Brain delivery of supplemental docosahexaenoic acid (DHA): A randomized placebo-controlled clinical trial

Abstract

Background: Past clinical trials of docosahexaenoic Acid (DHA) supplements for the prevention of Alzheimer's disease (AD) dementia have used lower doses and have been largely negative. We hypothesized that larger doses of DHA are needed for adequate brain bioavailability and that APOE4 is associated with reduced delivery of DHA and eicosapentaenoic acid (EPA) to the brain before the onset of cognitive impairment.

Methods: 33 individuals were provided with a vitamin B complex (1 mg vitamin B12, 100 mg of vitamin B6 and 800 mcg of folic acid per day) and randomized to 2,152 mg of DHA per day or placebo over 6 months. 26 individuals completed both lumbar punctures and MRIs, and 29 completed cognitive assessments at baseline and 6 months. The primary outcome was the change in CSF DHA. Secondary outcomes included changes in CSF EPA levels, MRI hippocampal volume and entorhinal thickness; exploratory outcomes were measures of cognition.

Findings: A 28% increase in CSF DHA and 43% increase in CSF EPA were observed in the DHA treatment arm compared to placebo (mean difference for DHA (95% CI): 0.08 µg/mL (0.05, 0.10), p<0.0001; mean difference for EPA: 0.008 µg/mL (0.004, 0.011), p<0.0001). The increase in CSF EPA in non-APOE4 carriers after supplementation was three times greater than APOE4 carriers. The change in brain volumes and cognitive scores did not differ between groups.

Interpretation: Dementia prevention trials using omega-3 supplementation doses equal or lower to 1 g per day may have reduced brain effects, particularly in APOE4 carriers.

Trial registration: NCT02541929.

Funding: HNY was supported by R01AG055770, R01AG054434, R01AG067063 from the National Institute of Aging and NIRG-15-361854 from the Alzheimer's Association, and MGH by the L. K. Whittier Foundation. This work was also supported by P50AG05142 (HCC) from the National Institutes of Health. Funders had no role in study design, data collection, data analysis, interpretation, or writing of the report.

Keywords: APOE; Alzheimer's disease; DHA; Dementia; Omega-3; RCT.

Fig. 1

Consort diagram. From 117 participants screened for eligibility, 33 were randomized into placebo (n = 15, APOE4=7, non-APOE4=8) and DHA (n = 18, APOE4=8, non-APOE4=10) treatment arms.

Fig. 2

Comparison of post-intervention difference in CSF DHA and EPA levels at baseline and 6-months based on treatment arm and APOE4 status. Comparison of a) change in CSF DHA between DHA and placebo treatments arms separated by APOE4 status, b) change in CSF EPA between treatment arms separated by APOE4 status, c) change in plasma DHA between treatments arms separated by APOE4 status, and d) change in plasma EPA between treatment arms separated by APOE4 status, e) mean DHA% change compared to baseline in CSF and plasma, f) mean% change in EPA compared to baseline in CSF and plasma. The p values were derived from a linear model ANCOVA.