Omega-3 fatty acid supplementation and cognitive function: are smaller dosages more beneficial?

Figures & data

Table 1 Methodological, sample, and intervention characteristics of studies included in meta-analysis

Study characteristics				Sample characteristics	Intervention characteristics					Study quality
Reference	a. Setting b. Sample recruited from	Sample size a. Total b. Intervention c. Control	Study design	a. Ratio of women to men b. Mean age ± SD (if not age range)	Description of intervention	Description of control	Measure/s of cognitive function	Duration of: a. Intervention b. Follow-up/s	Daily dose	a. Blinding (yes/no) b. Randomization (yes/no) c. Treatment concealment (yes/no) d. % loss to follow-up
Hamazaki et al^Citation11	a. Two universities, Japan b. Second and fourth year university students (healthy student volunteers)	a. 53 b. 22# c. 19#	RCT Parallel design, two groups Double-blind	a. 34 F: 19 M b. 21–30	Intervention group asked to take 10–12 capsules of DHA for 3 months	Control group asked to take 10–12 capsules of control oil for 3 months	Stroop test: to measure accuracy and speed of instantaneous judgement Dementia-detecting test revised to assess higher function of brain	a. 3 months b. 3 months	1.5–1.8 g DHA	a. Yes (double-blind) b. Yes c. Yes d. NC
Fenton et al^Citation17	a. Not reported b. Outpatients aged 18–65 who met DSM-IV criteria for schizophrenia/schizoaffective disorder	a. 87 b. 43 c. 44	RCT Parallel design, two groups Double-blind	a. 34 F: 53 M b. 40 ±10	Six 500 mg capsules of ethyl EPA (3 g)	Six capsules of mineral oil	Cognitive function measured by the RBANS	a. 16 weeks b. Follow-ups at several time points (data for week-16 used here)	3 g EPA	a. Yes b. Yes c. Yes d. 13.8%
de Groot et al^Citation22	a. Regions in the Netherlands b. Pregnant women attending midwives and obstetrics and Gynaecology departments in hospitals	a. 56 b. 30 c. 26	RCT Parallel design, two groups Double-blind	a. All female b. 29.45	Intervention group consumed 25 g per day of special margarine containing 2.82 g ALA + 9.02 g LA per day	Control group consumed 25 g per day of margarine containing 0.03 g ALA and 10.94 g LA per day	Cognitive function measured by several scales; only the WLTtot is reported here	a. Not clear b. Follow-ups at several time points, Data at baseline and at week-36 used here	2.82 g ALA	a. Yes b. Yes c. NR d. NC
Freund-Levi et al^Citation19	a. Stockholm, Sweden b. AD patients attending specialist memory clinics with MMSE scores of 15–30	a. 204 b. 103 c. 101 (NB: 174 completed study; 91 for intervention, 87 for control)	RCT Parallel design, two groups for first 6 months then open treatment (cross-over) for another 6 months Double-blind	a. 110 F: 94 M b. 74±9	Intervention group received 4×1 g capsules containing 430 g DHA+ 150 g EPA per day for 6 months	Control group received 4×1 g of placebo (containing 1 g of corn oil + 0.6 g of linolenic acid) per day for 6 months	Cognitive function measured by MMSE and ADAS-cog and global function by CDR	a. 6 and 12 months (6 months used due to crossover) b. 6 months used	430 mg DHA + 150 mg EPA (total n-3 LC-PUFA 580 mg)	a. Yes b. Yes c. Yes d. 12.75% in 6 months 14.7% in 12 months
Johnson et al^Citation13	a. Boston, MA USA b. General/healthy population (healthy nonsmoking women)	a. 57 b. 14* c. 10*	RCT Parallel design, four groups (only two, DHA/placebo compared) Double-blind	a. All female b. 68	Subjects consumed capsules of DHA supplements with a given nutritional drink	Controls consumed placebo capsules identical to intervention (content not clearly described)	Verbal fluency determined by number of items named from a category within a minute; Stroop test used to determine processing speed	a. 4 months b. 4 months	DHA 800 mg	a. Yes b. Yes c. Yes d. 14%
