Review Article | Published:

Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy

Nature Reviews Neurology volume 9, pages 106118 (2013) | Download Citation

  • A Correction to this article was published on 26 March 2013

This article has been updated

Abstract

Apolipoprotein E (Apo-E) is a major cholesterol carrier that supports lipid transport and injury repair in the brain. APOE polymorphic alleles are the main genetic determinants of Alzheimer disease (AD) risk: individuals carrying the ε4 allele are at increased risk of AD compared with those carrying the more common ε3 allele, whereas the ε2 allele decreases risk. Presence of the APOE ε4 allele is also associated with increased risk of cerebral amyloid angiopathy and age-related cognitive decline during normal ageing. Apo-E–lipoproteins bind to several cell-surface receptors to deliver lipids, and also to hydrophobic amyloid-β (Aβ) peptide, which is thought to initiate toxic events that lead to synaptic dysfunction and neurodegeneration in AD. Apo-E isoforms differentially regulate Aβ aggregation and clearance in the brain, and have distinct functions in regulating brain lipid transport, glucose metabolism, neuronal signalling, neuroinflammation, and mitochondrial function. In this Review, we describe current knowledge on Apo-E in the CNS, with a particular emphasis on the clinical and pathological features associated with carriers of different Apo-E isoforms. We also discuss Aβ-dependent and Aβ-independent mechanisms that link Apo-E4 status with AD risk, and consider how to design effective strategies for AD therapy by targeting Apo-E.

Key points

  • The ε4 allele of the apolipo protein E (APOE) gene is the main genetic risk factor for Alzheimer disease (AD)

  • APOE ε4 carriers have enhanced AD pathology, accelerated age-dependent cognitive decline and worse memory performance than do noncarriers

  • Numerous structural and functional brain changes associated with AD pathogenesis are detected in APOE ε4 carriers before clinical symptoms become evident

  • Apo-E affects amyloid-β (Aβ) clearance, aggregation and deposition in an isoform-dependent manner

  • Apo-E4 also contributes to AD pathogenesis by Aβ-independent mechanisms that involve synaptic plasticity, cholesterol homeostasis, neurovascular functions, and neuroinflammation

  • Apo-E-targeted AD therapy should focus on restoration of the physiological function of Apo-E through increased expression and lipidation, and inhibition of the detrimental effects of Apo-E4

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Change history

  • 26 March 2013

    In the version of this article initially published, in the author list, Chia-Chen Liu's name was misspelt. The error has been corrected for the HTML and PDF versions of the article.

References

  1. 1.

    Alzheimer's Association. 2012 Alzheimer's disease facts and figures. Alzheimers Dement. 8, 131–168 (2012).

  2. 2.

    & The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353–356 (2002).

  3. 3.

    , & Alzheimer's disease. Lancet 368, 387–403 (2006).

  4. 4.

    et al. Reducing endogenous tau ameliorates amyloid β-induced deficits in an Alzheimer's disease mouse model. Science 316, 750–754 (2007).

  5. 5.

    & Biology and pathophysiology of the amyloid precursor protein. Mol. Neurodegener. 6, 27 (2011).

  6. 6.

    et al. Decreased clearance of CNS β-amyloid in Alzheimer's disease. Science 330, 1774 (2010).

  7. 7.

    et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921–923 (1993).

  8. 8.

    Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy. Nat. Rev. Neurosci. 10, 333–344 (2009).

  9. 9.

    & Alzheimer mechanisms and therapeutic strategies. Cell 148, 1204–1222 (2012).

  10. 10.

    et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. JAMA 278, 1349–1356 (1997).

  11. 11.

    & Apolipoprotein E: far more than a lipid transport protein. Annu. Rev. Genomics Hum. Genet. 1, 507–537 (2000).

  12. 12.

    et al. Apolipoprotein E genotype and cardiovascular disease in the Framingham Heart Study. Atherosclerosis 154, 529–537 (2001).

  13. 13.

    & Structural differences between apoE3 and apoE4 may be useful in developing therapeutic agents for Alzheimer's disease. Proc. Natl Acad. Sci. USA 109, 8913–8918 (2012).

  14. 14.

    , & Topology of human apolipoprotein E3 uniquely regulates its diverse biological functions. Proc. Natl Acad. Sci. USA 108, 14813–14818 (2011).

  15. 15.

