The benefit of docosahexaenoic acid for the adult brain in aging and dementia

Beydoun, 2007, Plasma n-3 fatty acids and the risk of cognitive decline in older adults: the atherosclerosis risk in communities study, Am. J. Clin. Nutr., 85, 1103, 10.1093/ajcn/85.4.1103 Heude, 2003, Cognitive decline and fatty acid composition of erythrocyte membranes – the EVA study, Am. J. Clin. Nutr., 77, 803, 10.1093/ajcn/77.4.803 Conquer, 2000, Fatty acid analysis of blood plasma of patients with Alzheimer׳s disease, other types of dementia, and cognitive impairment, Lipids, 35, 1305, 10.1007/s11745-000-0646-3 Schaefer, 2006, Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease: the Framingham Heart Study, Arch. Neurol., 63, 1545, 10.1001/archneur.63.11.1545 van de Rest, 2009, Intakes of (n-3) fatty acids and fatty fish are not associated with cognitive performance and 6-year cognitive change in men participating in the Veterans Affairs Normative Aging Study, J. Nutr., 139, 2329, 10.3945/jn.109.113647 Barberger-Gateau, 2002, Fish, meat, and risk of dementia: cohort study, Br. Med. J., 325, 932, 10.1136/bmj.325.7370.932 Morris, 2003, Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease, Arch. Neurol., 60, 940, 10.1001/archneur.60.7.940 Cederholm, 2013, Omega-3 fatty acids in the prevention of cognitive decline in humans, Adv. Nutr. (Bethesda, Md), 4, 672, 10.3945/an.113.004556 Marszalek, 2005, Docosahexaenoic acid, fatty acid-interacting proteins, and neuronal function: breastmilk and fish are good for you, Annu. Rev. Cell Dev. Biol., 21, 633, 10.1146/annurev.cellbio.21.122303.120624 Barberger-Gateau, 2007, Dietary patterns and risk of dementia: the three-city cohort study, Neurology, 69, 1921, 10.1212/01.wnl.0000278116.37320.52 Huang, 2005, Benefits of fatty fish on dementia risk are stronger for those without APOE epsilon4, Neurology, 65, 1409, 10.1212/01.wnl.0000183148.34197.2e Whalley, 2008, n-3 Fatty acid erythrocyte membrane content, APOE epsilon 4, and cognitive variation: an observational follow-up study in late adulthood, Am. J. Clin. Nutr., 87, 449, 10.1093/ajcn/87.2.449 Raji, 2014, Regular fish consumption and age-related brain gray matter loss, Am. J. Prev. Med., 47, 444, 10.1016/j.amepre.2014.05.037 Daiello, 2014, Association of fish oil supplement use with preservation of brain volume and cognitive function, Alzheimers Dement. Yurko-Mauro, 2010, Beneficial effects of docosahexaenoic acid on cognition in age-related cognitive decline, Alzheimers Dement., 6, 456, 10.1016/j.jalz.2010.01.013 Benton, 2013, Supplementation with DHA and the psychological functioning of young adults, Br. J. Nutr., 109, 155, 10.1017/S0007114512000566 Jackson, 2012, No effect of 12 weeks and apos; supplementation with 1g DHA-rich or EPA-rich fish oil on cognitive function or mood in healthy young adults aged 18–35 years, Br. J. Nutr., 107, 1232, 10.1017/S000711451100403X Quinn, 2010, Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial, J. Am. Med. Assoc., 304, 1903, 10.1001/jama.2010.1510 Dangour, 2010, Effect of 2-y n-3 long-chain polyunsaturated fatty acid supplementation on cognitive function in older people: a randomized, double-blind, controlled trial, Am. J. Clin. Nutr., 91, 1725, 10.3945/ajcn.2009.29121 Stonehouse, 2013, DHA supplementation improved both memory and reaction time in healthy young adults: a randomized controlled trial, Am. J. Clin. Nutr., 97, 1134, 10.3945/ajcn.112.053371 Stough, 2012, The effects of 90-day supplementation with the omega-3 essential fatty acid docosahexaenoic acid (DHA) on cognitive function and visual acuity in a healthy aging population, Neurobiol. Aging, 