The vast majority of Alzheimer's disease (AD) cases are late onset (LOAD), which is genetically complex with heritability estimates up to 80%. Apolipoprotein E () has been irrefutably recognized as the major genetic risk factor, with semidominant inheritance, for LOAD. Although the mechanisms that underlie the pathogenic nature of APOE in AD are still not completely understood, emerging data suggest that APOE contributes to AD pathogenesis through both amyloid-β (Aβ)-dependent and Aβ-independent pathways. Given the central role for APOE in the modulation of AD pathogenesis, many therapeutic strategies have emerged, including converting APOE conformation, regulating APOE expression, mimicking APOE peptides, blocking the APOE/Aβ interaction, modulating APOE lipidation state, and gene therapy. Accumulating evidence also suggests the utility of genotyping in AD diagnosis, risk assessment, prevention, and treatment response.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Alzheimer's Assoc 2013. Alzheimer's disease facts and figures. Alzheimer's Dement. 9:208–45 [Google Scholar]
  2. Andrews-Zwilling Y, Bien-Ly N, Xu Q, Li G, Bernardo A. et al. 2010. Apolipoprotein E4 causes age- and tau-dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice. J. Neurosci. 30:13707–17 [Google Scholar]
  3. Arold S, Sullivan P, Bilousova T, Teng E, Miller CA. et al. 2012. Apolipoprotein E level and cholesterol are associated with reduced synaptic amyloid β in Alzheimer's disease and apoE TR mouse cortex. Acta Neuropathol. 123:39–52 [Google Scholar]
  4. Bachmeier C, Paris D, Beaulieu-Abdelahad D, Mouzon B, Mullan M, Crawford F. 2013. A multifaceted role for apoE in the clearance of β-amyloid across the blood-brain barrier. Neurodegener. Dis. 11:13–21 [Google Scholar]
  5. Baitsch D, Bock HH, Engel T, Telgmann R, Muller-Tidow C. et al. 2011. Apolipoprotein E induces anti-inflammatory phenotype in macrophages. Arterioscler. Thromb. Vasc. Biol. 31:1160–68 [Google Scholar]
  6. Bales KR, Liu F, Wu S, Lin S, Koger D. et al. 2009. Human APOE isoform-dependent effects on brain β-amyloid levels in PDAPP transgenic mice. J. Neurosci. 29:6771–79 [Google Scholar]
  7. Basak JM, Kim J. 2010. Differential effects of ApoE isoforms on dendritic spines in vivo: linking an Alzheimer's disease risk factor with synaptic alterations. J. Neurosci. 30:4526–27 [Google Scholar]
  8. Basak JM, Verghese PB, Yoon H, Kim J, Holtzman DM. 2012. Low-density lipoprotein receptor represents an apolipoprotein E-independent pathway of Aβ uptake and degradation by astrocytes. J. Biol. Chem. 287:13959–71 [Google Scholar]
  9. Bell RD, Winkler EA, Singh I, Sagare AP, Deane R. et al. 2012. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485:512–16 [Google Scholar]
  10. Bennett RE, Esparza TJ, Lewis HA, Kim E, Mac Donald CL. et al. 2013. Human apolipoprotein E4 worsens acute axonal pathology but not amyloid-β immunoreactivity after traumatic brain injury in 3xTG-AD mice. J. Neuropathol. Exp. Neurol. 72:396–403 [Google Scholar]
  11. Bettens K, Sleegers K, Van Broeckhoven C. 2013. Genetic insights in Alzheimer's disease. Lancet Neurol. 12:92–104 [Google Scholar]
  12. Bien-Ly N, Andrews-Zwilling Y, Xu Q, Bernardo A, Wang C, Huang Y. 2011. C-terminal-truncated apolipoprotein (apo) E4 inefficiently clears amyloid-beta (Aβ) and acts in concert with Aβ to elicit neuronal and behavioral deficits in mice. Proc. Natl. Acad. Sci. USA 108:4236–41 [Google Scholar]
  13. Bien-Ly N, Gillespie AK, Walker D, Yoon SY, Huang Y. 2012. Reducing human apolipoprotein E levels attenuates age-dependent Aβ accumulation in mutant human amyloid precursor protein transgenic mice. J. Neurosci. 32:4803–11 [Google Scholar]
  14. Brecht WJ, Harris FM, Chang S, Tesseur I, Yu GQ. et al. 2004. Neuron-specific apolipoprotein e4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J. Neurosci. 24:2527–34 [Google Scholar]
