title: Association of Docosahexaenoic Acid Supplementation With Alzheimer Disease Stage in Apolipoprotein E ε4 Carriers: A Review.
abstract: OBJECTIVE
  The apolipoprotein E ε4 (APOE4) allele identifies a unique population that is at significant risk for developing Alzheimer disease (AD). Docosahexaenoic acid (DHA) is an essential ω-3 fatty acid that is critical to the formation of neuronal synapses and membrane fluidity. Observational studies have associated ω-3 intake, including DHA, with a reduced risk for incident AD. In contrast, randomized clinical trials of ω-3 fatty acids have yielded mixed and inconsistent results. Interactions among DHA, APOE genotype, and stage of AD pathologic changes may explain the mixed results of DHA supplementation reported in the literature.
  
  
  METHODS
  Although randomized clinical trials of ω-3 in symptomatic AD have had negative findings, several observational and clinical trials of ω-3 in the predementia stage of AD suggest that ω-3 supplementation may slow early memory decline in APOE4 carriers. Several mechanisms by which the APOE4 allele could alter the delivery of DHA to the brain may be amenable to DHA supplementation in predementia stages of AD. Evidence of accelerated DHA catabolism (eg, activation of phospholipases and oxidation pathways) could explain the lack of efficacy of ω-3 supplementation in AD dementia. The association of cognitive benefit with DHA supplementation in predementia but not AD dementia suggests that early ω-3 supplementation may reduce the risk for or delay the onset of AD symptoms in APOE4 carriers. Recent advances in brain imaging may help to identify the optimal timing for future DHA clinical trials.
  
  
  CONCLUSIONS
  High-dose DHA supplementation in APOE4 carriers before the onset of AD dementia can be a promising approach to decrease the incidence of AD. Given the safety profile, availability, and affordability of DHA supplements, refining an ω-3 intervention in APOE4 carriers is warranted.
authors.affiliation: Division of Endocrinology, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles.
authors.forename: Hussein N
authors.initials: HN
authors.lastname: Yassine
authors.affiliation: Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey.
authors.forename: Meredith N
authors.initials: MN
authors.lastname: Braskie
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles.
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Mack
authors.affiliation: Department of Neurosciences, Huntington Medical Research Institutes, Pasadena, California.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Castor
authors.affiliation: Department of Neurosciences, Huntington Medical Research Institutes, Pasadena, California.
authors.forename: Alfred N
authors.initials: AN
authors.lastname: Fonteh
authors.affiliation: Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles6Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles.
authors.forename: Lon S
authors.initials: LS
authors.lastname: Schneider
authors.affiliation: Department of Neurosciences, Huntington Medical Research Institutes, Pasadena, California.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Harrington
authors.affiliation: Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles.
authors.forename: Helena C
authors.initials: HC
authors.lastname: Chui
mesh_terms: D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics / Q000517:prevention & control; D053327:Apolipoprotein E4 / Q000235:genetics*; D004281:Docosahexaenoic Acids / Q000008:administration & dosage*; D006801:Humans
chemical_list: D053327:Apolipoprotein E4; D004281:Docosahexaenoic Acids