Chiu et al^Citation20	a. Taipei City hospital, Taiwan. b. AD and MCI patients as defined by MMSE 10–26 and CDR score of 1 or 2	a. 46 b. 24 c. 22	RCT Parallel design, two groups Double-blind	a. 20 F: 15 M b. 75.25	Six capsules containing 1080 mg EPA + 720 mg DHA per day	Six capsules containing olive oil esters per day	Cognitive function assessed using ADAS-cog and CIBIC-plus	a. 24 weeks b. Follow-ups at several time points baseline and week-24 data used	1,080 mg EPA + 720 mg DHA (total n-3 PUFA 1,800 mg)	a. Yes b. Yes c. Yes d. 24% (31% in placebo and 23% in intervention)
Rogers et al^Citation21	a. Bristol, UK b. Mild to moderately depressed adults (determined using screening questionnaires) recruited mainly from general practice surgeries	a. 218 b. 109 c. 109 (NB: 190 completed the study)	RCT Parallel design, two groups Double-blind	a. 168 F: 50 M b. 38.1	Three capsules containing 630 mg EPA + 850 mg DHA per day	Three capsules containing 2360 mg olive oil per day	Cognitive function measured by several tasks. Scores for the simple reaction time is used in this review	a. 12 weeks b. Follow-ups at weeks 4 and 12 (12-week data used here)	1.5 g of n-3 PUFA (630 mg EPA + 850 mg DHA)	a. Yes b. Yes c. Yes e. 28 of 218 (12.8%)
van de Rest et al^Citation12	a. Wageningen University, the Netherlands b. Database of volunteers aged >65 years (healthy elderly)	a. 302 (202 relevant for this study) b. 96 c. 106	RCT Parallel design, three groups (two groups compared in this study) Double-blind	a. 135 F: 167 M b. 70	High dose group (six daily capsules containing a total of 1800 mg EPA-DHA)	Placebo group (six capsules containing oleic acid)	Cognitive function determined using five different instruments. Results for the WLT (immediate recall-75 words) are used here	a. 26 weeks b. Follow-ups at weeks 13 and 26 (26-week data used here)	1,800 mg of EPA-DHA	a. Yes b. Yes c. Yes d. 9 of 302 (3%)
Antypa et al^Citation14	a. The Netherlands (specific place not reported) b. Healthy volunteers with BMI 18–27	a. 54 b. 27 c. 27	RCT Parallel design, two groups Double-blind	a. 44 F: 10 M b. 22	Three capsules containing 3 g of fish oil per day	Three capsules containing olive oil	Cognitive function assessed using 15-word memory test	a. 4 weeks b. 4 weeks	3 g of fish oil (2.3 of n-3 PUFA (1.74 g EPA+0.25 g DHA). Total n-3 PUFA 1.99 g	a. Yes b. Yes c. Yes d. 2 of 56 (3.6%)
Yurko-Mauro et al^Citation15	a. 19 clinical sites, USA b. Healthy subjects with ARCD with MMSE >26	a. 485 b. 242 c. 243	RCT Parallel design, two groups Double-blind	a. 116 F: 84 M b. 70	Three capsules containing a total of 900 mg/day of DHA	Three capsules containing 50% corn oil + 50% soy oil per day	Cognitive function determined by 24 week Cantab^® PAL (number of Cantab pattern errors)	a. 24 weeks b. 24 weeks	900 g of DHA	a. Yes b. Yes c. Yes d. 10% (9.5% in DHA; 10.3% in placebo)
Quinn et al^Citation18	a. 51 clinical research sites, USA b. Volunteers with probable Alzheimer’s disease (MMSE 14–26)	a. 402 b. 238 c. 164 Completers a. 295 b. 171 c. 124	RCT Parallel design, two groups Double-blind	a. 210 F: 192 M b. 76	Two capsules containing 2 g of DHA per day	Two capsules containing corn or soy oil per day	Change in cognitive function assessed using ADAS-cog	a. 18 months b. Follow ups at 6, 12, and 18 months (18 months data used)	2 g of DHA	a. Yes b. Yes c. Yes d. 107 of 402 (27%)
Dangour et al^Citation16	a. England and Wales b. Healthy adults from 20 general practices	a. 867 b. 434 c. 433	RCT Parallel design, two groups Double-blind	a. 390 F: 477 M b. 75	Two capsules containing 700 mg n-3 PUFAs (200 mg EPA + 500 mg DHA) per day	Two capsules containing olive oil per day	Cognitive function measured by CVLT	a. 24 months b. 24 months	700 mg n-3 PUFAs (200 mg EPA + 500 mg DHA)	a. Yes b. Yes c. Yes d. 14%