  15. Brodbeck J, McGuire J, Liu Z, Meyer-Franke A, Balestra ME. et al. 2011. Structure-dependent impairment of intracellular apolipoprotein E4 trafficking and its detrimental effects are rescued by small-molecule structure correctors. J. Biol. Chem. 286:17217–26 [Google Scholar]
  16. Broussard GJ, Mytar J, Li RC, Klapstein GJ. 2012. The role of inflammatory processes in Alzheimer's disease. Inflammopharmacology 20:109–26 [Google Scholar]
  17. Bu G. 2009. Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy. Nat. Rev. Neurosci. 10:333–44 [Google Scholar]
  18. Cacabelos R, Martinez R, Fernandez-Novoa L, Carril JC, Lombardi V. et al. 2012. Genomics of dementia: APOE- and CYP2D6-related pharmacogenetics. Int. J. Alzheimer's Dis. 2012:518901 [Google Scholar]
  19. Carlo AS, Gustafsen C, Mastrobuoni G, Nielsen MS, Burgert T. et al. 2013. The pro-neurotrophin receptor sortilin is a major neuronal apolipoprotein E receptor for catabolism of amyloid-β peptide in the brain. J. Neurosci. 33:358–70 [Google Scholar]
  20. Caselli RJ, Dueck AC, Osborne D, Sabbagh MN, Connor DJ. et al. 2009. Longitudinal modeling of age-related memory decline and the APOE ε4 effect. N. Engl. J. Med. 361:255–63 [Google Scholar]
  21. Cash JG, Kuhel DG, Basford JE, Jaeschke A, Chatterjee TK. et al. 2012. Apolipoprotein E4 impairs macrophage efferocytosis and potentiates apoptosis by accelerating endoplasmic reticulum stress. J. Biol. Chem. 287:27876–84 [Google Scholar]
  22. Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB. et al. 2011. Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci. Transl. Med. 3:89ra57 [Google Scholar]
  23. Chartier-Harlin MC, Parfitt M, Legrain S, Perez-Tur J, Brousseau T. et al. 1994. Apolipoprotein E, ε4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimer's disease: analysis of the 19q13.2 chromosomal region. Hum. Mol. Genet. 3:569–74 [Google Scholar]
  24. Chen HK, Ji ZS, Dodson SE, Miranda RD, Rosenblum CI. et al. 2011a. Apolipoprotein E4 domain interaction mediates detrimental effects on mitochondria and is a potential therapeutic target for Alzheimer disease. J. Biol. Chem. 286:5215–21 [Google Scholar]
  25. Chen HK, Liu Z, Meyer-Franke A, Brodbeck J, Miranda RD. et al. 2012. Small molecule structure correctors abolish detrimental effects of apolipoprotein E4 in cultured neurons. J. Biol. Chem. 287:5253–66 [Google Scholar]
  26. Chen J, Li Q, Wang J. 2011b. Topology of human apolipoprotein E3 uniquely regulates its diverse biological functions. Proc. Natl. Acad. Sci. USA 108:14813–18 [Google Scholar]
  27. Chen Y, Durakoglugil MS, Xian X, Herz J. 2010. ApoE4 reduces glutamate receptor function and synaptic plasticity by selectively impairing ApoE receptor recycling. Proc. Natl. Acad. Sci. USA 107:12011–16 [Google Scholar]
  28. Christensen DZ, Schneider-Axmann T, Lucassen PJ, Bayer TA, Wirths O. 2010. Accumulation of intraneuronal Aβ correlates with ApoE4 genotype. Acta Neuropathol. 119:555–66 [Google Scholar]
  29. Colca JR, Feinstein DL. 2012. Altering mitochondrial dysfunction as an approach to treating Alzheimer's disease. Adv. Pharmacol. 64:155–76 [Google Scholar]
  30. Conejero-Goldberg C, Hyde TM, Chen S, Dreses-Werringloer U, Herman MM. et al. 2011. Molecular signatures in post-mortem brain tissue of younger individuals at high risk for Alzheimer's disease as based on APOE genotype. Mol. Psychiatry 16:836–47 [Google Scholar]
  31. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC. et al. 1993. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261:921–23 [Google Scholar]
  32. Cramer PE, Cirrito JR, Wesson DW, Lee CY, Karlo JC. et al. 2012. ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models. Science 335:1503–6 [Google Scholar]
  33. Cruchaga C, Kauwe JS, Nowotny P, Bales K, Pickering EH. et al. 2012. Cerebrospinal fluid APOE levels: an endophenotype for genetic studies for Alzheimer's disease. Hum. Mol. Genet. 21:4558–71 [Google Scholar]
