Role of apolipoprotein E in neurodegenerative diseases

Neuropsychiatric Disease and Treatment

Volumn 11, Issue , 2015, Pages 1723-1737

  Giau, Vo Van ^a   Bagyinszky, Eva ^a   An, Seong Soo A ^a   Kim, Sang Yun ^b  

^a Gachon University College of Medicine   (South Korea)

^b Seoul National University College of Medicine   (South Korea)

Author keywords

Apolipoprotein E; Diseases; Pathogenesis

Indexed keywords

APOLIPOPROTEIN E;

ALZHEIMER DISEASE; BRAIN ISCHEMIA; DEGENERATIVE DISEASE; DNA POLYMORPHISM; GENE MUTATION; GENETIC ASSOCIATION; HUMAN; HYPERLIPOPROTEINEMIA TYPE 3; MULTIINFARCT DEMENTIA; MULTIPLE SCLEROSIS; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PARKINSON DISEASE; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; RISK ASSESSMENT;

EID: 84937553252     PISSN: None     EISSN: 11782021     Source Type: Journal    
DOI: 10.2147/NDT.S84266     Document Type: Review

References (191)

1. Rall SC Jr, Weisgraber KH, Mahley RW. Human apolipoprotein E. The complete amino acid sequence. J Biol Chem. 1982;257(8):4171-4178.
2. Mahley RW, Huang Y. Apolipoprotein E: from atherosclerosis to Alzheimer's disease and beyond. Curr Opin Lipidol. 1999; 10(3):207-217.
3. Mahley RW, Rall SC. Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet. 2000;1:507-537.
4. Rall SC, Weisgraber KH, Innerarity TL, Mahley RW. Structural basis for receptor binding heterogeneity of apolipoprotein E from type III hyperlipoproteinemic subjects. Proc Natl Acad Sci U S A. 1982; 79(15):4696-4700.
5. Emi M, Wu LL, Robertson MA, et al. Genotyping and sequence analysis of apolipoprotein Eisoforms. Genomics. 1988;3(4):373-379.
6. Utermann G, Hees M, Steinmetz A. Polymorphism of apolipoprotein E and occurrence of dysbetalipoproteinaemia in man. Nature. 1977;269(5629):604-607.
7. Ehnholm C, Lukka M, Kuusi T, Nikkilä E, Utermann G. Apolipoprotein E polymorphism in the Finnish population: gene frequencies and relation to lipoprotein concentrations. J Lipid Res. 1986;27(3):227-235.
8. Eichner JE, Dunn ST, Perveen G, Thompson DM, Stewart KE, Stroehla BC. Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review. Am J Epidemiol. 2002;155(6):487-495.
9. Nguyen D, Dhanasekaran P, Nickel M, et al. Molecular basis for the differences in lipid and lipoprotein binding properties of human apolipoproteins E3 and E4. Biochemistry. 2010;49(51):10881-10889.
10. Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988;240(4852):622-630.
11. Zannis VI, Breslow JL, Utermann G, et al. Proposed nomenclature of apoE isoproteins, apoE genotypes, and phenotypes. J Lipid Res. 1982;23(6):911-914.
12. Zhang H, Wu LM, Wu J. Cross-talk between apolipoprotein E and cytokines. Mediators Inflamm. 2011;2011:949072.
13. Dietschy JM, Turley SD. Thematic review series: brain Lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal. J Lipid Res. 2004;45(8):1375-1397.
14. Saher G, Brügger B, Lappe-Siefke C, et al. High cholesterol level is essential for myelin membrane growth. Nat Neurosci. 2005;8(4):468-475.
15. Mauch DH, Nägler K, Schumacher S, et al. CNS synaptogenesis promoted by glia-derived cholesterol. Science. 2001;294(5545): 1354-1357.
16. Pfrieger FW. Cholesterol homeostasis and function in neurons of the central nervous system. Cell Mol Life Sci. 2003;60(6):1158-1171.
17. Poirier J, Hess M, May PC, Finch CE. Astrocytic apolipoprotein E mRNA and GFAP mRNA in hippocampus after entorhinal cortex lesioning. Brain Res Mol Brain Res. 1991;11(2):97-106.
18. Bien-Ly N, Gillespie AK, Walker D, Yoon SY, Huang Y. Reducing human apolipoprotein E levels attenuates age-dependent Aβ accumulation in mutant human amyloid precursor protein transgenic mice. J Neurosci. 2012;32(14):4803-4811.
19. Kim J, Jiang H, Park S, et al. Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of amyloid-beta amyloidosis. J Neurosci. 2011;31(49):18007-18012.
20. Ordovas JM, Litwack-Klein L, Wilson PW, Schaefer MM, Schaefer EJ. Apolipoprotein E isoform phenotyping methodology and population frequency with identification of apoE1 and apoE5 isoforms. J Lipid Res. 1987;28(4):371-380.
21. Singh PP, Singh M, Mastana SS. APOE distribution in world populations with new data from India and the UK. Ann Hum Biol. 2006;33(3):279-308.
22. Wetterau JR, Aggerbeck LP, Rall SC, Weisgraber KH. Human apolipoprotein E3 in aqueous solution. I. Evidence for two structural domains. J Biol Chem. 1988;263(13):6240-6248.
