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, prompt delivery but mice transgenic for familial dominant AD mutations that elevate ??-amyloid (A??) production are vulnerable to dietary DHA depletion. DHA and its metabolites pleiotropically impact A?? production, insulin/neurotrophic signaling, tau kinase activation and synaptic plasticity [1]. Although DHA had no impact on cognitive or functional decline based on intent to treat AD, in non-ApoE4 carriers, DHA supplementation appeared to reduce declines in MMSE and Alzheimer Disease Assessment Scale-Cognitive (ADAS-Cog).

This commentary discusses the trial’s results and important questions raised, including the need for optimization of dose and antioxidant combinations and whether there should be further investigation of the impact of DHA on slowing cognitive decline in non-ApoE4 carriers. Perhaps a larger issue is whether agents directed at amyloid or tau pathology or associated with reduced AD risk should be translated with an intent-to-treat earlier disease stages rather than mild to moderate AD. The randomized trial of DHA for AD provides evidence that DHA supplementation provides no general benefit to AD patients, including no overall impact on Clinical Dementia Rating (CDR) scale, ADAS- Cog, MMSE, Neuropsychiatric Inventory (NPI; P = 0.

11) and Activities of Daily Living (ADL) [2]. The authors argue that DHA may still have potential for prevention. Thus, a fundamental question arising out of this study is the stage at which we should treat. First, three smaller studies showed an apparent benefit from fish oil treatment in mild cognitive impairment but not in mild to moderate AD subjects [3-5]. With age-associated memory impairment, one small trial [6] and the larger 485-subject Dacomitinib MIDAS (Memory Improvement with DHA Study) trial [7] found significant cognitive benefits with DHA. While there have been two fish oil trials in unimpaired elderly in which no cognitive never benefits were observed [8,9], subjects in both were cognitively normal at baseline, and the latter failed to show significant cognitive decline in the placebo group. Th is study argues that fish oil is not a cognitive enhancer, but does not examine disease modification in subjects with pathology-driven memory deficits.