  34. Cui W, Sun Y, Wang Z, Xu C, Peng Y, Li R. 2012. Liver X receptor activation attenuates inflammatory response and protects cholinergic neurons in APP/PS1 transgenic mice. Neuroscience 210:200–10 [Google Scholar]
  35. De Jager PL, Shulman JM, Chibnik LB, Keenan BT, Raj T. et al. 2012. A genome-wide scan for common variants affecting the rate of age-related cognitive decline. Neurobiol. Aging 33:1017e1–15 [Google Scholar]
  36. Dean DC 3rd, Jerskey BA, Chen K, Protas H, Thiyyagura P. et al. 2014. Brain differences in infants at differential genetic risk for late-onset Alzheimer disease: a cross-sectional imaging study. JAMA Neurol. 71:11–22 [Google Scholar]
  37. Di Paolo G, Kim TW. 2011. Linking lipids to Alzheimer's disease: cholesterol and beyond. Nat. Rev. Neurosci. 12:284–96 [Google Scholar]
  38. Dodart JC, Marr RA, Koistinaho M, Gregersen BM, Malkani S. et al. 2005. Gene delivery of human apolipoprotein E alters brain Aβ burden in a mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. USA 102:1211–16 [Google Scholar]
  39. Dong LM, Parkin S, Trakhanov SD, Rupp B, Simmons T. et al. 1996. Novel mechanism for defective receptor binding of apolipoprotein E2 in type III hyperlipoproteinemia. Nat. Struct. Biol. 3:718–22 [Google Scholar]
  40. Donkin JJ, Stukas S, Hirsch-Reinshagen V, Namjoshi D, Wilkinson A. et al. 2010. ATP-binding cassette transporter A1 mediates the beneficial effects of the liver X receptor agonist GW3965 on object recognition memory and amyloid burden in amyloid precursor protein/presenilin 1 mice. J. Biol. Chem. 285:34144–54 [Google Scholar]
  41. Dore GA, Elias MF, Robbins MA, Elias PK, Nagy Z. 2009. Presence of the APOE ε4 allele modifies the relationship between type 2 diabetes and cognitive performance: the Maine-Syracuse Study. Diabetologia 52:2551–60 [Google Scholar]
  42. Dumanis SB, Tesoriero JA, Babus LW, Nguyen MT, Trotter JH. et al. 2009. ApoE4 decreases spine density and dendritic complexity in cortical neurons in vivo. J. Neurosci. 29:15317–22 [Google Scholar]
  43. Filippini N, MacIntosh BJ, Hough MG, Goodwin GM, Frisoni GB. et al. 2009. Distinct patterns of brain activity in young carriers of the APOE-ε4 allele. Proc. Natl. Acad. Sci. USA 106:7209–14 [Google Scholar]
  44. Fitz NF, Cronican AA, Lefterov I, Koldamova R. 2013. Comment on “ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models.”. Science 340:924 [Google Scholar]
  45. Frieden C, Garai K. 2012. Structural differences between apoE3 and apoE4 may be useful in developing therapeutic agents for Alzheimer's disease. Proc. Natl. Acad. Sci. USA 109:8913–18 [Google Scholar]
  46. Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA. et al. 2006. Role of genes and environments for explaining Alzheimer disease. Arch. Gen. Psychiatry 63:168–74 [Google Scholar]
  47. Genin E, Hannequin D, Wallon D, Sleegers K, Hiltunen M. et al. 2011. APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol. Psychiatry 16:903–7 [Google Scholar]
  48. Ghosal K, Stathopoulos A, Thomas D, Phenis D, Vitek MP, Pimplikar SW. 2013. The apolipoprotein-E-mimetic COG112 protects amyloid precursor protein intracellular domain-overexpressing animals from Alzheimer's disease-like pathological features. Neurodegener. Dis. 12:51–58 [Google Scholar]
  49. Gibson GE, Haroutunian V, Zhang H, Park LC, Shi Q. et al. 2000. Mitochondrial damage in Alzheimer's disease varies with apolipoprotein E genotype. Ann. Neurol. 48:297–303 [Google Scholar]
  50. Green RC, Roberts JS, Cupples LA, Relkin NR, Whitehouse PJ. et al. 2009. Disclosure of APOE genotype for risk of Alzheimer's disease. N. Engl. J. Med. 361:245–54 [Google Scholar]
  51. Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E. et al. 2013. TREM2 variants in Alzheimer's disease. N. Engl. J. Med. 368:117–27 [Google Scholar]
  52. Gupta VB, Laws SM, Villemagne VL, Ames D, Bush AI. et al. 2011. Plasma apolipoprotein E and Alzheimer disease risk: the AIBL study of aging. Neurology 76:1091–98 [Google Scholar]
