An 18-mo randomized, double-blind, placebo-controlled trial of DHA-rich fish oil to prevent age-related cognitive decline in cognitively normal older adults.

Randomized, double-blind, placebo-controlled trial in cognitively healthy, community-dwelling older adults in Adelaide, South Australia. Adults aged 65-90 years were randomized 1:1; 403 were randomized overall, with 194 assigned to DHA-rich fish oil and 196 to placebo, and 390 participants were included in the baseline analysis.

Participants received oral DHA-rich fish oil capsules for 18 months, 4 capsules per day. Each capsule provided 430 mg DHA and 150 mg EPA, for a daily dose of 1720 mg DHA and 600 mg EPA (2.3 g/day total fish oil), compared with low-polyphenol olive oil placebo.

DHA-rich fish oil did not slow or improve cognitive performance over 18 months. The main cognitive findings were small negative effects on psychomotor speed (treatment = -0.02; 95% CI: -0.04 to 0.00; P = 0.03; d = 0.24) and on simple and choice reaction time (treatment = -0.02; 95% CI: -0.03 to 0.01; P = 0.05; d = 0.20). Sex and APOE-ε4 carrier status moderated some outcomes, including greater decline in retrieval fluency in women and improvement in reasoning among APOE-ε4 carriers. Secondary findings included worse perceived cognitive mistakes (Cognitive Failures Questionnaire, d = 0.24; P = 0.003), higher oxidative stress, increased HDL cholesterol, and decreased triglycerides (P < 0.01 for both); no serious adverse events were reported.

The trial was modest in size for subgroup analyses, and the sex and APOE-ε4 interactions should be considered exploratory. Loss to follow-up occurred over 18 months, and the sample was limited to cognitively healthy older adults from one Australian region, which may reduce generalizability. Some outcomes were secondary or mechanistic, so clinical relevance of the observed changes is uncertain.