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CNS target engagement of high-dose DHA supplementation in older adults at risk for dementia: a randomised, double-blind, placebo-controlled trial

Year: 2026

Type: article

Study designs: Randomized Controlled Trial, Clinical Trial

Abstract: BACKGROUND: APOE ε4 carriers have increased Alzheimer's disease risk and altered omega-3 metabolism. No large-scale prevention trials have tested high-dose docosahexaenoic acid (DHA) supplementation specifically in non-demented APOE ε4 carriers with low baseline omega-3 intake for early intervention. METHODS: We conducted a phase IIa 24-month, randomised, double-blind, placebo-controlled trial (NCT03613844) at the University of Southern California between September 2018 and May 2024. Participants aged 55-80 years without dementia, low dietary DHA intake (<200 mg/day), and ≥1 dementia risk factor were stratified by cerebrospinal fluid (CSF) collection willingness into lumbar puncture (LP) or no-LP arms. Within each arm, participants were randomised 1:1 to receive 2 g/day DHA or placebo, stratified by APOE ε4 status. Primary outcome was the 6-month CSF DHA-to-arachidonic acid (AA) ratio change. Secondary and exploratory outcomes included 24-month neuroimaging and cognitive measures. FINDINGS: Of 739 screened individuals, 365 participants were randomised (181 LP arm, 184 no-LP arm). Mean age was 66.4 years (SD 5.7), 210 (58%) were female, 142 (39%) were Hispanic, 173 (47%) were APOE ε4 carriers. DHA supplementation increased CSF DHA/AA ratio at 6 months vs placebo (0.17 [95% CI 0.15-0.18] vs -0.02 [95% CI -0.04 to -0.0004]; difference 0.19 [95% CI 0.16-0.21]; p < 0.0001), independent of APOE ε4 status (interaction p = 0.71). Dropout was 38%, mainly due to COVID-19. No treatment differences were observed in brain volumes or cognitive performance over 24 months. Adverse events were comparable between groups, with no serious adverse events attributed to treatment. INTERPRETATION: High-dose DHA achieved CNS target engagement in non-demented older adults with low baseline omega-3 intake, independent of APOE ε4. Despite biochemical target engagement, no differences in cognition or brain structure were observed over 24 months. Future research should prioritise brain DHA metabolism over further supplementation trials. FUNDING: National Institute on Aging (R01AG057684) and the ADDF (GC-201711-2014197).

Source: EBioMedicine

DOI: 10.1016/j.ebiom.2026.106316