23. Chen J, Li Q, Wang J. Topology of human apolipoprotein E3 uniquely regulates its diverse biological functions. Proc Natl Acad Sci U S A. 2011;108(36):14813-14818.
24. Segrest JP, Jones MK, De Loof H, Brouillette CG, Venkatachalapathi YV, Anantharamaiah GM. The amphipathic helix in the exchangeable apolipoproteins: a review of secondary structure and function. J Lipid Res. 1992;33(2):141-166.
25. Westerlund JA, Weisgraber KH. Discrete carboxyl-terminal segments of apolipoprotein E mediate lipoprotein association and protein oligomerization. J Biol Chem. 1993;268(21):15745-15750.
26. Weisgraber KH, Rall SC, Mahley RW. Human E apoprotein heterogeneity. Cysteine-arginine interchanges in the amino acid sequence of the apo-E isoforms. J Biol Chem. 1981;256(17):9077-9083.
27. Papaioannou I, Simons JP, Owen JS. Targeted In Situ Gene Correction of Dysfunctional APOE Alleles to Produce Atheroprotective Plasma ApoE3 Protein. Cardiol Res Pract. 2012;2012:148796.
28. Ezquerra M, Campdelacreu J, Gaig C, et al. Lack of association of APOE and tau polymorphisms with dementia in Parkinson's disease. Neurosci Lett. 2008;448(1):20-23.
29. Federoff M, Jimenez-Rolando B, Nalls MA, Singleton AB. A large study reveals no association between APOE and Parkinson's disease. Neurobiol Dis. 2012;46(2):389-392.
30. Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013;9(2):106-118.
31. Russo C, Angelini G, Dapino D, et al. Opposite roles of apolipoprotein E in normal brains and in Alzheimer's disease. Proc Natl Acad Sci U S A. 1998;95(26):15598-15602.
32. Tokuda T, Calero M, Matsubara E, et al. Lipidation of apolipoprotein E influences its isoform-specific interaction with Alzheimer 's amyloid beta peptides. Biochem J. 2000;348 Pt 2:359-365.
33. Manelli AM, Stine WB, Van Eldik LJ, LaDu MJ. ApoE and Abeta1-42 interactions: effects of isoform and conformation on structure and function. J Mol Neurosci. 2004;23(3):235-246.
34. LaDu MJ, Munson GW, Jungbauer L, et al. Preferential interactions between ApoE-containing lipoproteins and Aβ revealed by a detection method that combines size exclusion chromatography with non-reducing gel-shift. Biochim Biophys Acta. 2012;1821(2): 295-302.
35. Lehtinen S, Lehtimäki T, Sisto T, et al. Apolipoprotein E polymorphism, serum lipids, myocardial infarction and severity of angiographically verified coronary artery disease in men and women. Atherosclerosis. 1995;114(1):83-91.
36. Muros M, Rodríguez-Ferrer C. Apolipoprotein E polymorphism influence on lipids, apolipoproteins and Lp(a) in a Spanish population underexpressing apo E4. Atherosclerosis. 1996;121(1):13-21.
37. Ribalta J, Vallvé JC, Girona J, Masana L. Apolipoprotein and apolipoprotein receptor genes, blood lipids and disease. Curr Opin Clin Nutr Metab Care. 2003;6(2):177-187.
38. Alzheimer A. Uber eine eigenartige Erkrankung der Hinrinde (Concerning a novel Disease of the cortex). Allgemeine Zeitschrift for Psychiatrie. 1907;64:146-148. German.
39. Alzheimer's Association. 2013 Alzheimer's disease facts and figures. Alzheimers Dement. 2013;9(2):208-245.
40. Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA. Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol. 2003;60(8):1119-1122.
41. Näslund J, Thyberg J, Tjernberg LO, et al. Characterization of stable complexes involving apolipoprotein E and the amyloid beta peptide in Alzheimer's disease brain. Neuron. 1995;15(1):219-228.
42. Wisniewski T, Frangione B. Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid. Neurosci Lett. 1992;135(2):235-238.
43. Poirier J, Davignon J, Bouthillier D, Kogan S, Bertrand P, Gauthier S. Apolipoprotein E polymorphism and Alzheimer's disease. Lancet. 1993;342(8873):697-699.
44. Rebeck GW, Reiter JS, Strickland DK, Hyman BT. Apolipoprotein E in sporadic Alzheimer's disease: allelic variation and receptor interactions. Neuron. 1993;11(4):575-580.
45. Strittmatter WJ, Saunders AM, Schmechel D, et al. 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 U S A. 1993;90(5):1977-1981.
46. Carrasquillo MM, Zou F, Pankratz VS, et al. Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer's disease. Nat Genet. 2009;41(2):192-198.
47. Li H, Wetten S, Li L, et al.Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease. Arch Neurol. 2008;65(1):45-53.
48. Reiman EM, Webster JA, Myers AJ, et al. GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers. Neuron. 2007;54(5):713-720.
49. Namba Y, Tomonaga M, Kawasaki H, Otomo E, Ikeda K. Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer's disease and kuru plaque amyloid in Creutzfeldt-Jakob disease. Brain Res. 1991;541(1):163-166.
50. Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993;261(5123):921-923.