33, 10.1016/j.neurobiolaging.2011.03.019 Lee, 2013, Docosahexaenoic acid-concentrated fish oil supplementation in subjects with mild cognitive impairment (MCI): a 12-month randomised, double-blind, placebo-controlled trial, Psychopharmacology. (Berl)., 225, 605, 10.1007/s00213-012-2848-0 Witte, 2013, Long-chain omega-3 fatty acids improve brain function and structure in older adults, Cereb. cortex Henderson, 2009, Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer׳s disease: a randomized, double-blind, placebo-controlled, multicenter trial, Nutr. Metab. (Lond), 6, 31, 10.1186/1743-7075-6-31 Relkin, 2014, Clinical trials of intravenous immunoglobulin for Alzheimer׳s disease, J. Clin. Immunol., 34, S74, 10.1007/s10875-014-0041-4 Salloway, 2014, Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer׳s disease, N. Engl. J. Med., 370, 322, 10.1056/NEJMoa1304839 Risner, 2006, Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer׳s disease, Pharmacogenomics J., 6, 246, 10.1038/sj.tpj.6500369 Donnelly, 2008, Apolipoprotein E genotypes are associated with lipid-lowering responses to statin treatment in diabetes: a Go-DARTS study, Pharmacogenet. Genomics., 18, 279, 10.1097/FPC.0b013e3282f60aad Harrington, 2011, Rosiglitazone does not improve cognition or global function when used as adjunctive therapy to AChE inhibitors in mild-to-moderate Alzheimer׳s disease: two phase 3 studies, Curr. Alzheimer Res., 8, 592, 10.2174/156720511796391935 Sano, 2011, A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease, Neurology, 77, 556, 10.1212/WNL.0b013e318228bf11 Noetzli, 2013, Pharmacodynamic, pharmacokinetic and pharmacogenetic aspects of drugs used in the treatment of Alzheimer׳s disease, Clin. Pharmacokinet., 52, 225, 10.1007/s40262-013-0038-9 Farrer, 1997, Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium, J. Am. Med. Assoc., 278, 1349, 10.1001/jama.1997.03550160069041 Hauser, 2011, from lipid transport to neurobiology, Prog Lipid Res., 50, 62, 10.1016/j.plipres.2010.09.001 Leduc, 2010, APOE and cholesterol homeostasis in Alzheimer׳s disease, Trends Mol. Med., 16, 469, 10.1016/j.molmed.2010.07.008 Ward, 2012, Prevalence of apolipoprotein E4 genotype and homozygotes (APOE e4/4) among patients diagnosed with Alzheimer׳s disease: a systematic review and meta-analysis, Neuroepidemiology, 38, 1, 10.1159/000334607 Teter, 2007, Life-span influences of apoE4 on CNS function, Neurobiol. Aging, 28, 693, 10.1016/j.neurobiolaging.2006.06.028 Pitas, 1987, Lipoproteins and their receptors in the central nervous system. Characterization of the lipoproteins in cerebrospinal fluid and identification of apolipoprotein B, E (LDL) receptors in the brain, J. Biol. Chem., 262, 14352, 10.1016/S0021-9258(18)47945-8 Aoki, 2003, Increased expression of neuronal apolipoprotein E in human brain with cerebral infarction, Stroke, 34, 875, 10.1161/01.STR.0000064320.73388.C6 Bu, 2009, Apolipoprotein E and its receptors in Alzheimer׳s disease: pathways, pathogenesis and therapy, Nat. Rev. Neurosci., 10, 333, 10.1038/nrn2620 Kim, 2009, The role of apolipoprotein E in Alzheimer׳s disease, Neuron, 63, 287, 10.1016/j.neuron.2009.06.026 Mahley, 2012, Apolipoprotein e sets the stage: response to injury triggers neuropathology, Neuron, 76, 871, 10.1016/j.neuron.2012.11.020 Näslund, 1995, Characterization of stable complexes involving apolipoprotein E and the amyloid beta peptide in Alzheimer׳s disease brain, Neuron, 15, 219, 10.1016/0896-6273(95)90079-9 Strittmatter, 1993, Avid binding of beta A amyloid peptide to its own precursor, Exp. Neurol., 122, 327, 10.1006/exnr.1993.1132 Strittmatter, 