    & Understanding the association of apolipoprotein E4 with Alzheimer disease: clues from its structure. J. Biol. Chem. 284, 6027–6031 (2009).

  16. 16.

    et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat. Genet. 41, 1088–1093 (2009).

  17. 17.

    et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat. Genet. 41, 1094–1099 (2009).

  18. 18.

    et al. 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, 569–574 (1994).

  19. 19.

    et al. ApoE genotype is a risk factor in nonpresenilin early-onset Alzheimer's disease families. Am. J. Med. Genet. 81, 117–121 (1998).

  20. 20.

    , , & Apolipoprotein E in sporadic Alzheimer's disease: allelic variation and receptor interactions. Neuron 11, 575–580 (1993).

  21. 21.

    et al. A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease. Pharmacogenomics J. 10, 375–384 (2010).

  22. 22.

    et al. Association and expression analyses with single-nucleotide polymorphisms in TOMM40 in Alzheimer disease. Arch. Neurol. 68, 1013–1019 (2011).

  23. 23.

    et al. Cerebral amyloid angiopathy in the brains of patients with Alzheimer's disease: the CERAD experience, Part XV. Neurology 46, 1592–1596 (1996).

  24. 24.

    , , , & Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer's disease and kuru plaque amyloid in Creutzfeldt–Jakob disease. Brain Res. 541, 163–166 (1991).

  25. 25.

    et al. Apolipoprotein E-dependent accumulation of Alzheimer disease-related lesions begins in middle age. Ann. Neurol. 65, 650–657 (2009).

  26. 26.

    et al. Apolipoprotein E, dementia, and cortical deposition of β-amyloid protein. N. Engl. J. Med. 333, 1242–1247 (1995).

  27. 27.

    et al. Increased amyloid β-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc. Natl Acad. Sci. USA 90, 9649–9653 (1993).

  28. 28.

    et al. Imaging brain amyloid in Alzheimer's disease with Pittsburgh compound-B. Ann. Neurol. 55, 306–319 (2004).

  29. 29.

    et al. Cerebral amyloid-β PET with florbetaben (18F) in patients with Alzheimer's disease and healthy controls: a multicentre phase 2 diagnostic study. Lancet Neurol. 10, 424–35 (2011).

  30. 30.

    et al. Fibrillar amyloid-β burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease. Proc. Natl Acad. Sci. USA 106, 6820–6825 (2009).

  31. 31.

    et al. Exercise engagement as a moderator of the effects of APOE genotype on amyloid deposition. Arch. Neurol. 69, 636–643 (2012).

  32. 32.

    , , , & APOE ε4 allele is associated with reduced cerebrospinal fluid levels of Aβ42. Neurology 62, 2116–2118 (2004).

  33. 33.

    et al. Apolipoprotein E ε4 and age effects on florbetapir positron emission tomography in healthy aging and Alzheimer disease. Neurobiol. Aging 34, 1–12 (2013).

  34. 34.

    , , & APOE ε2 is associated with intact cognition but increased Alzheimer pathology in the oldest old. Neurology 72, 829–834 (2009).

  35. 35.

    et al. Apolipoprotein E ε4 is associated with the presence and earlier onset of hemorrhage in cerebral amyloid angiopathy. Stroke 27, 1333–1337 (1996).

  36. 36.

    et al. Variants at APOE influence risk of deep and lobar intracerebral hemorrhage. Ann. Neurol. 68, 934–943 (2010).

  37. 37.

    Cerebral amyloid angiopathy. A critical review. Stroke 18, 311–324 (1987).

  38. 38.

    et al. Mild cognitive impairment represents early-stage Alzheimer disease. Arch. Neurol. 58, 397–405 (2001).

  39. 39.

    et al. Mild cognitive impairment: clinical characterization and outcome. Arch. Neurol. 56, 303–308 (1999).

  40. 40.

    et al. Clinical-neuroimaging characteristics of dysexecutive mild cognitive impairment. Ann. Neurol. 65, 414–423 (2009).

  41. 41.

    et al. Impact of APOE in mild cognitive impairment. Neurology 63, 1898–1901 (2004).

  42. 42.

    et al. Apolipoprotein E genotype influences cognitive 'phenotype' in patients with Alzheimer's disease but not in healthy control subjects. Neurology 50, 355–362 (1998).