51. Roses AD. Apolipoprotein E alleles as risk factors in Alzheimer's disease. Annu Rev Med. 1996;47:387-400.
52. Selkoe DJ, Schenk D. Alzheimer's disease: molecular understanding predicts amyloid-based therapeutics. Annu Rev Pharmacol Toxicol. 2003;43:545-584.
53. Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE. Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet. 2007;39(1):17-23.
54. Corder EH, Saunders AM, Risch NJ, et al. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet. 1994;7(2):180-184.
55. Farrer LA, Cupples LA, Haines JL, et al. 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. JAMA. 1997;278(16):1349-1356.
56. Hébert R, Brayne C. Epidemiology of vascular dementia. Neuroepidemiology. 1995;14(5):240-257.
57. Jellinger KA. Pathology and pathogenesis of vascular cognitive impairment-a critical update. Front Aging Neurosci. 2013;5:17.
58. Kalaria RN. Comparison between Alzheimer's disease and vascular dementia: implications for treatment. Neurol Res. 2003;25(6):661-664.
59. Laitinen MH, Ngandu T, Rovio S, et al. Fat intake at midlife and risk of dementia and Alzheimer's disease: a population-based study. Dement Geriatr Cogn Disord. 2006;22(1):99-107.
60. Luchsinger JA, Tang MX, Shea S, Mayeux R. Caloric intake and the risk of Alzheimer disease. Arch Neurol. 2002;59(8):1258-1263.
61. Baum L, Lam LCW, Kwok T, et al. Apolipoprotein E ε4 allele is associated with vascular dementia. Dement Geriatr Cogn Disord. 2006;22(4):301-305.
62. Chuang YF, Hayden KM, Norton MC, et al. Association between APOE epsilon4 allele and vascular dementia: The Cache County study. Dement Geriatr Cogn Disord. 2010;29(3):248-253.
63. Liu X, Li L, Liu F, et al. ApoE gene polymorphism and vascular dementia in Chinese population: a meta-analysis. J Neural Transm. 2012;119(3):387-394.
64. Yin YW, Li JC, Wang JZ, et al. Association between apolipoprotein E gene polymorphism and the risk of vascular dementia: a metaanalysis. Neurosci Lett. 2012;514(1):6-11.
65. Helisalmi S, Linnaranta K, Lehtovirta M, et al. Apolipoprotein E polymorphism in patients with different neurodegenerative disorders. Neurosci Lett. 1996;205(1):61-64.
66. Kawamata J, Tanaka S, Shimohama S, Ueda K, Kimura J. Apolipoprotein E polymorphism in Japanese patients with Alzheimer's disease or vascular dementia. J Neurol Neurosurg Psychiatry. 1994;57(11): 1414-1416.
67. Prince M, Lovestone S, Cervilla J, et al. The association between APOE and dementia does not seem to be mediated by vascular factors. Neurology. 2000;54(2):397-402.
68. Fuster V, Kelly BB. Promoting Cardiovascular Health in the Developing World: A Critical Challenge to Achieve Global Health. Washington, DC: National Academies Press; 2010.
69. Stengård JH, Weiss KM, Sing CF. An ecological study of association between coronary heart disease mortality rates in men and the relative frequencies of common allelic variations in the gene coding for apolipoprotein E. Hum Genet. 1998;103(2):234-241.
70. Eichner JE, Kuller LH, Orchard TJ, et al. Relation of apolipoprotein E phenotype to myocardial infarction and mortality from coronary artery disease. Am J Cardiol. 1993;71(2):160-165.
71. Stengård JH, Pekkanen J, Sulkava R, Ehnholm C, Erkinjuntti T, Nissinen A. Apolipoprotein E polymorphism, Alzheimer's disease and vascular dementia among elderly Finnish men. Acta Neurol Scand. 1995;92(4):297-298.
72. Schiele F, De Bacquer D, Vincent-Viry M, et al. Apolipoprotein E serum concentration and polymorphism in six European countries: the ApoEurope Project. Atherosclerosis. 2000;152(2):475-488.
73. Mahley RW, Huang Y, Rall SC Jr. Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia). Questions, quandaries, and paradoxes. J Lipid Res. 1999;40(11):1933-1949.
74. Mabuchi H, Itoh H, Takeda M, et al. A young type III hyperlipoproteinemic patient associated with apolipoprotein E deficiency. Metabolism. 1989;38(2):115-119.
75. Schaefer EJ, Gregg RE, Ghiselli G, et al. Familial apolipoprotein E deficiency. J Clin Invest. 1986;78(5):1206-1219.
76. Davignon J, Gregg RE, Sing CF. Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis. 1988;8(1):1-21.
77. Visser ME, Dallinga-Thie GM, Pinto-Sietsma SJ, Defesche JC, Stroes ES, van der Valk PR. APOE1 mutation in a patient with type III hyperlipoproteinaemia: detailed genetic analysis required. Neth J Med. 2012;70(6):278-280.
78. de Knijff P, van den Maagdenberg AM, Boomsma DI, et al. Variable expression of familial dysbetalipoproteinemia in apolipoprotein E*2 (Lys146 → Gln) Allele carriers. J Clin Invest. 1994;94(3):1252-1262.
79. Hoffer MJ, Niththyananthan S, Naoumova RP, et al. Apolipoprotein E1-Hammersmith E1 (Lys146Asn; Arg147Trp), due to a dinucleotide substitution, is associated with early manifestation of dominant type III hyperlipoproteinaemia. Atherosclerosis. 1996;124(2):183-189.
