CNS target engagement of high-dose DHA supplementation in older adults at risk for dementia: a randomised, double-blind, placebo-controlled trial.
Level 2 - randomized trial
Randomized, double-blind, placebo-controlled trial
PubMed 42315445 · doi:10.1016/j.ebiom.2026.106316
What was done
A phase IIa 24-month, randomized, double-blind, placebo-controlled trial evaluated 365 non-demented adults aged 55–80 years with low dietary DHA intake (<200 mg/day) and at least one dementia risk factor. Participants were stratified by willingness to undergo lumbar puncture (181 in the LP arm, 184 in the no-LP arm) and randomized 1:1 within arms to receive 2 g/day of oral DHA or placebo, stratified by APOE ε4 status. The primary endpoint was the change in CSF DHA-to-arachidonic acid (AA) ratio at 6 months; secondary and exploratory endpoints included 24-month neuroimaging and cognitive measures.
What was found
DHA supplementation significantly increased the CSF DHA/AA ratio at 6 months compared with placebo (0.17 [95% CI 0.15 to 0.18] vs -0.02 [95% CI -0.04 to -0.0004]; difference 0.19 [95% CI 0.16 to 0.21]; p < 0.0001). This effect was independent of APOE ε4 status (interaction p = 0.71). Across 24 months, no treatment differences were observed in brain volumes or cognitive performance. Adverse events were comparable between groups with no serious adverse events attributed to treatment.
Why it matters
High-dose oral DHA successfully engages its biochemical target across the blood-brain barrier in at-risk older adults regardless of APOE genotype. However, achieving CNS penetration did not translate into detectable cognitive or structural brain benefits over 2 years.
Limits
There was a high dropout rate of 38%, primarily due to the COVID-19 pandemic. The 24-month follow-up window and sample size may also limit the detection of subtle clinical or neuroimaging divergence in non-demented individuals.
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