1993, Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease, Proc. Natl. Acad. Sci., 90, 8098, 10.1073/pnas.90.17.8098 Beffert, 1999, Apolipoprotein E and beta-amyloid levels in the hippocampus and frontal cortex of Alzheimer׳s disease subjects are disease-related and apolipoprotein E genotype dependent, Brain Res., 843, 87, 10.1016/S0006-8993(99)01894-6 Pirttila, 1997, Apolipoprotein E genotype and amyloid load in Alzheimer disease and control brains, Neurobiol. Aging, 18, 121, 10.1016/S0197-4580(96)00204-7 Tiraboschi, 2004, Impact of APOE genotype on neuropathologic and neurochemical markers of Alzheimer disease, Neurology, 62, 1977, 10.1212/01.WNL.0000128091.92139.0F Sullivan, 1998, Type III hyperlipoproteinemia and spontaneous atherosclerosis in mice resulting from gene replacement of mouse Apoe with human Apoe⁎2, J. Clin. Invest., 102, 130, 10.1172/JCI2673 Buttini, 2002, Modulation of Alzheimer-like synaptic and cholinergic deficits in transgenic mice by human apolipoprotein E depends on isoform, aging, and overexpression of amyloid beta peptides but not on plaque formation, J. Neurosci., 22, 10539, 10.1523/JNEUROSCI.22-24-10539.2002 Dolev, 2004, A nontransgenic mouse model shows inducible amyloid-beta (Abeta) peptide deposition and elucidates the role of apolipoprotein E in the amyloid cascade, Proc. Natl. Acad. Sci., 101, 13909, 10.1073/pnas.0404458101 Fitz, 2012, Abca1 deficiency affects Alzheimer׳s disease-like phenotype in human ApoE4 but not in ApoE3-targeted replacement mice, J. Neurosci., 32, 13125, 10.1523/JNEUROSCI.1937-12.2012 Castellano, 2011, Human apoE isoforms differentially regulate brain amyloid-beta peptide clearance, Sci. Trans. Med., 3, 10.1126/scitranslmed.3002156 Cerf, 2011, High ability of apolipoprotein E4 to stabilize amyloid-beta peptide oligomers, the pathological entities responsible for Alzheimer׳s disease, Fed. Am. Soc. Exp. Biol., 25, 1585 Deane, 2008, apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain, J. Clin. Invest., 118, 4002, 10.1172/JCI36663 Esler, 2002, Apolipoprotein E affects amyloid formation but not amyloid growth in vitro: mechanistic implications for apoE4 enhanced amyloid burden and risk for Alzheimer׳s disease, Amyloid, 9, 1, 10.3109/13506120209072439 Stratman, 2005, Isoform-specific interactions of human apolipoprotein E to an intermediate conformation of human Alzheimer amyloid-beta peptide, Chem. Phys. Lipids., 137, 52, 10.1016/j.chemphyslip.2005.06.005 Verghese, 2013, ApoE influences amyloid-beta (Abeta) clearance despite minimal apoE/Abeta association in physiological conditions, Proc. Natl. Acad. Sci., 110, E1807, 10.1073/pnas.1220484110 Bien-Ly, 2012, Reducing human apolipoprotein E levels attenuates age-dependent Abeta accumulation in mutant human amyloid precursor protein transgenic mice, J. Neurosci., 32, 4803, 10.1523/JNEUROSCI.0033-12.2012 Kim, 2011, Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of amyloid-beta amyloidosis, J. Neurosci., 31, 18007, 10.1523/JNEUROSCI.3773-11.2011 Drzezga, 2009, Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer disease, Neurology, 72, 1487, 10.1212/WNL.0b013e3181a2e8d0 Lehmann, 2014, Greater medial temporal hypometabolism and lower cortical amyloid burden in ApoE4-positive AD patients, J. Neurol. Neurosurg. Psychiatry., 85, 266, 10.1136/jnnp-2013-305858 Ossenkoppele, 2013, Differential effect of APOE genotype on amyloid load and glucose metabolism in AD dementia, Neurology, 80, 359, 10.1212/WNL.0b013e31827f0889 Rowe, 2010, Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, Neurobiol. Aging, 31, 1275, 10.1016/j.neurobiolaging.2010.04.007 Brecht, 