80. Hoffmann MM, Scharnagl H, Köster W, Winkler K, Wieland H, März W. Apolipoprotein E1 Baden (Arg(180) → Cys). A new apolipoprotein E variant associated with hypertriglyceridemia. Clin Chim Acta. 2001;303(1-2):41-48.
81. Mann AW, Gregg RE, Ronan R, Fairwell T, Hoeg JM, Brewer HB. Apolipoprotein E-I Harrisburg, a mutation in the receptor binding domain, that is dominant for dysbetalipoproteinemia results in defective ligand-receptor interactions. Clin Res. 1989;37(2):A520.
82. März W, Hoffmann MM, Scharnagl H, et al. Apolipoprotein E2 (Arg136Cys) mutation in the receptor binding domain of apoE is not associated with dominant type hyperlipoproteinemia. J Lipid Res. 1998;39(3):658-669.
83. Rall SC, Weisgraber KH, Innerarity TL, Bersot TP, Mahley RW, Blum CB. Identification of a new structural variant of human apolipoprotein E, E2(Lys146 leads to Gln), in a type III hyperlipoproteinemic subject with the E3/2 phenotype. J Clin Invest. 1983;72(4):1288-1297.
84. Walden CC, Huff MW, Leiter LA, Connelly PW, Hegele RA. Detection of a new apolipoprotein-E mutation in type III hyperlipidemia using deoxyribonucleic acid restriction isotyping. J Clin Endocrinol Metab. 1994;78(3):699-704.
85. Weisgraber KH, Rall SC, Innerarity TL, Mahley RW, Kuusi T, Ehnholm C. A novel electrophoretic variant of human apolipoprotein E. Identification and characterization of apolipoprotein E1. J Clin Invest. 1984;73(4):1024-1033.
86. Hughes AJ, Daniel SE, Lees AJ. The clinical features of Parkinson's disease in 100 histologically proven cases. Adv Neurol. 1993;60:595-599.
87. Li YJ, Hauser MA, Scott WK, et al. Apolipoprotein E controls the risk and age at onset of Parkinson disease. Neurology. 2004;62(11):2005-2009.
88. Pulkes T, Papsing C, Mahasirimongkol S, Busabaratana M, Kulkantrakorn K, Tiamkao S. Association between apolipoprotein E genotypes and Parkinson's disease. J Clin Neurosci. 2011; 18(10):1333-1335.
89. Buchanan DD, Silburn PA, Prince JA, Mellick GD. Association of APOE with Parkinson disease age-at-onset in women. Neurosci Lett. 2007;411(3):185-188.
90. Kurz MW, Dekomien G, Nilsen OB, Larsen JP, Aarsland D, Alves G. APOE alleles in Parkinson disease and their relationship to cognitive decline: a population-based, longitudinal study. J Geriatr Psychiatry Neurol. 2009;22(3):166-170.
91. Ryu HG, Kwon OD. Apolipoprotein E epsilon 4 allele is not associated with age at onset or MMSE of Parkinson's disease in a Korean study. Parkinsonism Relat Disord. 2010;16(9):615-617.
92. Harhangi BS, de Rijk MC, van Duijn CM, Van Broeckhoven C, Hofman A, Breteler MM. APOE and the risk of PD with or without dementia in a population-based study. Neurology. 2000;54(6):1272-1276.
93. Huang X, Chen PC, Poole C. APOE-[epsilon]2 allele associated with higher pevalence of sporadic Parkinson disease. Neurology. 2004;62(12):2198-2202.
94. Gulliford MC, Charlton J. Is relative mortality of type 2 diabetes mellitus decreasing? Am J Epidemiol. 2009;169(4):455-461.
95. King H, Aubert RE, Herman WH. Global burden of diabetes, 1995-2025: prevalence, numerical estimates, and projections. Diabetes Care. 1998;21(9):1414-1431.
96. Ripsin CM, Kang H, Urban RJ. Management of blood glucose in type 2 diabetes mellitus. Am Fam Physician. 2009;79(1):29-36.
97. Risérus U, Willett WC, Hu FB. Dietary fats and prevention of type 2 diabetes. Prog Lipid Res. 2009;48(1):44-51.
98. Stewart R, Liolitsa D. Type 2 diabetes mellitus, cognitive impairment and dementia. Diabet Med. 1999;16(2):93-112.
99. Li L, Hölscher C. Common pathological processes in Alzheimer disease and type 2 diabetes: a review. Brain Res Rev. 2007;56(2): 384-402.
100. Greenow K, Pearce NJ, Ramji DP. The key role of apolipoprotein E in atherosclerosis. J Mol Med (Berl). 2005;83(5):329-342.
101. Guan J, Zhao HL, Baum L, et al. Apolipoprotein E polymorphism and expression in type 2 diabetic patients with nephropathy: clinicopathological correlation. Nephrol Dial Transplant. 2009;24(6):1889-1895.
102. Shen HL, Liu LM, Xiang KS, et al. Relationship between ApoE gene polymorphism and type 2 diabetes mellitus with its nephropathy in Chinese. Chin J Diabetes. 2002;10:4-6. Chinese.