  53. Hall K, Murrell J, Ogunniyi A, Deeg M, Baiyewu O. et al. 2006. Cholesterol, APOE genotype, and Alzheimer disease: an epidemiologic study of Nigerian Yoruba. Neurology 66:223–27 [Google Scholar]
  54. Hao J, Zhang W, Zhang P, Liu R, Liu L. et al. 2010. Aβ20-29 peptide blocking apoE/Aβ interaction reduces full-length Aβ42/40 fibril formation and cytotoxicity in vitro. Neuropeptides 44:305–13 [Google Scholar]
  55. Hara M, Matsushima T, Satoh H, Iso-o N, Noto H. et al. 2003. Isoform-dependent cholesterol efflux from macrophages by apolipoprotein E is modulated by cell surface proteoglycans. Arterioscler. Thromb. Vasc. Biol. 23:269–74 [Google Scholar]
  56. Harris FM, Brecht WJ, Xu Q, Tesseur I, Kekonius L. et al. 2003. Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer's disease-like neurodegeneration and behavioral deficits in transgenic mice. Proc. Natl. Acad. Sci. USA 100:10966–71 [Google Scholar]
  57. Hashimoto T, Serrano-Pozo A, Hori Y, Adams KW, Takeda S. et al. 2012. Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid β peptide. J. Neurosci. 32:15181–92 [Google Scholar]
  58. Hatters D, Peters-Libeu C, Weisgraber KH. 2006. Apolipoprotein E structure: insights into function. Trends Biochem. Sci. 31:445–54 [Google Scholar]
  59. Hauser PS, Narayanaswami V, Ryan RO. 2011. Apolipoprotein E: from lipid transport to neurobiology. Prog. Lipid Res. 50:62–74 [Google Scholar]
  60. Hawkes CA, Sullivan PM, Hands S, Weller RO, Nicoll JA, Carare RO. 2012. Disruption of arterial perivascular drainage of amyloid-β from the brains of mice expressing the human APOE ε4 allele. PLoS ONE 7:e41636 [Google Scholar]
  61. Hoe HS, Freeman J, Rebeck GW. 2006. Apolipoprotein E decreases tau kinases and phospho-tau levels in primary neurons. Mol. Neurodegener. 1:18 [Google Scholar]
  62. Holtzman DM, Herz J, Bu G. 2012. Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. Cold Spring Harb. Perspect. Med. 2:a006312 [Google Scholar]
  63. Hong S, Quintero-Monzon O, Ostaszewski BL, Podlisny DR, Cavanaugh WT. et al. 2011. Dynamic analysis of amyloid β protein in behaving mice reveals opposing changes in ISF versus parenchymal Aβ during age-related plaque formation. J. Neurosci. 31:15861–69 [Google Scholar]
  64. in ‘t Veld BA, Ruitenberg A, Hofman A, Launer LJ, van Duijn CM. et al. 2001. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N. Engl. J. Med. 345:1515–21 [Google Scholar]
  65. Irizarry MC, Deng A, Lleo A, Berezovska O, Von Arnim CA. et al. 2004. Apolipoprotein E modulates γ-secretase cleavage of the amyloid precursor protein. J. Neurochem. 90:1132–43 [Google Scholar]
  66. James R, Searcy JL, Le Bihan T, Martin SF, Gliddon CM. et al. 2012. Proteomic analysis of mitochondria in APOE transgenic mice and in response to an ischemic challenge. J. Cereb. Blood Flow Metab. 32:164–76 [Google Scholar]
  67. Jiang Q, Lee CY, Mandrekar S, Wilkinson B, Cramer P. et al. 2008. ApoE promotes the proteolytic degradation of Aβ. Neuron 58:681–93 [Google Scholar]
  68. Jones L, Holmans PA, Hamshere ML, Harold D, Moskvina V. et al. 2010. Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. PLoS ONE 5:e13950 [Google Scholar]
  69. Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV. et al. 2013. Variant of TREM2 associated with the risk of Alzheimer's disease. N. Engl. J. Med. 368:107–16 [Google Scholar]
  70. Kariv-Inbal Z, Yacobson S, Berkecz R, Peter M, Janaky T. et al. 2012. The isoform-specific pathological effects of apoE4 in vivo are prevented by a fish oil (DHA) diet and are modified by cholesterol. J. Alzheimer's Dis. 28:667–83 [Google Scholar]
  71. Keene CD, Cudaback E, Li X, Montine KS, Montine TJ. 2011. Apolipoprotein E isoforms and regulation of the innate immune response in brain of patients with Alzheimer's disease. Curr. Opin. Neurobiol. 21:920–28 [Google Scholar]
  72. Kennedy RE, Cutter GR, Schneider LS. 2014. Effect of APOE genotype status on targeted clinical trials outcomes and efficiency in dementia and mild cognitive impairment resulting from Alzheimer's disease. Alzheimer's Dement. doi: 10.1016/j.jalz.2013.03.003. In press
