December 2, 2020

Does High-Dose Oral DHA Improve Dementia?

Results from a randomized, placebo-controlled trial
Supplementing with omega-3s in the short term (less than 6 months) may do little for preventing dementia, but the effects of long-term supplementation are still being researched.


Arellanes I, Choe N, Solomon V, et al. Brain delivery of supplemental docosahexaenoic acid (DHA): a randomized placebo-controlled clinical trial. EBioMedicine. 2020;59:102883.

Study Objective

This study was structured to assess whether high oral doses of docosahexaenoic acid (DHA) would improve cognitive function.

Study Design

Randomized, placebo-controlled trial


A total of 33 participants were randomized to either the intervention arm (n=18; 8 were APOE4 carriers) or placebo arm (n=15; 7 were APOE4 carriers). After 4 participants dropped out, a total of 15 participants (aged 58-90 years) remained in the intervention group, and 14 participants (aged 58-79 years) remained in the placebo group. All participants were female except for 6 men, all of whom were non-APOE4 carriers (placebo group, n=4; intervention group, n=2).

Racial characteristics of each arm: The intervention group was 61% White (non-Hispanic), 33% Hispanic, 6% Black, and 0% Asian. The placebo group was 47% White (non-Hispanic), 33% Hispanic, 13% Asian, 7% Other, and 0% Black.

All participants were residents of the Los Angeles area who were recruited between 2016 to 2018. All were cognitively unimpaired themselves but had a history of at least 1 first-degree relative with dementia.

Exclusion criteria included current smokers, history of cardiovascular disease, renal failure or blindness, a diagnosis of cancer in the last 6 months, uncontrolled thyroid function (hyper or hypo), anticoagulant medication intake, regular exercise (>150 minutes of aerobic exercise per week), heavy drinking (>30 units per week), and consumption of omega-3 fatty acid (polyunsaturated fatty acid [PUFA]) capsules in the prior 3 months.


Both groups received hefty doses of B vitamins: B12 1 mg, folic acid 800 mcg, and B6 100 mg along with trimethylglycine 2 g, and pyridoxal 5’-phosphate 12 mg. The treatment group also received oral omega-3 fatty acids containing primarily DHA (60%, for a DHA content of 2,152 mg) per day for 6 months. This capsule contained essentially no EPA.

Primary Outcome Measures

The primary outcome was any change in DHA levels at 6 months versus baseline. Secondary outcomes included changes in cerebrospinal fluid (CSF) eicosapentaenoic acid (EPA) and magnetic resonance imaging (MRI) image changes (hippocampal volume and entorhinal cortex thickness). Exploratory outcomes included Montreal Cognitive Assessment (assessment of global cognition), Craft Stories and California Verbal Learning Test 2 (assessment of verbal memory), and Trail Making Tests A and B (assessment of speed and executive functions).

Key Findings

There was an increase in DHA and EPA in the CSF (this, in itself, is interesting, since participants did not supplement with EPA) of the treatment group. There was a 28% increase in CSF DHA in the treatment group (mean difference for DHA [95% CI]: 0.08 mg/mL [0.05, 0.10], P<0.0001); and a 43% increase in CSF EPA in the treatment group (mean difference for EPA: 0.008 mg/mL [0.004, 0.011], P<0.0001).

There was no evidence, after 6 months, that DHA improved cognitive function or delayed dementia onset.

Also of importance, participants who were non-APOE4 carriers increased their CSF EPA levels 3 times as much as APOE4 carriers.

Practice Implications

What piqued my interest in this article was the wording of the title: “Brain Delivery of Supplemental DHA.” I was envisioning that the researchers were actually delivering the DHA right into the brain in some way, like an intrathecal injection. You may laugh at this notion, but I remember reading approximately 25 years ago about the intracerebral application of gamma-linolenic acid as a treatment for human gliomas, which showed some promise.1,2 I had wondered why I had never heard of anyone following up on this route of administration. So I thought this study was going to build on that. Sadly, it did not. This was oral supplementation. Briefly, the results of this study show that this intervention does not make sense as a single tool for delaying or treating dementia, at least in the short term (6 months).

This study leaves as many questions as it answers. The study proves that you can elevate CSF DHA by giving high doses. It also suggests that DHA may be converted to EPA. However, the goal of the study was to see if giving high-dose DHA could improve cognitive function and reduce the risk of dementia. There was no improvement for those 2 outcomes by the end of the study (6 months). This shouldn’t surprise us since 6 months is a relatively short time in the life of a 55-year-old brain.

Silver bullets rarely pierce their target, whether they are conventional or natural interventions.

The main question left hanging is: If you give high-dose DHA for a longer period of time, will it have the desired benefit? There is some evidence suggesting that high-dose DHA should be preventive for dementia,3,4 particularly for people who are not homozygous for the APOE4 gene, which is “selective” for early Alzheimer's disease. (An important note: The DHA used in these studies was the molecular form found in fish, not the deconstructed fatty acid form found in many nutritional supplements.)

My frustration with this article is that there is the assumption that there will be 1 nutrient that will be the answer to the Alzheimer's/dementia puzzle. Silver bullets rarely pierce their target, whether they are conventional or natural interventions. Chronic diseases are multifactorial and require multifactorial interventions. Various studies have pointed to various factors contributing to and solving this disheartening condition, such as central nervous system (CNS) sugar metabolism issues,5,6 exercise,7 sleep,8 viral infections,9 nutritional deficiencies,10,11 alcohol use,12 medication use,13 and more. It would be wonderful, but highly unlikely, for there to be 1 nutrient that will be the answer for preventing and treating this disease.

Categorized Under


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