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Objective Little is known about the transfer of essential fatty acids ( FAs) across the human blood-brain barrier ( BBB) in adulthood. In this study, we investigated whether oral supplementation with omega-3 ( n-3) FAs would change the FA profile of the cerebrospinal fluid ( CSF). Methods A total of 33 patients (18 receiving the n-3 FA supplement and 15 receiving placebo) were included in the study. These patients were participants in the double-blind, placebo-controlled randomized Omeg AD study in which 204 patients with mild Alzheimer's disease ( AD) received 2.3 g n-3 FA [high in docosahexaenoic acid ( DHA)] or placebo daily for 6 months. CSF FA levels were related to changes in plasma FA and to CSF biomarkers of AD and inflammation. Results At 6 months, the n-3 FA supplement group displayed significant increases in CSF (and plasma) eicosapentaenoic acid ( EPA), DHA and total n-3 FA levels ( P < 0.01), whereas no changes were observed in the placebo group. Changes in CSF and plasma levels of EPA and n-3 docosapentaenoic acid were strongly correlated, in contrast to those of DHA. Changes in DHA levels in CSF were inversely correlated with CSF levels of total and phosphorylated tau, and directly correlated with soluble interleukin-1 receptor type II. Thus, the more DHA increased in CSF, the greater the change in CSF AD/inflammatory biomarkers. Conclusions Oral supplementation with n-3 FAs conferred changes in the n-3 FA profile in CSF, suggesting transfer of these FAs across the BBB in adults. [ABSTRACT FROM AUTHOR]