  73. Kerchner GA, Berdnik D, Shen JC, Bernstein JD, Fenesy MC. et al. 2014. APOE ε4 worsens hippocampal CA1 apical neuropil atrophy and episodic memory. Neurology 82:691–97 [Google Scholar]
  74. Kim J, Basak JM, Holtzman DM. 2009. The role of apolipoprotein E in Alzheimer's disease. Neuron 63:287–303 [Google Scholar]
  75. Kim J, Eltorai AE, Jiang H, Liao F, Verghese PB. et al. 2012. Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis. J. Exp. Med. 209:2149–56 [Google Scholar]
  76. Kim J, Jiang H, Park S, Eltorai AE, Stewart FR. et al. 2011. Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of amyloid-β amyloidosis. J. Neurosci. 31:18007–12 [Google Scholar]
  77. Klein RC, Mace BE, Moore SD, Sullivan PM. 2010. Progressive loss of synaptic integrity in human apolipoprotein E4 targeted replacement mice and attenuation by apolipoprotein E2. Neuroscience 171:1265–72 [Google Scholar]
  78. Koffie RM, Hashimoto T, Tai HC, Kay KR, Serrano-Pozo A. et al. 2012. Apolipoprotein E4 effects in Alzheimer's disease are mediated by synaptotoxic oligomeric amyloid-β. Brain 135:2155–68 [Google Scholar]
  79. Korwek KM, Trotter JH, Ladu MJ, Sullivan PM, Weeber EJ. 2009. ApoE isoform-dependent changes in hippocampal synaptic function. Mol. Neurodegener. 4:21 [Google Scholar]
  80. Kuszczyk MA, Sanchez S, Pankiewicz J, Kim J, Duszczyk M. et al. 2013. Blocking the interaction between apolipoprotein E and Aβ reduces intraneuronal accumulation of Aβ and inhibits synaptic degeneration. Am. J. Pathol. 182:1750–68 [Google Scholar]
  81. Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R. et al. 2013. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat. Genet. 45:1452–58 [Google Scholar]
  82. Lambert JC, Perez-Tur J, Dupire MJ, Galasko D, Mann D. et al. 1997. Distortion of allelic expression of apolipoprotein E in Alzheimer's disease. Hum. Mol. Genet. 6:2151–54 [Google Scholar]
  83. Landreth GE, Cramer PE, Lakner MM, Cirrito JR, Wesson DW. et al. 2013. Response to comments on “ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models.”. Science 340:924 [Google Scholar]
  84. Lautenschlager NT, Cox KL, Flicker L, Foster JK, van Bockxmeer FM. et al. 2008. Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial. J. Am. Med. Assoc. 300:1027–37 [Google Scholar]
  85. Lee CY, Tse W, Smith JD, Landreth GE. 2012. Apolipoprotein E promotes β-amyloid trafficking and degradation by modulating microglial cholesterol levels. J. Biol. Chem. 287:2032–44 [Google Scholar]
  86. Leoni V. 2011. The effect of apolipoprotein E (ApoE) genotype on biomarkers of amyloidogenesis, tau pathology and neurodegeneration in Alzheimer's disease. Clin. Chem. Lab. Med. 49:375–83 [Google Scholar]
  87. Li J, Kanekiyo T, Shinohara M, Zhang Y, LaDu MJ. et al. 2012. Differential regulation of amyloid-β endocytic trafficking and lysosomal degradation by apolipoprotein E isoforms. J. Biol. Chem. 287:44593–601 [Google Scholar]
  88. Liu CC, Kanekiyo T, Xu H, Bu G. 2013. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat. Rev. Neurol. 9:106–18 [Google Scholar]
  89. Liu Q, Wu WH, Fang CL, Li RW, Liu P. et al. 2011. Mapping ApoE/Aβ binding regions to guide inhibitor discovery. Mol. Biosyst. 7:1693–700 [Google Scholar]
  90. Mahley RW, Huang Y. 2012. Apolipoprotein E sets the stage: response to injury triggers neuropathology. Neuron 76:871–85 [Google Scholar]
  91. Mandrekar-Colucci S, Karlo JC, Landreth GE. 2012. Mechanisms underlying the rapid peroxisome proliferator-activated receptor-γ-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer's disease. J. Neurosci. 32:10117–28 [Google Scholar]
  92. Mattsson N, Zetterberg H, Hansson O, Andreasen N, Parnetti L. et al. 2009. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. J. Am. Med. Assoc. 302:385–93 [Google Scholar]
  93. Mauch DH, Nagler K, Schumacher S, Goritz C, Muller EC. et al. 2001. CNS synaptogenesis promoted by glia-derived cholesterol. Science 294:1354–57 [Google Scholar]