2004, Neuron-specific apolipoprotein e4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice, J. Neurosci., 24, 2527, 10.1523/JNEUROSCI.4315-03.2004 Rohn, 2013, Proteolytic cleavage of apolipoprotein E4 as the keystone for the heightened risk associated with Alzheimer׳s disease, Int. J. Mol. Sci., 14, 14908, 10.3390/ijms140714908 Buttini, 2000, Dominant negative effects of apolipoprotein E4 revealed in transgenic models of neurodegenerative disease, Neuroscience, 97, 207, 10.1016/S0306-4522(00)00069-5 Ladu, 1994, Isoform-specific binding of apolipoprotein E to beta-amyloid, J. Biol. Chem., 269, 23403, 10.1016/S0021-9258(17)31529-6 Strittmatter, 1993, Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease, Proc. Natl. Acad. Sci., 90, 1977, 10.1073/pnas.90.5.1977 Strittmatter, 1994, Isoform-specific interactions of apolipoprotein E with microtubule-associated protein tau: implications for Alzheimer disease, Proc. Natl. Acad. Sci., 91, 11183, 10.1073/pnas.91.23.11183 Aboud, 2012, Apolipoprotein epsilon 3 alleles are associated with indicators of neuronal resilience, BMC Med., 10, 35, 10.1186/1741-7015-10-35 Dumanis, 2011, ApoE receptor 2 regulates synapse and dendritic spine formation, PLoS ONE, 6, e17203, 10.1371/journal.pone.0017203 Sen, 2012, Apolipoprotein E3 (ApoE3) but not ApoE4 protects against synaptic loss through increased expression of protein kinase C epsilon, J. Biol. Chem., 287, 15947, 10.1074/jbc.M111.312710 Arendt, 1997, Plastic neuronal remodeling is impaired in patients with Alzheimer׳s disease carrying apolipoprotein epsilon 4 allele, J. Neurosci., 17, 516, 10.1523/JNEUROSCI.17-02-00516.1997 Bertrand, 1995, Association of apolipoprotein E genotype with brain levels of apolipoprotein E and apolipoprotein J (clusterin) in Alzheimer disease, Brain Res. Mol. Brain Res., 33, 174, 10.1016/0169-328X(95)00097-C Pirttila, 1996, Apolipoprotein E (apoE) levels in brains from Alzheimer disease patients and controls, Brain Res., 722, 71, 10.1016/0006-8993(96)00183-7 Ramassamy, 2000, Oxidative insults are associated with apolipoprotein E genotype in Alzheimer׳s disease brain, Neurobiol. Dis., 7, 23, 10.1006/nbdi.1999.0273 Ringman, 2012, Plasma signaling proteins in persons at genetic risk for Alzheimer disease: influence of APOE genotype, Arch. Neurol., 69, 757, 10.1001/archneurol.2012.277 Schiele, 2000, Apolipoprotein E serum concentration and polymorphism in six European countries: the ApoEurope Project, Atherosclerosis, 152, 475, 10.1016/S0021-9150(99)00501-8 van Vliet, 2009, Parental history of Alzheimer disease associated with lower plasma apolipoprotein E levels, Neurology, 73, 681, 10.1212/WNL.0b013e3181b59c2e Johnson, 2014, Apolipoprotein E-low density lipoprotein receptor interaction affects spatial memory retention and brain ApoE levels in an isoform-dependent manner, Neurobiol. Dis., 64, 150, 10.1016/j.nbd.2013.12.016 Riddell, 2008, Impact of apolipoprotein E (ApoE) polymorphism on brain ApoE levels, J. Neurosci., 28, 11445, 10.1523/JNEUROSCI.1972-08.2008 Ulrich, 2013, In vivo measurement of apolipoprotein E from the brain interstitial fluid using microdialysis, Mol. Neurodegener., 8, 13, 10.1186/1750-1326-8-13 Vandal, 2014, Reduction in DHA transport to the brain of mice expressing human APOE4 compared to APOE2, J. Neurochem., 129, 516, 10.1111/jnc.12640 Wahrle, 2008, Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease, J. Clin. Invest., 118, 671 Bray, 2004, Allelic expression of APOE in human brain: effects of epsilon status and promoter haplotypes, Hum. Mol. Genet., 13, 2885, 10.1093/hmg/ddh299 Growdon, 1999, Lack of allelic imbalance in APOE