What was lost in translation in the DHA trial is whom you should intend to treat

One potential misconception is that what works for prevention will slow progression in AD subjects.Preclinical studies with DHA supported the rationale for early stage intervention; and three epidemiological studies indicated DHA intake was associated with reduced risk in non-apolipoprotein E4 (ApoE4) carriers. Putative drugs are initially tested for impact on progression because prevention approaches are problematic. However, should a drug be discarded for prevention if it fails to modify progression? Consistent with epidemiology, DHA significantly benefited two measures of cognition in mild to moderate non-ApoE4 carriers. Although the results of this trial were overall negative, failing to modify other outcomes, this commentary discusses important questions raised by them. Should future trials pursue DHA in non-ApoE4 carriers for slowing progression? Since in vivo oxidation of DHA may have adverse effects, particularly in ApoE4 patients, should preclinical and clinical studies be performed to optimize dose and mitigate oxidation before pursuing intervention or prevention trials with DHA? And finally, should DHA be tested now for mild cognitive impairment or prevention?Subjects with baseline mini-mental state examination (MMSE) scores of mild to moderate Alzheimer's disease (AD) were treated with algal docosahexaenoic acid (DHA, 2,000 mg/day) for 18 months in a randomized double-blind placebo-controlled trial to determine the impact on AD progression. The rationale for testing DHA was strong. It is enriched in neuronal membranes but depleted in AD. Multiple epidemiological studies report diets rich in fish or DHA reduce AD risk, most clearly in non-apolipoprotein E4 (ApoE4) carriers [1]. Preclinical studies with DHA have not yet modeled ApoE isoform pharmacogenomics, but mice transgenic for familial dominant AD mutations that elevate β-amyloid (Aβ) production are vulnerable to dietary DHA depletion. DHA and its metabolites pleiotropically impact Aβ production, insu