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- APOE 4 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.

Importance of EPA and DHA Blood Levels in Brain Structure and Function

“…This demonstrated that two thirds of the “age-dependent” loss of gray matter in the placebo group was a symptom of a deficit in EPA and DHA [ 126 ]. Carriers of the genetic trait ApoE4 had less increase of DHA in plasma after dietary intake and only one third uptake of DHA into the brain, compared with non-carriers [ 128 , 129 ]. Additionally, important interactions between status in vitamin B and homocysteine and the effects of Omega-3 fatty acids on cognition have been observed [ 130 , 131 , 132 ].…”

The Impact of Nutrients on Mental Health and Well-Being: Insights From the Literature

“…However, a meta-analysis of RCTs indicated the need of longer-term studies to confirm these effects ( 42 ). Of interest, a recent RCT including subjects without cognitive impairment but at risk of dementia, treated with 2,152 mg per day of DHA or placebo for over 6 months, indicated that larger doses of DHA are needed for adequate brain bioavailability, as confirmed by analysis of the cerebrospinal fluid ( 43 ). Moreover, a stratification of study participants by APOE4 status revealed its association with the level of delivery of DHA and EPA to the brain before the onset of cognitive impairment.…”

Can Natural Products Exert Neuroprotection without Crossing the Blood–Brain Barrier?

“…However, these proportions can be modulated, through BBB transport, peripheral metabolism and pathological status. For instance, brain transport [ 69 ] and bioavailability [ 70 ] are decreased by the expression of apolipoprotein ε4 (ApoE4) [ 51 ]. Brain uptake is also modulated by AD transgene expression in the mouse brain [ 22 , 71 ].…”