Notes:

* Sample sizes for groups used in meta-analysis;

# sample size reported for completers; ^†groups compared in meta-analysis.

Abbreviations: ARCD, age-related cognitive decline; BMI, body mass index; F, female; M, male; NC, not clear; CDR, Clinical Dementia Rating score; AD, Alzheimer’s disease; MCI, mild/moderate cognitive impairment; WLT, Word Learning Test; WLTtot, total Words Learning Test; SD, standard deviation; RCT, randomized controlled trial; MMSE, Mini-Mental State Examination; NR, not reported; NC, not clear from the data; ALA, alpha linolenic acid; LA, linolenic acid; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; PUFA, polyunsaturated fatty acids; CIBIC-plus, Clinician Interview-Based Impression of Change, plus carer interview; ADAS-cog, Alzheimer’s Disease Assessment Scale-Cognitive Subscale; CVLT, California Verbal Learning Test; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders Fourth Edition; PAL, paired associate learning; RBANS, Repeatable Battery for the Assessment of Neuropsychological Status.

Table 2 Data analysis strategy, measures of cognitive function, and results from included studies

Study reference	Analysis strategy (ITT/PP)	Measures of cognitive function used in current study	Indicator of cognitive improvement (↑↓)	Outcome of interest (intervention group)	Outcome of interest (control group)
Hamazaki et al^Citation11	PP	Stroop test (100%)	↑ (+)	BL, 50.8±11.4 Final, 57.4±15.2	BL, 51.1±12.7 Final, 59.3±14.6
		Dementia-detecting test (DDT) (100%)	↓ (−)	BL, 46.6±8.0 Final, 55.5±9.1	BL, 49.1±9.9 Final, 57.9±8.7
Fenton et al^Citation17	ITT	RBANS	↑ (+)	BL, 75±15 Final, 76±18	BL, 77±40 Final, 74±14
de Groot et al^Citation22	NC	(WLTtot)	↑ (+)	BL, 9.9±1.3 Final, 10.9±1.5	BL, 10.5±1.8 Final, 11.4±1.4
Freund-Levi et al^Citation19	ITT/PP but results reported in PP	MMSE (0–30 points)	↑ (+)	BL, 23.6 (22.8–24.4) Final, 22.8 (21.9–23.7)	BL, 23.2 (22.4–24.0)
		ADAS-cog (0–85 points)	↓ (−)	BL, 25.7 (23.6–27.8) Final, 27.7 (25.4–30.0)	BL, 27.2 (25.1–29.4) Final, 28.3 (26.0–30.6)
		CDR global score (0–3 points)	↓ (−)	BL, 1.0 (0.9–1.1) Final, 1.1 (1.0–1.2)	BL, 1.1 (1.0–1.2) Final, 1.1 (1.0–1.3)
Johnson et al^Citation13	PP	Verbal fluency	↑ (+)	BL, 15.0±4.9 Final, 17.8±3.1*	BL, 12.9±6.2 Final, 13.8±3.5
		Stroop test (total RT-interference)	↑ (+)	BL, 21.5±10.0 Final, 19.7±8.3	BL, 25.0±14.8 Final, 23.1±22.0
Chiu et al^Citation20	ITT/PP	ADAS-cog	↓ (−)	BL, 9.17±7.19 Final, 5.90±5.63	BL, 7.99±7.13* Final, 5.57±4.76
		MMSE	↑ (+)	BL, 25.06±3.99 Final, 25.47±3.81	BL, 25.27±3.34 Final, 25.09±3.67
Rogers et al^Citation21	ITT/PP PP used for cognitive function tests	Cognitive function measured using various tasks. Scores for simple reaction time is used	↓ (−)	BL, 370±75 Final, 391±85	BL, 381±56 Final, 398±71
van de Rest et al^Citation12	ITT	WLT (immediate recall-75 words)	↑ (+)	BL, 39.3±8.8 Final, 44.9±9.9	BL, 39.6±9.7 Final, 44.8±9.4
Antypa et al^Citation14	PP	15-word list memory test: Delayed recall	↑ (+)	BL, 9.55±2.48 Final, 9.36±3.24	BL, 9.04±2.54 Final, 9.92±3.22
		Immediate recall	↑ (+)	BL, 11.04±2.66 Final,11.0±2.83	BL, 10.72±2.56 Final, 11.04±2.61
Yurko-Mauro et al^Citation15	ITT	Cantab^® PAL	↓ (−)	BL, 13.4±11.6 Final, 8.8±9.9	BL, 12.1±10.9 Final, 9.7±10.7
		MMSE	↑ (+)	BL, 28.3±1.3 Final, 28.0±1.9	BL, 28.2±1.3 Final, 27.9±1.9
Quinn et al^Citation18	ITT	ADAS-cog	↓ (−)	Mean change (95% CI)	Mean change (95% CI)
	PP used in secondary analysis	CDR, sum of boxes	↓ (−)	7.98 (6.51–9.45) 2.87 (2.44–3.30)	8.27 (6.72–9.82) 2.93 (2.44–3.42)
		MMSE	↑ (+)	−3.70 (–4.44, –2.96);	−4.04 (−4.85, −3.23)
Dangour et al^Citation16	ITT	CVLT-total words recalled	↑ (+)	BL, 24.1±6.0 Final, 24.1±6.7	BL, 23.9±5.7 Final, 24.4±6.4
		Immediate story recall	↑ (+)	BL, 11.1±3.9 Final, 11.0±4.3	BL, 10.7±3.9 Final, 10.9±3.9
		Delayed story recall	↑ (+)	BL, 8.9±3.8 Final, 9.3±4.2	BL, 8.8±3.7 Final, 9.1±3.8
		Verbal fluency	↑ (+)	BL, 19.8±5.1 Final, 19.1±5.4	BL, 19.9±5.0 Final, 19.5±5.3