103. Xiang Q, Wu YB, Song DP, et al. The study of the association of apolipoprotein E (ApoE) gene polymorphism with diabetic nephropathy in type 2 diabetic patients. Chin J Diabetes. 2010;18:185-186. Chinese.
104. Zhang GW, Zhang AZ, Xu ZF. Association study of apolipoprotein E gene polymorphism and type 2 diabetic nephropathy in Chinese population. Zhejiang Clin Med J. 2007;9:735-736.
105. Pan XR, Yang WY, Li GW, Liu J. Prevalence of diabetes and its risk factors in China, 1994. National Diabetes Prevention and Control Cooperative Group. Diabetes Care. 1997;20(11):1664-1669.
106. Ramachandran A, Snehalatha C, Baskar AD, et al. Temporal changes in prevalence of diabetes and impaired glucose tolerance associated with lifestyle transition occurring in the rural population in India. Diabetologia. 2004;47(5):860-865.
107. Yin YW, Qiao L, Sun QQ, et al. Influence of apolipoprotein E gene polymorphism on development of type 2 diabetes mellitus in Chinese Han population: a meta-analysis of 29 studies. Metabolism. 2014;63(4):532-541.
108. Xie YQ, Wang H, Wu YP, Yin DH, Wang ZS, Huang YH. Association of APOE polymorphisms and insulin resistance with TCM syndromes in type 2 diabetes patients with macroangiopathy. Mol Med Rep. 2011;4(6):1219-1223.
109. Xiong Y, Zhou X, Liu SM, et al. The association of apolipoprotein E genotype with type 2 diabetes mellitus. Chin J Microcirc. 2008;18:28-33.
110. Yang XJ, Xiang GD, Ding XH, et al. Relation between coronary heart disease and apolipoprotein E genotype in NIDDM patients in Wuhan. Chin J Endocrinol Metab. 1995;11:206-210.
111. Dore GA, Elias MF, Robbins MA, Elias PK, Nagy Z. Presence of the APOE epsilon4 allele modifies the relationship between type 2 diabetes and cognitive performance: the Maine-Syracuse Study. Diabetologia. 2009;52(12):2551-2560.
112. Berer K, Krishnamoorthy G. Microbial view of central nervous system autoimmunity. FEBS Lett. 2014;588(22):4207-4213.
113. Milo R, Kahana E. Multiple sclerosis: geoepidemiology, genetics and the environment. Autoimmun Rev. 2010;9(5):A387-A394.
114. Pericak-Vance MA, Rimmler JB, Haines JL, et al. Investigation of seven proposed regions of linkage in multiple sclerosis: an American and French collaborative study. Neurogenetics. 2004;5(1):45-48.
115. Sawcer S, Maranian M, Setakis E, et al. A whole genome screen for linkage disequilibrium in multiple sclerosis confirms disease associations with regions previously linked to susceptibility. Brain. 2002;125(Pt 6):1337-1347.
116. Parmenter BA, Shucard JL, Benedict RH, Shucard DW. Working memory deficits in multiple sclerosis: comparison between the n-back task and the Paced Auditory Serial Addition Test. J Int Neuropsychol Soc. 2006;12(5):677-687.
117. Savettieri G, Messina D, Andreoli V, et al. Gender-related effect of clinical and genetic variables on the cognitive impairment in multiple sclerosis. J Neurol. 2004;251(10):1208-1214.
118. Pinholt M, Frederiksen JL, Christiansen M. The association between apolipoprotein E and multiple sclerosis. Eur J Neurol. 2006;13(6):573-580.
119. Shi J, Zhao CB, Vollmer TL, Tyry TM, Kuniyoshi SM. APOE epsilon 4 allele is associated with cognitive impairment in patients with multiple sclerosis. Neurology. 2008;70(3):185-190.
120. van der Walt A, Stankovich J, Bahlo M, et al. Apolipoprotein genotype does not influence MS severity, cognition, or brain atrophy. Neurology. 2009;73(13):1018-1025.
121. Oliveri RL, Cittadella R, Sibilia G, et al. APOE and risk of cognitive impairment in multiple sclerosis. Acta Neurol Scand. 1999;100(5): 290-295.
122. Koutsis G, Panas M, Giogkaraki E, et al. APOE epsilon4 is associated with impaired verbal learning in patients with MS. Neurology. 2007;68(8):546-549.
123. Lill CM, Liu T, Schjeide BM, et al; ANZgene Consortium. Closing the case of APOE in multiple sclerosis: no association with disease risk in over 29,000 subjects. J Med Genet. 2012;49(9):558-562.
124. Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet. 2006;367(9524):1747-1757.
125. Feigin VL, Forouzanfar MH, Krishnamurthi R, et al; Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) and the GBD Stroke Experts Group. Global and regional burden of stroke during 1990-2010: findings from the Global Burden of Disease Study 2010. Lancet. 2014;383(9913):245-254.
126. Wilson PW, Schaefer EJ, Larson MG, Ordovas JM. Apolipoprotein E alleles and risk of coronary disease. A meta-analysis. Arterioscler Thromb Vasc Bioi. 1996;16(10):1250-1255.
127. Luthra K, Prasad K, Kumar P, Dwivedi M, Pandey RM, Das N. Apolipoprotein E gene polymorphism in cerebrovascular disease: a case-control study. Clin Genet. 2002;62(1):39-44.
