Does high-dose oral DHA improve dementia?

Relation

Arellanes I, Choe N, Solomon V, et al. Delivery of supplemental docosahexaenoic acid (DHA) to the brain: 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

Participant

A total of 33 participants were randomly assigned to either the intervention arm (n=18; 8 wereAPOE4carrier) or placebo arm (n=15; 7 wereAPOE4Carrier). After the withdrawal of 4 participants, 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, with the exception of 6 men, all of whom were non-APOE4Vehicle (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 recruited between 2016 and 2018. All were not cognitively impaired 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 cancer diagnosis in the last 6 months, uncontrolled thyroid function (hyper or hypo), use of anticoagulant medications, regular exercise (>150 minutes of aerobic exercise per week). ), heavy drinking (>30 units per week), and consumption of omega-3 fatty acids (polyunsaturated fatty acids [PUFA]) capsules in the past 3 months.

intervention

Both groups received hefty doses of B vitamins: B₁₂1 mg, folic acid 800 mcg and B₆100 mg together with trimethylglycine 2 g and pyridoxal 5′-phosphate 12 mg. The treatment group also received oral omega-3 fatty acids containing primarily DHA (60%, with a DHA content of 2,152 mg) daily for 6 months. This capsule contained essentially no EPA.

Primary outcome measures

The primary endpoint was any change from baseline in DHA levels at 6 months. Secondary endpoints 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 insights

There was an increase in DHAandEPA in the CSF (which is interesting in itself since the participants did not supplement with EPA) of the treatment group. In the treatment group there was a 28% increase in CSF DHA (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 the onset of dementia.

Participants who do not are also importantAPOE4Carriers increased their CSF EPA levels threefoldAPOE4Carrier.

Practice implications

What caught my interest in this article was the wording of the title: “Brain Delivery of Supplemental DHA.” I imagined that the researchers would actually deliver the DHA directly to the brain in some way, like an intrathecal injection. You may laugh at this idea, but I remember reading about 25 years ago about the intracerebral use of gamma-linolenic acid to treat human gliomas, which had some promise.^1.2I had been wondering why I had never heard of anyone pursuing this route of administration. So I thought this study would build on that. Unfortunately not. This was an oral supplement. In short, the results of this study show that this intervention is not useful as a sole tool to delay or treat dementia, at least in the short term (6 months).

This study leaves as many questions as it answers. The study proves that you can increase CSF DHA by giving high doses. It also suggests that DHA can be converted into EPA. However, the aim of the study was to see whether giving high doses of DHA could improve cognitive function and reduce the risk of dementia. At the end of the study (6 months) there was no improvement for these 2 endpoints. This shouldn't surprise us, as 6 months is a relatively short time in the life of a 55-year-old brain.

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

The main question that remains is: If you give high-dose DHA over a long period of time, will it have the desired benefit? There is evidence that high doses of DHA should prevent dementia,^3.4especially for people who are not homozygous for theAPOE4Gene that 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 supplements.)

My frustration with this article is that it assumes that there will be one nutrient that will be the answer to the Alzheimer's/dementia puzzle. Silver bullets rarely penetrate their target, whether they are conventional or natural interventions. Chronic diseases are multifactorial and require multifactorial interventions. Various studies have pointed out various factors that contribute to and resolve this discouraging condition such as: B. Problems with sugar metabolism in the central nervous system (CNS),^5.6Exercise,⁷sleep,⁸viral infections,⁹nutritional deficiencies,^10,11alcohol consumption,¹²taking medication,¹³and more. It would be wonderful, but highly unlikely, if there was a single nutrient that was the solution to preventing and treating this disease.