Table 2.
Clinical trials investigating the association between supplementary ω3 intake and cognitive function
| References | Study design | Year | Sample | Diagnostic approach | Dose and method of supplementation | Exposure period | Outcome Measures | Findings |
|---|---|---|---|---|---|---|---|---|
| [58] | Randomised double-blind placebo-controlled trial (OmegAD) | 2006 |
Mild to moderate AD patients n 174 Mean age: 74 |
Clinical diagnosis: DSM-IV, medical history, psychometric testing, blood analyses, MRI |
1700 mg/day DHA and 600 mg/day EPA as capsules Placebo: corn oil capsules |
12 months | MMSE, ADAS-cog | No statistically significant difference in cognition between groups. A subset with very mild cognitive decline showed a significant decrease in rate of cognitive decline |
| [59] | 2015 |
AD patients n 174 Mean age: 74 |
Significant positive association between changes in plasma DHA and decrease in cognitive decline rate. Plasma EPA associated with slower decline rate based on several ADAS-cog parameters. No associations with level of AD | |||||
| [80] | 2009 |
Mild to moderate AD patients n 35 Mean age: 70 |
6 months | Inflammatory markers in plasma (IL-6, TNF-α, sIL-1RII) and cerebrospinal fluid (tau, hyperphosphorylated tau, Aβ42) | No significant effect on biomarkers | |||
| [81] | 2014 |
Moderate AD patients n 40 Mean age: 70.5 |
Change in levels of F2-isoprostane, 8-iso-PGF2α and 15-keto-dihydro-PGF2α | No significant effect on biomarkers | ||||
| [84] | 2013 |
Mild to moderate AD patients n 174 Mean age: 75 |
12 months | Transthyretin in plasma and cerebrospinal fluid as indicated by nephelometry | Significant increase in plasma transthyretin, non-significant increase in cerebrospinal fluid transthyretin | |||
| [60] | Randomised double-blind placebo-controlled trial | 2008 |
Mild to moderate AD or MCI n 29 Mean age: 75.1 |
DSM-IV interview and medical assessment by psychiatrist or neurologist |
720 mg/day DHA and 1080 mg/day EPA as capsules Placebo: olive oil capsules |
5.5 months | CIBIC, ADAS-cog | Improvement in general clinical function but not cognitive function. Significant improvement in ADAS-cog score in ω3 MCI group compared to placebo, but not observed in AD group |
| [28] | Randomised double-blind placebo-controlled trial | 2017 |
MCI n 219 Mean age: 74.5 |
Clinical diagnosis by neurologist: Petersen’s criteria MCI, medical history, NINCDS-ADRDA criteria for AD incidence |
2000 mg/day DHA derived from algae as capsules Placebo: soybean oil capsule |
12 months | Chinese version of the WAIS-R, MRI | Increased hippocampal volume and significant improvement in scores for Full Scale Intelligence Quotient, Information and Digit Span for intervention group compared to placebo |
| [61] | 2018 |
MCI n 217 Mean age: 73.6 |
24 months | Significant improvement in scores for Full Scale Intelligence Quotient, Verbal Intelligence Quotient, Information and Digit Span for intervention group compared to placebo | ||||
| [27] | Randomised double-blind placebo-controlled trial | 2010 |
Mild to moderate AD n 295 Mean age: 76 |
Alzheimer’s Disease Cooperative Study clinic institutional review boards |
2000 mg/day DHA derived from algae as capsules Placebo: corn or soy oil capsules |
18 months | ADAS-cog, sum-of-boxes CDR, rate of brain atrophy | No effect on any measures of cognitive decline |
| [62] | Randomised double-blind placebo-controlled trial | 2010 |
Age-related cognitive decline n 485 Mean age: 70 |
900 mg/day DHA as capsules Placebo: corn and soy oil |
5.5 months | CANTAB paired associate learning, Verbal Recognition Memory, Pattern Recognition Memory, Stockings of Cambridge, Spatial Working Memory, MMSE | Two-fold increase in plasma DHA levels that correlated with significantly fewer PAL errors and was associated with improved immediate and delayed Verbal Recognition Memory | |
| [63] | Randomised double-blind placebo-controlled trial | 2012 |
MCI n 35 Mean age: 64.9 |
Neuropsychological assessment by clinical psychologists |
1300 mg/day DHA and 450 mg/day EPA derived from fish as capsules Placebo: corn oil capsules |
12 months | Neuropsychological battery comprised of components from: WMS-R, RAVLT, WAIS-R, CDT and WAIS-III | Significant improvement in short-term and working memory, immediate verbal memory, delayed recall capability and change in memory over 12 months |
| [64] | Randomised placebo-controlled trial | 2006 |
MCI, organic brain lesions, AD n 39 Mean age: 64.9 |
Petersen’s criteria assessed by authors |
240 mg/day ARA and 240 mg/day DHA as capsules Placebo: olive oil capsules |
3 months | Japanese version of the RBANS test | Significantly improved immediate memory in MCI and organic lesions compared to placebo, not in AD |
| [65] | Randomised double-blind placebo-controlled trial | 2015 |
CIND, early AD n 76 Mean age: 71.1 |
Medical and neuropsychological history from memory clinic referral, NINCDS-ADRDA criteria, MRI, blood analyses |
625 mg/day DHA and 600 mg/day EPA as capsules Placebo: olive oil capsules |
4 months | MMSE Serial Sevens, MMSE World Backwards, immediate, delayed and recognition verbal memory | No significant effects observed in any cognitive function measures |