  94. Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T. et al. 2010. Decreased clearance of CNS β-amyloid in Alzheimer's disease. Science 330:1774 [Google Scholar]
  95. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr. et al. 2011. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimer's Dement. 7:263–69 [Google Scholar]
  96. Minami SS, Cordova A, Cirrito JR, Tesoriero JA, Babus LW. et al. 2010. ApoE mimetic peptide decreases Aβ production in vitro and in vivo. Mol. Neurodegener. 5:16 [Google Scholar]
  97. Morris JC, Roe CM, Xiong C, Fagan AM, Goate AM. et al. 2010. APOE predicts amyloid-β but not tau Alzheimer pathology in cognitively normal aging. Ann. Neurol. 67:122–31 [Google Scholar]
  98. Mosconi L, De Santi S, Brys M, Tsui WH, Pirraglia E. et al. 2008. Hypometabolism and altered cerebrospinal fluid markers in normal apolipoprotein E E4 carriers with subjective memory complaints. Biol. Psychiatry 63:609–18 [Google Scholar]
  99. Nakamura T, Watanabe A, Fujino T, Hosono T, Michikawa M. 2009. Apolipoprotein E4 (1–272) fragment is associated with mitochondrial proteins and affects mitochondrial function in neuronal cells. Mol. Neurodegener. 4:35 [Google Scholar]
  100. Namjoshi DR, Martin G, Donkin J, Wilkinson A, Stukas S. et al. 2013. The liver X receptor agonist GW3965 improves recovery from mild repetitive traumatic brain injury in mice partly through apolipoprotein E. PLoS ONE 8:e53529 [Google Scholar]
  101. Nishitsuji K, Hosono T, Nakamura T, Bu G, Michikawa M. 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. 286:17536–42 [Google Scholar]
  102. Noguchi S, Murakami K, Yamada N. Kaye J. Payami H et al. 1993. Apolipoprotein E genotype and Alzheimer's disease. Lancet 342:737–38 [Google Scholar]
  103. Osei-Hwedieh DO, Amar M, Sviridov D, Remaley AT. 2011. Apolipoprotein mimetic peptides: mechanisms of action as anti-atherogenic agents. Pharmacol. Ther. 130:83–91 [Google Scholar]
  104. Ossenkoppele R, van der Flier WM, Zwan MD, Adriaanse SF, Boellaard R. et al. 2013. Differential effect of APOE genotype on amyloid load and glucose metabolism in AD dementia. Neurology 80:359–65 [Google Scholar]
  105. Pastor P, Roe CM, Villegas A, Bedoya G, Chakraverty S. et al. 2003. Apolipoprotein Eε4 modifies Alzheimer's disease onset in an E280A PS1 kindred. Ann. Neurol. 54:163–69 [Google Scholar]
  106. Patterson CE, Todd SA, Passmore AP. 2011. Effect of apolipoprotein E and butyrylcholinesterase genotypes on cognitive response to cholinesterase inhibitor treatment at different stages of Alzheimer's disease. Pharmacogenomics J. 11:444–50 [Google Scholar]
  107. Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R. et al. 2005. Vitamin E and donepezil for the treatment of mild cognitive impairment. N. Engl. J. Med. 352:2379–88 [Google Scholar]
  108. Pocivavsek A, Burns MP, Rebeck GW. 2009. Low-density lipoprotein receptors regulate microglial inflammation through c-Jun N-terminal kinase. Glia 57:444–53 [Google Scholar]
  109. Price AR, Xu G, Siemienski ZB, Smithson LA, Borchelt DR. et al. 2013. Comment on “ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models.”. Science 340:924 [Google Scholar]
  110. Protas HD, Chen K, Langbaum JB, Fleisher AS, Alexander GE. et al. 2013. Posterior cingulate glucose metabolism, hippocampal glucose metabolism, and hippocampal volume in cognitively normal, late-middle-aged persons at 3 levels of genetic risk for Alzheimer disease. JAMA Neurol. 70:320–25 [Google Scholar]
  111. Ramanan VK, Risacher SL, Nho K, Kim S, Swaminathan S. et al. 2013. APOE and BCHE as modulators of cerebral amyloid deposition: a florbetapir PET genome-wide association study. Mol. Psychiatry 19:351–57 [Google Scholar]
  112. Rapp A, Gmeiner B, Huttinger M. 2006. Implication of apoE isoforms in cholesterol metabolism by primary rat hippocampal neurons and astrocytes. Biochimie 88:473–83 [Google Scholar]
