Table 8.

Summary of randomized, controlled trials of omega-3 fatty acids in cognitively healthy subjects

First Author Year, Ref #	Number subjects Age range Age, mean±SD, years Study length % Male	Intervention	COWAT	DSST	TMT A	TMT B	Rey Auditory Verbal Learning Test
							RAVLT1 Immediate Recall	RAVLT2 Short delay	RAVLT3 Delayed recall	RAVLT 4 Delayed recognition
			P values
Malik 67 2021 CAD subjects	N=250 30 months Mean age, yrs Placebo: 63.9 ±7.4 years EPA/DHA: 62.9±7.6 years 83.2% male	DHA 1.5 g EPA 1.86 g Placebo: none, open label	0.011	0.12	.015	0.043	0.38	0.44	0.33	0.18
Kulzow 68 2016 *	N=44 50-75 years Mean age: years EPA/DHA: 63±6 Placebo: 61±6 26 weeks Male: 45%	EPA: 1,320 mg DHA: 880 mg Both with Vit E: 15 mg Placebo: sunflower oil 406 mg	Words starting with S: 0.25 Fruits: 0.62			0.55	0.33		0.48	0.87
Howe 69 2018	N=38 40-85 years Mean age: years EPA:63.2±1.6 Placebo:64.1±2.3 20 weeks Male: 68% Mildly Hypertensive	EPA: 400mg DHA: 1,600 mg Placebo: corn oil			P=0.5 for the sum of TMT A and TMT B
van de Rest 70 2008	N=302 Age ≥ 65 years Mean age: years EPA/DHA: 1800 mg: 69.9±3.4 EPA/DHA: 400 mg: 69.5±3.2 Placebo:70.1±4 26 weeks Male: 55%	High dose: EPA: 1,093 mg DHA 847 mg Low dose: EPA:226 mg DHA: 174 mg Placebo: high – oleic sunflower oil	NS		NS	NS	NS		NS	NS
Dangour 71 2010 †	N=867 70-79 years Mean age: years Fish oil: 74.7±2.5 Placebo:74.6±3 24 months Male: 55%	EPA: 200 mg DHA: 500 mg Placebo: olive oil	NS	NS			0.14		0.46
Chew 72 2015 ‡	N=3501 50-85 years Mean age: years 72.7±7.7 5 years Male: 42.5%	EPA 650 mg DHA 350 mg vs AREDS formulation Vit C, E, beta carotene and zinc	Animals: 0.34 Letters starting with F, A and S: 0.78
Witte 73 2014 §	N=65 ages 50-75 years Mean age: years 63.9 ± 6.6 26 weeks Male: 53.9%	EPA 1,320 mg DHA 880 mg placebo: sunflower oil	0.009
Mazereeuw 74 2016 CAD subjects	N=92 Mean age: years 61.7 ± 8.7 12 weeks 76% male	DHA,1200 mg/d EPA,600 mg/d EPA:DHAratio,1:2 Other: LC-PUFAs,100 mg/d Placebo: soybean/corn oil	NS			NS	No benefit on CVLT which is similar to RAVLT
Geleijnse 75 2012 Post-MI patients	N=2911 40 months Mean age, yrs Men: 68.7+5.5 years Women: 70.3+5.6 years	1. EPA:DHA 400mg/d EPA:DHAratio,3:2 2.EPA/DHA,400 mg/d ALA, 2g/d EPA:DHAratio,3:2 Placebo: margarine	No change in MMSE
Konagai 76 2013	N=45 3 months Mean age, yrs 67.1+3.4 years 100% male	1.Krill oil: DHA, 92mg/d EPA, 193mg/d DHA:EPAratio,1:2 2.Sardine oil: DHA, 251mg/d EPA, 491mg/d Placebo: medium chain triglyceride	Both krill oil & sardine oil had better P 300 ‖ compared to placebo
Maltais 77 2022	N=193 6 months 20-80 yrs	EPA, 1.7 g DHA, 0.8 g Ethyl ester; Placebo: high oleic acid soybean/corn oil	No difference in cognitive performance but those with low episodic memory score improved scores P = 0.043 ApoE genotype was not effect modifier
Ichinose 78 2021	N=53 12 months Mean age, yrs 69.1±5.3 55% female	EPA, 137 mg DHA, 297 mg in 200 ml milk beverage Placebo: 200 ml milk beverage	MMSE and HSD-R scores higher P < 0.05 in DHA compared to placebo at 12 months but only mean difference in MMSE was higher P < 0.05
Kang 79 2022	N=4,218 2-3 years Mean age, yrs 70.9±5.8 58.1% female	EPA: 460 mg DHA: 380 mg	No difference in annual rate of cognitive change using a global score for 8 neuropsychological tests.
Kuhn 80 2022	N=57 12 weeks Mean age, yrs 72±7 74% female	Canned pilchards and fish spread – 2.2 g omega-3 daily Control: canned meatballs and texturized soya	Significantly higher cognitive abilities screening instrument (CASI) score in intervention (P < 0.05).
Danthiir 81 2018	N=390 18 months Mean age, yrs 73.1±5.4 53% female	DHA: 1720 mg EPA: 600 mg Placebo: 990 mg oleic acid	No difference except negative effect on psychomotor speed in men. Treatment interaction with sex. ApoE4 carriers improved on reasoning (P=0.02)

^*Kulzow et al.⁶⁸ employed LOCATO which examines visual spatial object location of buildings and the RAVLT. After adjustment for changes in diet, those on omega-3 fatty acids did better on the LOCATO (p=0.004). As noted above, the RAVLT was not significant.

^†California Verbal Learning Test (CVLT) was performed which is similar to Rey Auditory Verbal Learning Test (RAVLT).

^‡This is an ancillary study of the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. A composite score was computed to obtain an overall score for a battery of 8 cognitive function tests and was not significant. The composite score included the scores of the following: Telephone Interview Cognitive Status-Modified –TISC-M word list for immediate recall, Verbal fluency with animal category, Verbal fluency with letter category, Verbal fluency alternating between animal and letter categories, Wechsler logical memory I and Wechsler logical memory II which measured immediate and delayed recall of 2 stories, Digits backward and TICS-M delayed recall. All test results were converted into z scores which were then added.

^§Witte et al.⁷³ calculated a composite executive score which was significant at P = 0.023. The composite executive score was defined as the sum of phonemic fluency and semantic fluency minus TMT (part B – part A)/part A and minus STROOP (part 3 – (part 1 + part 2))/2]/4. Preservation of both the integrity of the microstructure of white mass and the volume of gray mass was observed with a dose of 1320 mg of EPA plus 880 mg of DHA per day for 26 weeks.

^‖P 300 measures working memory by measuring event–related potentials using an electroencephalograph.⁷⁵ P300 depicts central nervous system activity involved in the processing of new information when attention is engaged to update memory representation. P300 has two components: latency, which reflects cognitive processing speed, and amplitude, which measures attentional resources engaged in task completion. Latency is prolonged and amplitude is decreased with aging, a finding suggesting that P300 testing can evaluate cognitive function in healthy elderly adults.

Abbreviations: ARA indicates arachidonic acid; COWAT, Controlled Oral Word Association Test; DSST, Digit-Symbol Substitution tests; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; MMSE, Mini-Mental Status examination; RAVLT, Rey Auditory Verbal Learning Test; RAVLT 1, immediate recall as a sum of 4 trials; RAVLT 2, short delay recall; RAVLT 3, delayed recall; RAVLT 4, delayed recognition; TMT, Trail Making Test.