| [66] | Randomised placebo-controlled superiority trial (MAPT) | 2017 |
Memory complaints n 1680 Mean age: 75.3 |
Medical history from general practitioner, MMSE |
800 mg/day DHA and 225 mg/day EPA as capsules Placebo: paraffin oil capsules |
36 months | Battery of tests including free and total recall of Free and Cued Selective Reminding Test, 10 items on MMSE, COWAT, Digit Symbol Substitution Test, Category Naming Test, CDR, TMT | No significant effect on composite score with or without combination with multi-domain intervention |
| [67] | 2018 | No significant effect on battery test score | ||||||
| [71] | 2017 |
Lowest quartile of ω3 index Memory complaints n 183 Mean age: 76 |
ω3 supplementation group showed reduced decline in COWAT scores compared to placebo. No significant difference in scores for other tests, although all scores lower in intervention group | |||||
| [68] | Double-blind placebo-controlled trial (Alpha Omega Trial) | 2012 |
No cognitive impairment n 2911 Mean age: 69.1 |
N/A |
160 mg/day DHA and 240 mg/day EPA as margarine treated with fish oil, with or without 2000 mg ALA Placebo: standard margarine |
40 months | MMSE | No significant effect on MMSE score |
| [69] | Randomised double-blind placebo-controlled trial | 2015 |
No cognitive impairment, adult macular degeneration n 3424 Mean age: 72.7 |
N/A |
350 mg/day DHA and 650 mg/day EPA as capsules Placebo: standard AREDS formulation |
60 months | Composite scores for: TICS-M, letter fluency, category fluency, alternating fluency, WMS-III, Backward Counting, delayed recall of TICS-M and WMS-III | No significant effect on composite scores |
| [70] | Double-blind placebo-controlled trial | 2016 |
No cognitive impairment n 44 Age: 50–70 |
N/A |
880 mg/day DHA and 1320 mg/day EPA derived from fish as capsules Placebo: sunflower oil capsules |
6 months | Object Location Memory | Significant increase in OLM scores observed in supplementation group compared to placebo |
| [72] | Randomised double-blind placebo-controlled trial | 2014 |
Mild to moderate cognitive impairment n 199 Mean age: 74.6 |
12-month follow-up and screening prior to intervention using DSM-IV, MMSE |
180 mg/day DHA and 120 mg/day EPA as cod liver oil capsule Placebo: coconut oil capsule |
6 months | MMSE, AMT | No significant effect on MMSE or AMT scores |
| [73] | Randomised double-blind placebo-controlled trial | 2010 |
Mild AD n 225 Mean age: 73.7 |
NINCDS-ADRDA criteria, MMSE, MRI |
1200 mg/day DHA and 300 mg/day EPA as Fortasyn Connect nutrition combination in Souvenaid drink Placebo: isocaloric drink |
3 months | WMS-R delayed verbal recall task, ADAS-cog, CIBIC | Fewer reduced scores and significantly more improved scores in WMS-R compared to placebo |
| [74] | Randomised double-blind placebo-controlled trial | 2017 |
Prodromal AD n 311 Mean age: 71 |
NINCDS-ADRDA criteria, CSF, MRI, 18F fluorodeoxyglucose PET analysis by clinician |
1200 mg/day DHA and 300 mg/day EPA as Fortasyn Connect nutrition combination in Souvenaid drink Placebo: isocaloric drink |
24 months | Modified version of Neuropsychological Test Battery | No significant effect on composite score, although cognitive decline much lower than expected |
| [78] | Randomised placebo-controlled trial | 2014 |
Probable AD n 39 Mean age: 75.9 |
NINCDS-ADRDA criteria, MMSE, CDR |
675 mg/day DHA and 975 mg/day EPA derived from fish as capsules; or 675 mg/day DPA, 975 mg/day EPA derived from fish plus 600 mg/day alpha lipoic acid as tablet ω3 placebo: soybean oil as capsule with 5% fish oil |
12 months | Change in levels of F2-isoprostane, MMSE, ADL/IADL, ADAS-cog | No significant difference in isoprostane levels. Effects on cognition more significant with addition of LA than omega-3 s alone |
| [82] | Randomised double-blind placebo-controlled trial | 2017 |
MCI n 13 Mean age: 66.5 |
Mayo clinic criteria for MCI by neurology specialist |
880 mg/day DHA and 1320 mg/day EPA as capsules Placebo: sunflower oil capsules |
6 months | Cerebral perfusion as indicated by cerebral blood flow and cerebral blood volume | Increase in cerebral blood flow and volume larger in omega-3 intervention than placebo group |
| [83] | Open studya | 2015 |
MCI, AD n 29 Mean age: 77.4 |
NINCDS-ADRDA criteria, Petersen’s criteria for MCI, MMSE | 1000 mg/day DHA and 1000 mg/day EPA as Smartfish drink (also contained 10ug vitamin D3 and resveratrol) | 17 months | Aβ phagocytosis (as indicated by flow cytometry and microscopy), transcription of inflammatory genes (as indicated by RC-PCR), resolvin-D1 production (as indicated by enzyme immunoassay), MMSE | Aβ phagocytosis increased significantly in MCI but not in AD. No other significant associations |
DSM-IV diagnostic and statistical manual of mental disorders fourth edition, NINCDS-ADRDA National Institute of neurological and communicative disorders and stroke and the Alzheimer’s disease and related disorders association
aNot classified as a clinical trial but was included in the table for the purpose of comparison to other biomarker studies