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Efficacy and acceptability of anti-inflammatory eicosapentaenoic acid for cognitive function in Alzheimer’s dementia: a network meta-analysis of randomized, placebo-controlled trials with omega-3 fatty acids and FDA-approved pharmacotherapy

Tseng P-T, Zeng B-S, Suen M-W, Wu Y-C, Correll CU, Zeng B-Y, Kuo JS, Chen Y-W, Chen T-Y, Tu Y-K, Lin P-Y, Carvalho AF, Stubbs B, Li D-J, Liang C-S, Hsu C-W, Sun C-K, Cheng Y-S, Yeh P-Y, Wu M-K, Shiue Y-L, Su K-P (2023) Brain, Behavior, and Immunity May 5 S0889-1591(23)00115-0. doi: 10.1016/j.bbi.2023.04.017. Online ahead of print. 

Web URL: View this and related abstracts via PubMed here


Alzheimer's dementia (AD) is a major contributor to global disability, and effective therapies to modify disease progression are currently lacking. The neuro-inflammatory theory is a potential etiology underlying this neurodegenerative disease.

Previous randomized, controlled trials (RCTs) have provided inconclusive results regarding efficacy of omega-3 polyunsaturated fatty acids (PUFAs) regimens, which might provide anti-inflammatory benefits in the management of AD, in improving cognitive function among participants with AD.

The objective of this frequentist-model based network meta-analysis (NMA) was to evaluate the potential advantages of omega-3 PUFAs and currently FDA-approved medications for AD on overall cognitive function in AD individuals.

The primary outcomes were: (1) changes in cognitive function, and (2) acceptability, which refers to all-cause discontinuation. Additionally, secondary outcomes included quality of life, behavioral disturbances and safety/tolerability, which was assessed through the frequency of any reported adverse event.

This NMA included 52 RCTs (6 with omega-3 PUFAs and 46 with FDA-approved medications) involving 21,111 participants. The results showed that long-term high-dose (1500 - 2000 mg/day) of eicosapentaenoic acid (EPA)-dominant omega-3 PUFAs augmented with anti-oxidants had the highest potential for cognitive improvement among all investigated treatments [standardized mean difference=3.00, 95% confidence intervals (95%CIs)=1.84-4.16].

Compared to placebo, omega-3 PUFAs had similar acceptability [odds ratio (OR)=0.46, 95%CIs=0.04 to 5.87] and safety profiles (OR=1.24, 95%CIs=0.66 to 2.33)o.

These findings support the potential neurotherapeutic effects of high dosage EPA-dominant omega-3 PUFAs for the amelioration of cognitive decline in patients with AD. Future large-scale, long-term RCTs should focus on different dosages of EPA-dominant omega-3 PUFAs regimens on improving cognitive dysfunction in patients with AD at different levels of inflammatory status and psychopathology.


High-dose treatment with omega-3 EPA - one of the main long-chain polyunsaturated fatty acids found in fish oils - showed better potential for improving overall cognitive function in patients with Alzheimers dementia than did FDA-approved medications, according to this new meta-analytic network analysis of 52 randomised controlled trials, involving more than 20,000 patients.

Long-term treatment with Omega-3 EPA - one of the main long-chain polyunsaturated fatty acids (LC-PUFA) found in fish oils - was also found to be just as safe and acceptable to patients with dementia as placebo treatment.
Just 6 of the 52 trials in this meta-analysis involved EPA treatment (at 1500-2000mg/day, augmented with antioxidants), while 46 involved FDA-approved medications.

As the researchers concluded, these findings indicate the need for further large-scale, long-term trials of EPA-dominant formulations of omega-3 LC-PUFA for the prevention and management of age-related cognitive impairment and dementia.

Particular issues for further exploration include both the effects of different dosages, and the possible relevance of patients' inflammatory status - as EPA has well-documented anti-inflammatory actions, which could help to explain the benefits observed. 

At doses of 1000-2000mg/day, clinical trials and meta-analyses have already shown omega-3 EPA to be effective as an adjunctive treatment for clinical depression. For detailed treatment guidelines based on this evidence, see:

Like Alzheimer's disease, clinical depression is often - but not always - associated with excessive inflammation. Ongoing research into the use of omega-3 EPA for depression is therefore already exploring biomarkers of both inflammation and other factors that may help to predict treatment response, as well as dose-ranging studies.  

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