Notes: ⁻This study used a cross-over design, thus results for first 6 months are compared;

* P<0.05. The upward arrows and (+) indicate cognitive improvement in cognitive outcome in intervention group compared to the control group. Similarly, downward arrow and (−) indicate decline in cognitive outcome in intervention group compared to control group.

Abbreviations: BL, baseline; CVLT, California Verbal Learning Test; ITT, intention-to-treat analysis; NC, not clear from data; PP, per protocol analysis; CDR, Clinical Dementia Rating score; WLT, Word Learning Test; WLTtot, total Words Learning Test; MMSE, Mini-Mental State Examination: ADAS-cog, Alzheimer’s Disease Assessment Scale-Cognitive Subscale; RBANS, Repeatable Battery for the Assessment of Neuropsychological Status; CI, confidence interval; PAL, paired associate learning; RT, total interference from Stroop test for speed and accuracy of processing.

Figure 1 Search results and number of studies included at various stages.

Figure 2 Forest plot for omega-3 fatty acid supplementation and cognitive decline.

Abbreviations: ADAS-cog, Alzheimer’s Disease Assessment Scale-Cognitive Subscale; CI, confidence interval; CVLT, California Verbal Learning Test; DDT, dementia detecting test; WLTtot, total Words Learning Test; 15-WLMT, Word List (memory) Test; RBANS, Repeatable Battery for the Assessment of Neuropsychological Status; MMSE, Mini-Mental State Examination; WLT, Word Learning Test; PAL, paired associate learning; CDR, Clinical Dementia Rating; SMD, standardized mean difference; SRT, simple reaction time.

Figure 3 Forest plot of omega-3 fatty acid for low and high dose compared with no supplementation (control).

Abbreviations: ADAS-cog, Alzheimer’s Disease Assessment Scale-Cognitive Subscale; CVLT, California Verbal Learning Test; DDT, dementia detecting test; WLTtot, total Words Learning Test; 15-WLMT, Word List (memory) Test; RBANS, Repeatable Battery for the Assessment of Neuropsychological Status; MMSE, Mini-Mental State Examination; WLT, Word Learning Test; PAL, paired associate learning; CDR, Clinical Dementia Rating; SMD, standardized mean difference; SRT, simple reaction time; CI, confidence interval.

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