  113. Reiman EM, Chen K, Liu X, Bandy D, Yu M. et al. 2009. Fibrillar amyloid-β burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease. Proc. Natl. Acad. Sci. USA 106:6820–25 [Google Scholar]
  114. Rhinn H, Fujita R, Qiang L, Cheng R, Lee JH, Abeliovich A. 2013. Integrative genomics identifies APOE ε4 effectors in Alzheimer's disease. Nature 500:45–50 [Google Scholar]
  115. Ringman JM, Elashoff D, Geschwind DH, Welsh BT, Gylys KH. et al. 2012. Plasma signaling proteins in persons at genetic risk for Alzheimer disease: influence of APOE genotype-plasma biomarkers and AD genetic risk. Arch. Neurol. 69:757–64 [Google Scholar]
  116. Risner ME, Saunders AM, Altman JF, Ormandy GC, Craft S. et al. 2006. Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease. Pharmacogenomics J. 6:246–54 [Google Scholar]
  117. Ronnemaa E, Zethelius B, Sundelof J, Sundstrom J, Degerman-Gunnarsson M. et al. 2008. Impaired insulin secretion increases the risk of Alzheimer disease. Neurology 71:1065–71 [Google Scholar]
  118. Sadowski MJ, Pankiewicz J, Scholtzova H, Mehta PD, Prelli F. et al. 2006. Blocking the apolipoprotein E/amyloid-β interaction as a potential therapeutic approach for Alzheimer's disease. Proc. Natl. Acad. Sci. USA 103:18787–92 [Google Scholar]
  119. Salloway S, Sperling R, Gilman S, Fox NC, Blennow K. et al. 2009. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 73:2061–70 [Google Scholar]
  120. Samieri C, Feart C, Proust-Lima C, Peuchant E, Dartigues JF. et al. 2011. Omega-3 fatty acids and cognitive decline: modulation by ApoEε4 allele and depression. Neurobiol. Aging 32:2317e13–22 [Google Scholar]
  121. Sarantseva S, Timoshenko S, Bolshakova O, Karaseva E, Rodin D. et al. 2009. Apolipoprotein E-mimetics inhibit neurodegeneration and restore cognitive functions in a transgenic Drosophila model of Alzheimer's disease. PLoS ONE 4:e8191 [Google Scholar]
  122. Schipper HM. 2011. Presymptomatic apolipoprotein E genotyping for Alzheimer's disease risk assessment and prevention. Alzheimer's Dement. 7:e118–23 [Google Scholar]
  123. Sen A, Alkon DL, Nelson TJ. 2012. Apolipoprotein E3 (ApoE3) but not ApoE4 protects against synaptic loss through increased expression of protein kinase C epsilon. J. Biol. Chem. 287:15947–58 [Google Scholar]
  124. Sheline YI, Morris JC, Snyder AZ, Price JL, Yan Z. et al. 2010. APOE4 allele disrupts resting state fMRI connectivity in the absence of amyloid plaques or decreased CSF Aβ42. J. Neurosci. 30:17035–40 [Google Scholar]
  125. Shenk JC, Liu J, Fischbach K, Xu K, Puchowicz M. et al. 2009. The effect of acetyl-L-carnitine and R-α-lipoic acid treatment in ApoE4 mouse as a model of human Alzheimer's disease. J. Neurol. Sci. 283:199–206 [Google Scholar]
  126. Sperling R, Salloway S, Brooks DJ, Tampieri D, Barakos J. et al. 2012. Amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol. 11:241–49 [Google Scholar]
  127. Strittmatter WJ, Weisgraber KH, Goedert M, Saunders AM, Huang D. et al. 1994. Hypothesis: microtubule instability and paired helical filament formation in the Alzheimer disease brain are related to apolipoprotein E genotype. Exp. Neurol. 125:163–71 discuss. 72–74 [Google Scholar]
  128. Strum JC, Shehee R, Virley D, Richardson J, Mattie M. et al. 2007. Rosiglitazone induces mitochondrial biogenesis in mouse brain. J. Alzheimer's Dis. 11:45–51 [Google Scholar]
  129. Szekely CA, Breitner JC, Fitzpatrick AL, Rea TD, Psaty BM. et al. 2008. NSAID use and dementia risk in the Cardiovascular Health Study: role of APOE and NSAID type. Neurology 70:17–24 [Google Scholar]
  130. Tai LM, Bilousova T, Jungbauer L, Roeske SK, Youmans KL. et al. 2013. Levels of soluble apolipoprotein E/amyloid-beta (Aβ) complex are reduced and oligomeric Aβ increased with APOE4 and Alzheimer disease in a transgenic mouse model and human samples. J. Biol. Chem. 288:5914–26 [Google Scholar]
  131. Terwel D, Steffensen KR, Verghese PB, Kummer MP, Gustafsson JA. et al. 2011. Critical role of astroglial apolipoprotein E and liver X receptor-α expression for microglial Aβ phagocytosis. J. Neurosci. 31:7049–59 [Google Scholar]