128. Peng DQ, Zhao SP, Wang JL. Lipoprotein (a) and apolipoprotein E epsilon 4 as independent risk factors for ischemic stroke. J Cardiovasc Risk. 1999;6(1):1-6.
129. McCarron MO, Delong D, Alberts MJ. APOE genotype as a risk factor for ischemic cerebrovascular disease: a meta-analysis. Neurology. 1999;53(6):1308-1311.
130. Treger I, Froom P, Ring H, Friedman G. Association between apolipoprotein E4 and rehabilitation outcome in hospitalized ischemic stroke patients. Arch Phys Med Rehabil. 2003;84(7):973-976.
131. Paternoster L, Martínez González NA, Lewis S, Sudlow C. Association between apolipoprotein E genotype and carotid intima-media thickness may suggest a specific effect on large artery atherothrombotic stroke. Stroke. 2008;39:48-54.
132. Smith LC, Pownall HJ, Gotto AM Jr. The plasma lipoproteins: structure and metabolism. Annu Rev Biochem. 1978;47:751-757.
133. Corbo RM, Scacchi R, Mureddu L, Mulas G, Alfano G. Apolipoprotein E polymorphism in Italy investigated in native plasma by a simple polyacrylamide gel isoelectric focusing technique. Comparison with frequency data of other European populations. Ann Hum Genet. 1995;59(Pt 2):197-209.
134. Gerdes LU, Klausen IC, Sihm I, Faergeman O. Apolipoprotein E polymorphism in a Danish population compared to findings in 45 other study populations around the world. Genet Epidemiol. 1992;9(3):155-167.
135. Braeckman L, De Bacquer D, Rosseneu M, De Backer G. Apolipoprotein E polymorphism in middle-aged Belgian men: phenotype distribution and relation to serum lipids and lipoproteins. Atherosclerosis. 1996;120(1-2):67-73.
136. Lucotte G, Loirat F, Hazout S. Pattern of gradient of apolipoprotein E allele *4 frequencies in western Europe. Hum Biol. 1997;69(2):253-262.
137. Kowalska A, Wiechmann I, Walter H. Genetic variability of apolipoprotein E in a Polish population. Hum Biol. 1998;70(6):1093-1099.
138. Valveny N, Esteban E, Kandil M, Moral P. APO E polymorphism in Spanish and Moroccan populations. Clin Genet. 1997;51(5):354-356.
139. Atadzhanov M, Mwaba MH, Mukomena PN, et al. Frequency of APOE, MTHFR and ACE polymorphisms in the Zambian population. BMC Res Notes. 2014;7:194.
140. Oriá RB, Patrick PD, Oriá MO, et al. ApoE polymorphisms and diarrheal outcomes in Brazilian shanty town children. Braz J Med Biol Res. 2010;43(3):249-256.
141. Zekraoui L, Lagarde JP, Raisonnier A, Gérard N, Aouizérate A, Lucotte G. High frequency of the apolipoprotein E *4 allele in African pygmies and most of the African populations in sub-Saharan Africa. Hum Biol. 1997;69(4):575-581.
142. Sandholzer C, Delport R, Vermaak H, Utermann G. High frequency of the apo epsilon 4 allele in Khoi San from South Africa. Hum Genet. 1995;95(1):46-48.
143. Hallman DM, Boerwinkle E, Saha N, et al. The apolipoprotein E polymorphism: a comparison of allele frequencies and effects in nine populations. Am J Hum Genet. 1991;49(2):338-349.
144. Corbo RM, Scacchi R, Rickards O, Martinez-Labarga C, De Stefano GF. An investigation of human apolipoprotein B and E polymorphisms in two African populations from Ethiopia and Benin. Am J Hum Biol. 1999;11(3):297-304.
145. Ahmed MU, Akhteruzzaman S. Apolipoprotein E (Apo E) gene polymorphism in the Bangladeshi population and its comparison with other Asian populations. J Med Sci. 2006;6(2):203-208.
146. Gajra B, Candlish JK, Saha N, Mak JW, Tay JS. Effect of apolipoprotein E variants on plasma lipids and apolipoproteins in the Orang Asli ('Aborigines') of Malaysia. Hum Hered. 1994;44(4):209-213.
147. Evans AE, Zhang W, Moreel JF, et al. Polymorphisms of the apolipoprotein B and E genes and their relationship to plasma lipid variables in healthy Chinese men. Hum Genet. 1993;92(2):191-197.
148. Moon K, Sung SH, Chang YK, et al. [The association between Apolipoprotein E genotype and lipid profiles in healthy woman workers]. J Prev Med Public Health. 2010;43(3):213-221. Korean.
149. Scacchi R, Corbo RM, Rickards O, Mantuano E, Guevara A, De Stefano GF. Apolipoprotein B and E genetic polymorphisms in the Cayapa Indians of Ecuador. Hum Biol. 1997;69(3):375-382.
150. Kamboh MI. Apolipoprotein E polymorphism and susceptibility to Alzheimer's disease. Hum Biol. 1995;67(2):195-215.
151. Crews DE, Kamboh MI, Mancilha-Carvalho JJ, Kottke B. Population genetics of apolipoprotein A-4, E, and H polymorphisms in Yanomami Indians of Northwestern Brazil: associations with lipids, lipoproteins, and carbohydrate metabolism. Hum Biol. 1993;65(2):211-224.