epsilon 3/4 brain mRNA expression in Alzheimer׳s disease, Neurosci. Lett., 272, 83, 10.1016/S0304-3940(99)00557-1 Lambert, 1997, Distortion of allelic expression of apolipoprotein E in Alzheimer׳s disease, Hum. Mol. Genet., 6, 2151, 10.1093/hmg/6.12.2151 Arold, 2012, Apolipoprotein E level and cholesterol are associated with reduced synaptic amyloid beta in Alzheimer׳s disease and apoE TR mouse cortex, Acta Neuropathol., 123, 39, 10.1007/s00401-011-0892-1 Bekris, 2010, APOE mRNA and protein expression in postmortem brain are modulated by an extended haplotype structure, Am. J. Med. Genet. B. Neuropsychiatr. Genet., 153B, 409, 10.1002/ajmg.b.30993 Siest, 2000, Apolipoprotein E polymorphism and serum concentration in Alzheimer׳s disease in nine European centres: the ApoEurope study. ApoEurope group, Clin. Chem. Lab. Med., 38, 721, 10.1515/CCLM.2000.102 Matsui, 2007, Expression of APP pathway mRNAs and proteins in Alzheimer׳s disease, Brain Res., 1161, 116, 10.1016/j.brainres.2007.05.050 Yamagata, 2001, High expression of apolipoprotein E mRNA in the brains with sporadic Alzheimer׳s disease, Dement. Geriatr. Cogn. Disord., 12, 57, 10.1159/000051236 Sastry, 1985, Lipids of nervous tissue: composition and metabolism, Prog. Lipid Res., 24, 69, 10.1016/0163-7827(85)90011-6 Handelmann, 1992, Effects of apolipoprotein E, beta-very low density lipoproteins, and cholesterol on the extension of neurites by rabbit dorsal root ganglion neurons in vitro, J. Lipid Res., 33, 1677, 10.1016/S0022-2275(20)41390-2 Mauch, 2001, CNS synaptogenesis promoted by glia-derived cholesterol, Science, 294, 1354, 10.1126/science.294.5545.1354 Poirier, 1994, Apolipoprotein E in animal models of CNS injury and in Alzheimer׳s disease, Trends Neurosci., 17, 525, 10.1016/0166-2236(94)90156-2 Calderon, 2007, Role of RXR in neurite outgrowth induced by docosahexaenoic acid, Prostaglandins. Leukot. Essent. Fatty Acids, 77, 227, 10.1016/j.plefa.2007.10.026 Darios, 2006, Omega-3 and omega-6 fatty acids stimulate cell membrane expansion by acting on syntaxin 3, Nature, 440, 813, 10.1038/nature04598 Martin, 2000, Uptake and incorporation of docosahexaenoic acid (DHA) into neuronal cell body and neurite/nerve growth cone lipids: evidence of compartmental DHA metabolism in nerve growth factor-differentiated PC12 cells, Neurochem. Res., 25, 715, 10.1023/A:1007575406896 Robson, 2010, Omega-3 polyunsaturated fatty acids increase the neurite outgrowth of rat sensory neurones throughout development and in aged animals, Neurobiol. Aging, 31, 678, 10.1016/j.neurobiolaging.2008.05.027 Wurtman, 2009, Synapse formation is enhanced by oral administration of uridine and DHA, the circulating precursors of brain phosphatide, J. Nutr. Health Aging, 13, 189, 10.1007/s12603-009-0056-3 He, 2009, Improved spatial learning performance of fat-1 mice is associated with enhanced neurogenesis and neuritogenesis by docosahexaenoic acid, Proc. Natl. Acad. Sci., 106, 11370, 10.1073/pnas.0904835106 Arsenault, 2011, DHA improves cognition and prevents dysfunction of entorhinal cortex neurons in 3xTg-AD mice, PLoS ONE, 6, e17397, 10.1371/journal.pone.0017397 Ahmad, 2002, A decrease in cell size accompanies a loss of docosahexaenoate in the rat hippocampus, Nutr. Neurosci., 5, 103, 10.1080/10284150290018973 Bousquet, 2008, Beneficial effects of dietary omega-3 polyunsaturated fatty acid on toxin-induced neuronal degeneration in an animal model of Parkinson's disease, Fed. Am. Soc. Exp. Biol., 22, 1213 Bousquet, 2009, Modulation of brain-derived neurotrophic factor as a potential neuroprotective mechanism of action of omega-3 fatty acids in a