DESCRIPTION (provided by applicant): Over five million Americans have Alzheimer's disease (AD), and this number is expected to triple by 2050 unless effective preventive strategies are identified. Veterans are at an even higher risk for AD than the general population, possibly due to their increased exposure to factors that accelerate AD pathology, including vascular risk factors, traumatic brain injury, and post-traumatic stress disorder. AD pathology occurs decades before cognitive symptoms occur and is characterized by amyloid plaques, neurofibrillary tangles, and reduced regional cerebral blood flow in areas of the brain related to memory and learning. While cerebral arterial dysfunction occurs early in the development of AD pathology and decades before symptoms begin, the effects of treating such early vascular dysfunction in the brain are poorly understood. The omega-3 fatty acid eicosapentaenoic acid (EPA) improves arterial function and cerebral blood flow, attenuates adverse brain changes related to β-amyloid protein, and improves cognition in animals - changes that could all potentially protect against AD. However, it is not clear whether EPA beneficially affects these processes or cognitive performance in cognitively-healthy adults at increased risk for AD. In 2012, the Food and Drug Administration approved the first high-dose prescription EPA-only medication to treat hypertriglyceridemia, called icosapent ethyl (available as Vascepa(r) in the United States). This agent is readily available for use and has a good safety profile, making it a favorable agent to consider for AD prevention. The proposed study is a proof-of-concept, randomized, placebo-controlled, double-blind, parallel-group clinical trial assessing the efficacy of 18 months of icosapent ethyl therapy on magnetic resonance imaging (MRI), cerebrospinal fluid (CSF), and cognitive biomarkers for AD in 150 cognitively-healthy Veterans ages 50-70 with increased risk for developing AD due to parental history of the disease and increased prevalence of apolipoprotein E ε4 (APOE4) allele. The overarching goal of this trial is to assess whether icosapent ethyl beneficially affects intermediate physiological measures associated with onset of AD in order to evaluate whether larger, multi-site, longer-duration Alzheimer's prevention trials are warranted to assess more definitive clinical outcomes. Hypothesis: In middle-aged and older cognitively-healthy Veterans with parental history of AD and high APOE4 prevalence, 18 months of treatment with icosapent ethyl will beneficially modify preclinical AD biomarkers, including regional cerebral blood flow, CSF markers of AD pathology, and cognitive performance. Specific Aim 1: To investigate the effects of 18 months of icosapent ethyl 4 g daily vs. placebo on arterial spin-labeling MRI regional cerebral blood flow in a pre-defined statistically-identified region of interest affected early in preclinical AD; Specific Aim 2: To deter...