152. van den Maagdenberg AM, Weng W, de Bruijn IH, et al. Characterization of five new mutants in the carboxyl-terminal domain of human apolipoprotein E: no cosegregation with severe hyperlipidemia. Am J Hum Genet. 1993;52(5):937-946.
153. Matsunaga A, Sasaki J, Komatsu T, et al. A novel apolipoprotein E mutation, E2 (Arg25Cys), in lipoprotein glomerulopathy. Kidney Int. 1999;56(2):421-427.
154. Vialettes B, Reynier P, Atlan-Gepner C, et al. Dietary fat clearance in type V hyperlipoproteinaemia secondary to a rare variant of human apolipoprotein E: the apolipoprotein E3 (Arg 136 → Ser). Br J Nutr. 2000;83(6):615-622.
155. Richard P, de Zulueta MP, Beucler I, De Gennes JL, Cassaigne A, Iron A. Identification of a new apolipoprotein E variant (E2 Arg142 → Leu) in type III hyperlipidemia. Atherosclerosis. 1995;112(1):19-28.
156. Oikawa S, Matsunaga A, Saito T, et al. Apolipoprotein E Sendai (arginine 145 → proline): a new variant associated with lipoprotein glomerulopathy. J Am Soc Nephrol. 1997;8(5):820-823.
157. Okubo M, Aoyama Y, Harada K, et al. A novel apolipoprotein E2 variant, E2Toranomon (Q187E), identified in a type III hyperlipoproteinemia patient with coronary atherosclerosis. Atherosclerosis. 1998;140(1):187-190.
158. Moriyama K, Sasaki J, Takada Y, et al. Characterization of a novel variant of apolipoprotein E, E2 Fukuoka (Arg-224 → Gln) in a hyperlipidemic patient with xanthomatosis. Biochim Biophys Acta. 1996;1301(3):185-190.
159. Wardell MR, Rall SC, Brennan SO, et al. Apolipoprotein E2-Dunedin (228 Arg replaced by Cys): an apolipoprotein E2 variant with normal receptor-binding activity. J Lipid Res. 1990;31(3):535-543.
160. Lalazar A, Weisgraber KH, Rall SC Jr, et al. Site-specific mutagenesis of human apolipoprotein E. Receptor binding activity of variants with single amino acid substitutions. J Biol Chem. 1988; 263(8):3542-3545.
161. McLean JW, Elshourbagy NA, Chang DJ, Mahley RW, Taylor JM. Human apolipoprotein E mRNA. cDNA cloning and nucleotide sequencing of a new variant. J Biol Chem. 1984;259(10):6498-6504.
162. Miserez AR, Scharnagl H, Muller PY, et al. Apolipoprotein E3Basel: new insights into a highly conserved protein region. Eur J Clin Invest. 2003;33(8):677-685.
163. Minnich A, Weisgraber KH, Newhouse Y, et al. Identification and characterization of a novel apolipoprotein E variant, apolipoprotein E3′ (Arg136 → His): association with mild dyslipidemia and double pre-beta very low density lipoproteins. J Lipid Res. 1995;36(1):57-66.
164. Wieland H, Funke H, Krieg J, Luley C. ApoE3-Freiburg and apoE4-Freiburg are twon genetic apoE variants which are caused by exchanges of uncharged amino acids and do not appear to be associated with lipid disorders or heart disease. In: Abstract Book of the Ninth International Symposium on Atherosclerosis; Oct 6-11, 1991; Chicago, IL:164.
165. Suehiro T, Yoshida K, Yamano T, Ohno F. Identification and characterization of a new variant of apolipoprotein E (apo E-Kochi). Jpn J Med. 1990;29(6):587-594.
166. Lohse P, Mann WA, Stein EA, Brewer HB. Apolipoprotein E-4Philadelphia (Glu13----Lys, Arg145----Cys). Homozygosity for two rare point mutations in the apolipoprotein E gene combined with severe type III hyperlipoproteinemia. J Biol Chem. 1991;266(16):10479-10484.
167. Kamboh MI, Aston CE, Perez-Tur J, et al. A novel mutation in the apolipoprotein E gene (APOE*4 Pittsburgh) is associated with the risk of late-onset Alzheimer's disease. Neurosci Lett. 1999;263(2-3):129-132.
168. Orth M, Weng W, Funke H, et al. Effects of a frequent apolipoprotein E isoform, ApoE4Freiburg (Leu28 → Pro), on lipoproteins and the prevalence of coronary artery disease in whites. Arterioscler Thromb Vasc Biol. 1999;19(5):1306-1315.
169. Wardell MR, Rall SC, Schaefer EJ, Kane JP, Weisgraber KH. Two apolipoprotein E5 variants illustrate the importance of the position of additional positive charge on receptor-binding activity. J Lipid Res. 1991;32(3):521-528.
170. Mailly F, Xu CF, Xhignesse M, et al. Characterization of a new apolipoprotein E5 variant detected in two French-Canadian subjects. J Lipid Res. 1991;32(4):613-620.
171. Ruzicka V, März W, Russ A, Fisher E, Mondorf W, Gross W. Characterization of the gene for apolipoprotein E5-Frankfurt (Gln81 → Lys, Cys112 → Arg) by polymerase chain reaction, restriction isotyping, and temperature gradient gel electrophoresis. Electrophoresis. 1993;14(10):1032-1037.