parkinsonian animal model, Prog. Neuropsychopharmacol. Biol. Psychiatry, 33, 1401, 10.1016/j.pnpbp.2009.07.018 Wu, 2008, Docosahexaenoic acid dietary supplementation enhances the effects of exercise on synaptic plasticity and cognition, Neuroscience, 155, 751, 10.1016/j.neuroscience.2008.05.061 Kawakita, 2006, Docosahexaenoic acid promotes neurogenesis in vitro and in vivo, Neuroscience, 139, 991, 10.1016/j.neuroscience.2006.01.021 Igbavboa, 2002, A new role for apolipoprotein E: modulating transport of polyunsaturated phospholipid molecular species in synaptic plasma membranes, J. Neurochem., 80, 255, 10.1046/j.0022-3042.2001.00688.x Hayek, 1998, Antiatherosclerotic and antioxidative effects of captopril in apolipoprotein E-deficient mice, J. Cardiovasc. Pharmacol., 31, 540, 10.1097/00005344-199804000-00011 Smith, 1998, The relationship between apolipoprotein E and serum oxidation-related variables is apolipoprotein E phenotype dependent, Int. J. Clin. Lab. Res., 28, 116, 10.1007/s005990050030 Bassett, 2003, Lipoproteins and lipid peroxidation in Alzheimer׳s disease, J. Nutr. Health Aging, 7, 24 Chinnici, 2005, Absence of 12/15 lipoxygenase reduces brain oxidative stress in apolipoprotein E-deficient mice, Am. J. Pathol., 167, 1371, 10.1016/S0002-9440(10)61224-2 Reich, 2001, Brain regional quantification of F-ring and D-/E-ring isoprostanes and neuroprostanes in Alzheimer׳s disease, Am. J. Pathol., 158, 293, 10.1016/S0002-9440(10)63968-5 Reich, 2001, Interactions between apolipoprotein E gene and dietary alpha-tocopherol influence cerebral oxidative damage in aged mice, J. Neurosci., 21, 5993, 10.1523/JNEUROSCI.21-16-05993.2001 Montine, 2005, Fatty acid oxidation in the pathogenesis of Alzheimer׳s disease, Am. J. Pathol., 166, 1283, 10.1016/S0002-9440(10)62347-4 Lebbadi, 2011, Endogenous conversion of omega-6 into omega-3 fatty acids improves neuropathology in an animal model of Alzheimer׳s disease, J. Alzheimers Dis., 27, 853, 10.3233/JAD-2011-111010 Lim, 2005, A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model, J. Neurosci., 25, 3032, 10.1523/JNEUROSCI.4225-04.2005 Green, 2007, Dietary docosahexaenoic acid and docosapentaenoic acid ameliorate amyloid-beta and tau pathology via a mechanism involving presenilin 1 levels, J. Neurosci., 27, 4385, 10.1523/JNEUROSCI.0055-07.2007 Calon, 2004, Docosahexaenoic acid protects from dendritic pathology in an Alzheimer׳s disease mouse model, Neuron, 43, 633, 10.1016/j.neuron.2004.08.013 Calon, 2005, Dietary n-3 polyunsaturated fatty acid depletion activates caspases and decreases NMDA receptors in the brain of a transgenic mouse model of Alzheimer׳s disease, Eur. J. Neurosci., 22, 617, 10.1111/j.1460-9568.2005.04253.x Perez, 2010, DHA diet reduces AD pathology in young APPswe/PS1 Delta E9 transgenic mice: possible gender effects, J. Neurosci. Res., 88, 1026 Hooijmans, 2009, DHA and cholesterol containing diets influence Alzheimer-like pathology, cognition and cerebral vasculature in APPswe/PS1dE9 mice, Neurobiol. Dis., 33, 482, 10.1016/j.nbd.2008.12.002 Plourde, 2009, Plasma n-3 fatty acid response to an n-3 fatty acid supplement is modulated by apoE epsilon4 but not by the common PPAR-alpha L162V polymorphism in men, Br. J. Nutr., 102, 1121, 10.1017/S000711450938215X Samieri, 2013, Relationship between diet and plasma long-chain n-3 PUFAs in older people: impact of apolipoprotein E genotype, J. Lipid Res., 54, 2559, 10.1194/jlr.P036475 Chouinard-Watkins, 2013, Disturbance in uniformly 13C-labelled DHA metabolism in elderly human subjects carrying the apoE epsilon4 allele, Br. J. Nutr., 110, 1751, 10.1017/S0007114513001268 