistic and epidemiological work which suggests that n-3 LCPs play a role in cognitive function in later life. However, the extent of any protective effect awaits the results of on-going RCTs.
Acknowledgement: The funding for the OPAL study has been provided by the United Kingdom Food Standards Agency (NO5053).
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