172. Feussner G, Dobmeyer J, Gröne HJ, Lohmer S, Wohlfeil S. A 10-bp deletion in the apolipoprotein epsilon gene causing apolipoprotein E deficiency and severe type III hyperlipoproteinemia. Am J Hum Genet. 1996;58(2):281-291.
173. Yamamura T, Yamamoto A, Sumiyoshi T, Hiramori K, Nishioeda Y, Nambu S. New mutants of apolipoprotein E associated with atherosclerotic diseases but not to type III hyperlipoproteinemia. J Clin Invest. 1984;74(4):1229-1237.
174. Yamauchi K, Tozuka M, Nakabayashi T, et al. Higher avidity binding of apolipoprotein (E-AII) complex than of apolipoprotein E monomer to beta-amyloid. J Neurosci Res. 1999;58(2):301-307.
175. Lohse P, Rader DJ, Brewer HB. Heterozygosity for apolipoprotein E-4Philadelphia (Glu13----Lys, Arg145----Cys) is associated with incomplete dominance of type III hyperlipoproteinemia. J Biol Chem. 1992;267(19):13642-13646.
176. Feussner G, Feussner V, Hoffmann MM, Lohrmann J, Wieland H, März W. Molecular basis of the type III hyperlipoproteinemia in Germany. Hum Mutat. 1998;11(6):417-423.
177. Ando M, Sasaki J, Hua H, et al. A novel 18-amino acid deletion in apolipoprotein E associated with lipoprotein glomerulopathy. Kidney Int. 1999;56(4):1317-1323.
178. Konishi K, Saruta T, Kuramochi S, et al. Association of a novel 3-amino acid deletion mutation of apolipoprotein E (Apo E Tokyo) with lipoprotein glomerulopathy. Nephron. 1999;83(3):214-218.
179. Feussner G, Funke H, Weng W, Assmann G, Lackner KJ, Ziegler R. Severe type III hyperlipoproteinemia associated with unusual apolipoprotein E1 phenotype and epsilon 1/'null' genotype. Eur J Clin Invest. 1992;22(9):599-608.
180. Feussner G, Scharnagl H, Scherbaum C, et al. Apolipoprotein E5 (Glu212 → Lys): increased binding to cell surface proteoglycans but decreased uptake and lysosomal degradation in cultured fibroblasts. J Lipid Res. 1996;37(8):1632-1645.
181. Cladaras C, Hadzopoulou-Cladaras M, Felber BK, Pavlakis G, Zannis VI. The molecular basis of a familial apoE deficiency. An acceptor splice site mutation in the third intron of the deficient apoE gene. J Biol Chem. 1987;262(5):2310-2315.
182. Wardell MR, Weisgraber KH, Havekes LM, Rall SC. Apolipoprotein E3-Leiden contains a seven-amino acid insertion that is a tandem repeat of residues 121-127. J Biol Chem. 1989;264(35):21205-21210.
183. Yamanouchi Y, Takano T, Hamaguchi H, Tokunaga K. A novel apolipoprotein E5 variant with a 24-bp insertion causing hyperlipidemia. J Hum Genet. 2001;46(11):633-639.
184. Sanan DA, Weisgraber KH, Russell SJ, et al. Apolipoprotein E associates with beta amyloid peptide of Alzheimer's disease to form novel monofibrils. Isoform apoE4 associates more efficiently than apoE3. J Clin Invest. 1994;94(2):860-869.
185. Shuvaev VV, Siest G. Interaction between human amphipathic apolipoproteins and amyloid beta-peptide: surface plasmon resonance studies. FEBS Lett. 1996;383(1-2):9-12.
186. Yang DS, Smith JD, Zhou Z, Gandy SE, Martins RN. Characterization of the binding of amyloid-beta peptide to cell culture-derived native apolipoprotein E2, E3, and E4 isoforms and to isoforms from human plasma. J Neurochem. 1997;68(2):721-725.
187. Zhou Z, Relkin N, Ghiso J, Smith JD, Gandy S. Human cerebrospinal fluid apolipoprotein E isoforms are apparently inefficient at complexing with synthetic Alzheimer's amyloid-[beta] peptide (A[beta] 1-40) in vitro. Mol Med. 2002;8(7):376-381.
188. Gylys KH, Fein JA, Tan AM, Cole GM. Apolipoprotein E enhances uptake of soluble but not aggregated amyloid-beta protein into synaptic terminals. J Neurochem. 2003;84(6):1442-1451.
189. Stratman NC, Castle CK, Taylor BM, Epps DE, Melchior GW, Carter DB. Isoform-specific interactions of human apolipoprotein E to an intermediate conformation of human Alzheimer amyloid-beta peptide. Chem Phys Lipids. 2005;137(1-2):52-61.
190. Petrlova J, Hong HS, Bricarello DA, et al. A differential association of Apolipoprotein E isoforms with the amyloid-β oligomer in solution. Proteins. 2011;79(2):402-416.
191. Tai LM, Bilousova T, Jungbauer L, et al. Levels of soluble apolipoprotein E/amyloid-beta (Abeta) complex are reduced and oligomeric Abeta increased with APOE4 and Alzheimer disease in a transgenic mouse model and human samples. J Biol Chem. 2013;288(8):5914-5926.