Edmond, 2001, Essential polyunsaturated fatty acids and the barrier to the brain: the components of a model for transport, J. Mol. Neurosci., 16, 181, 10.1385/JMN:16:2-3:181 Mitchell, 2011, Fatty acid transport into the brain: of fatty acid fables and lipid tails, Prostaglandins Leukot. Essent. Fatty Acids, 85, 293, 10.1016/j.plefa.2011.04.007 Hamilton, 2007, A model for fatty acid transport into the brain, J. Mol. Neurosci., 33, 12, 10.1007/s12031-007-0050-3 Ouellet, 2009, Diffusion of docosahexaenoic and eicosapentaenoic acids through the blood–brain barrier: An in situ cerebral perfusion study, Neurochem. Int., 55, 476, 10.1016/j.neuint.2009.04.018 Hamilton, 2007, New insights into the roles of proteins and lipids in membrane transport of fatty acids, Prostaglandins Leukot. Essent. Fatty Acids, 77, 355, 10.1016/j.plefa.2007.10.020 Spector, 2001, Plasma free fatty acid and lipoproteins as sources of polyunsaturated fatty acid for the brain, J. Mol. Neurosci., 16, 159, 10.1385/JMN:16:2-3:159 Weisgraber, 1982, Abnormal lipoprotein receptor-binding activity of the human E apoprotein due to cysteine–arginine interchange at a single site, J. Biol. Chem., 257, 2518, 10.1016/S0021-9258(18)34954-8 Fullerton, 2001, Impairment of the blood–nerve and blood–brain barriers in apolipoprotein e knockout mice, Exp. Neurol., 169, 13, 10.1006/exnr.2001.7631 Hafezi-Moghadam, 2007, ApoE deficiency leads to a progressive age-dependent blood–brain barrier leakage, Am. J. Physiol. Cell Physiol., 292, C1256, 10.1152/ajpcell.00563.2005 Kalaria, 1995, Increased collagen content of cerebral microvessels in Alzheimer׳s disease, Brain Res., 705, 349, 10.1016/0006-8993(95)01250-8 Tong, 2005, Vascular remodeling versus amyloid beta-induced oxidative stress in the cerebrovascular dysfunctions associated with Alzheimer׳s disease, J. Neurosci., 25, 11165, 10.1523/JNEUROSCI.4031-05.2005 Zarow, 1997, Vascular basement membrane pathology and Alzheimer׳s disease, Ann. NY Acad. Sci., 826, 147, 10.1111/j.1749-6632.1997.tb48467.x Bourasset, 2009, Reduction of the cerebrovascular volume in a transgenic mouse model of Alzheimer׳s disease, Neuropharmacology, 56, 808, 10.1016/j.neuropharm.2009.01.006 Gama Sosa, 2010, Age-related vascular pathology in transgenic mice expressing presenilin 1-associated familial Alzheimer׳s disease mutations, Am. J. Pathol., 176, 353, 10.2353/ajpath.2010.090482 Salloway, 2002, Effect of APOE genotype on microvascular basement membrane in Alzheimer׳s disease, J. Neurol. Sci., 203–204, 183, 10.1016/S0022-510X(02)00288-5 Zipser, 2007, Microvascular injury and blood–brain barrier leakage in Alzheimer disease, Neurobiol. Aging, 28, 977, 10.1016/j.neurobiolaging.2006.05.016 Bell, 2012, Apolipoprotein E controls cerebrovascular integrity via cyclophilin A, Nature, 485, 512, 10.1038/nature11087 Nishitsuji, 2011, Apolipoprotein E regulates the integrity of tight junctions in an isoform-dependent manner in an in vitro blood–brain barrier model, J. Biol. Chem., 286, 17536, 10.1074/jbc.M111.225532 Emery, 2011, Alzheimer disease: are we intervening too late? Pro, J. Neural. Transm., 118, 1361, 10.1007/s00702-011-0663-0 Cummings, 2007, Disease-modifying therapies for Alzheimer disease: challenges to early intervention, Neurology, 69, 1622, 10.1212/01.wnl.0000295996.54210.69 Aisen, 2013, Moving towards early clinical trials for amyloid-targeted therapy in Alzheimer׳s disease, Nat. Rev. Drug Discov., 12, 324, 10.1038/nrd3842-c1 Calon, 2011, Omega-3 polyunsaturated fatty acids in Alzheimer׳s Disease: key questions and partial answers, Curr. Alzheimer. Res., 8, 470, 10.2174/156720511796391881