  132. Tesseur I, Lo AC, Roberfroid A, Dietvorst S, Van Broeck B. et al. 2013. Comment on “ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models.”. Science 340:924 [Google Scholar]
  133. Valla J, Yaari R, Wolf AB, Kusne Y, Beach TG. et al. 2010. Reduced posterior cingulate mitochondrial activity in expired young adult carriers of the APOE ε4 allele, the major late-onset Alzheimer's susceptibility gene. J. Alzheimer's Dis. 22:307–13 [Google Scholar]
  134. Veeraraghavalu K, Zhang C, Miller S, Hefendehl JK, Rajapaksha TW. et al. 2013. Comment on “ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models.”. Science 340:924 [Google Scholar]
  135. Vemuri P, Wiste HJ, Weigand SD, Knopman DS, Shaw LM. et al. 2010. Effect of apolipoprotein E on biomarkers of amyloid load and neuronal pathology in Alzheimer disease. Ann. Neurol. 67:308–16 [Google Scholar]
  136. Verghese PB, Castellano JM, Garai K, Wang Y, Jiang H. et al. 2013. ApoE influences amyloid-beta (Aβ) clearance despite minimal apoE/Aβ association in physiological conditions. Proc. Natl. Acad. Sci. USA 110:E1807–16 [Google Scholar]
  137. Villemagne VL, Pike KE, Chetelat G, Ellis KA, Mulligan RS. et al. 2011. Longitudinal assessment of Aβ and cognition in aging and Alzheimer disease. Ann. Neurol. 69:181–92 [Google Scholar]
  138. Vitek MP, Brown CM, Colton CA. 2009. APOE genotype-specific differences in the innate immune response. Neurobiol. Aging 30:1350–60 [Google Scholar]
  139. Vitek MP, Christensen DJ, Wilcock D, Davis J, Van Nostrand WE. et al. 2012. APOE-mimetic peptides reduce behavioral deficits, plaques and tangles in Alzheimer's disease transgenics. Neurodegener. Dis. 10:122–26 [Google Scholar]
  140. Wahrle SE, Jiang H, Parsadanian M, Hartman RE, Bales KR. et al. 2005. Deletion of Abca1 increases Aβ deposition in the PDAPP transgenic mouse model of Alzheimer disease. J. Biol. Chem. 280:43236–42 [Google Scholar]
  141. Wahrle SE, Jiang H, Parsadanian M, Kim J, Li A. et al. 2008. Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease. J. Clin. Investig. 118:671–82 [Google Scholar]
  142. Wahrle SE, Jiang H, Parsadanian M, Legleiter J, Han X. et al. 2004. ABCA1 is required for normal central nervous system ApoE levels and for lipidation of astrocyte-secreted apoE. J. Biol. Chem. 279:40987–93 [Google Scholar]
  143. Wilson M, Montgomery H. 2007. Impact of genetic factors on outcome from brain injury. Br. J. Anaesth. 99:43–48 [Google Scholar]
  144. Xu Q, Bernardo A, Walker D, Kanegawa T, Mahley RW, Huang Y. 2006. Profile and regulation of apolipoprotein E (ApoE) expression in the CNS in mice with targeting of green fluorescent protein gene to the ApoE locus. J. Neurosci. 26:4985–94 [Google Scholar]
  145. Ye S, Huang Y, Mullendorff K, Dong L, Giedt G. et al. 2005. Apolipoprotein (apo) E4 enhances amyloid β peptide production in cultured neuronal cells: apoE structure as a potential therapeutic target. Proc. Natl. Acad. Sci. USA 102:18700–5 [Google Scholar]
  146. Youmans KL, Tai LM, Nwabuisi-Heath E, Jungbauer L, Kanekiyo T. et al. 2012. APOE4-specific changes in Aβ accumulation in a new transgenic mouse model of Alzheimer disease. J. Biol. Chem. 287:41774–86 [Google Scholar]
  147. Zhang H, Wu LM, Wu J. 2011. Cross-talk between apolipoprotein E and cytokines. Mediators Inflamm. 2011:949072 [Google Scholar]
  148. Zhong N, Weisgraber KH. 2009. Understanding the association of apolipoprotein E4 with Alzheimer disease: clues from its structure. J. Biol. Chem. 284:6027–31 [Google Scholar]
  149. Zhu Y, Nwabuisi-Heath E, Dumanis SB, Tai LM, Yu C. et al. 2012. APOE genotype alters glial activation and loss of synaptic markers in mice. Glia 60:559–69 [Google Scholar]
  150. Zlokovic BV. 2011. Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat. Rev. Neurosci. 12:723–38 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error