  43. 43.

    et al. The association between APOE genotype and memory dysfunction in subjects with mild cognitive impairment is related to age and Alzheimer pathology. Dement. Geriatr. Cogn. Disord. 26, 101–108 (2008).

  44. 44.

    et al. APOE-ε4 is associated with memory decline in cognitively impaired elderly. Neurology 54, 1492–1497 (2000).

  45. 45.

    et al. Influence of apolipoprotein E ε4 on rates of cognitive and functional decline in mild cognitive impairment. Alzheimers Dement. 6, 412–419 (2010).

  46. 46.

    et al. APOE ε4 allele predicts faster cognitive decline in mild Alzheimer disease. Neurology 70, 1842–1849 (2008).

  47. 47.

    et al. Clinical predictors of progression to Alzheimer disease in amnestic mild cognitive impairment. Neurology 68, 1588–1595 (2007).

  48. 48.

    , , , & Predictive value of APOE- ε4 allele for progression from MCI to AD-type dementia: a meta-analysis. J. Neurol. Neurosurg. Psychiatry 82, 1149–1156 (2011).

  49. 49.

    et al. Apolipoprotein E status as a predictor of the development of Alzheimer's disease in memory-impaired individuals. JAMA 273, 1274–1278 (1995).

  50. 50.

    et al. Effect of apolipoprotein E on biomarkers of amyloid load and neuronal pathology in Alzheimer disease. Ann. Neurol. 67, 308–316 (2010).

  51. 51.

    et al. β-amyloid imaging and memory in non-demented individuals: evidence for preclinical Alzheimer's disease. Brain 130, 2837–2844 (2007).

  52. 52.

    , , , & APOE and cognitive decline in preclinical Alzheimer disease and non-demented aging. Neurology 63, 816–821 (2004).

  53. 53.

    , , & Multimodal MRI neuroimaging biomarkers for cognitive normal adults, amnestic mild cognitive impairment, and Alzheimer's disease. Neurology Res. Int. 2012, 907409 (2012).

  54. 54.

    et al. Cognitive domain decline in healthy apolipoprotein E ε4 homozygotes before the diagnosis of mild cognitive impairment. Arch. Neurol. 64, 1306–1311 (2007).

  55. 55.

    et al. Longitudinal changes in cognition and behavior in asymptomatic carriers of the APOE e4 allele. Neurology 62, 1990–1995 (2004).

  56. 56.

    et al. Longitudinal modeling of age-related memory decline and the APOE ε4 effect. N. Engl. J. Med. 361, 255–263 (2009).

  57. 57.

    et al. Longitudinal modeling of frontal cognition in APOE ε4 homozygotes, heterozygotes, and noncarriers. Neurology 76, 1383–1388 (2011).

  58. 58.

    et al. The association of APOE genotype with cognitive function in persons aged 35 years or older. PLoS ONE 6, e27415 (2011).

  59. 59.

    et al. Better memory and neural efficiency in young apolipoprotein E ε4 carriers. Cereb. Cortex 17, 1934–1947 (2007).

  60. 60.

    , , & APOE ε4 differentially influences change in memory performance depending on age. The SMART-MR study. Neurobiol. Aging 33, 832 e15–e22 (2012).

  61. 61.

    , , & Decreased cognition in children with risk factors for Alzheimer's disease. Biol. Psychiatry 64, 904–906 (2008).

  62. 62.

    & The apolipoprotein E antagonistic pleiotropy hypothesis: review and recommendations. Int. J. Alzheimers Dis. 2011, 726197 (2011).

  63. 63.

    et al. Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci. Transl. Med. 3, 89ra57 (2011).

  64. 64.

    et al. APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann. Neurol. 67, 122–131 (2010).

  65. 65.

    , , , & The role of APOE ε4 in modulating effects of other risk factors for cognitive decline in elderly persons. JAMA 282, 40–46 (1999).

  66. 66.

    , & Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: the Honolulu-Asia Aging Study. Diabetes 51, 1256–1262 (2002).

  67. 67.

    , , & Cerebrovascular disease, the apolipoprotein e4 allele, and cognitive decline in a community-based study of elderly men. Stroke 27, 2230–2235 (1996).

  68. 68.

    et al. Enhanced risk for Alzheimer disease in persons with type 2 diabetes and APOE ε4: the Cardiovascular Health Study Cognition Study. Arch. Neurol. 65, 89–93 (2008).

  69. 69.

    et al. Insulin resistance is associated with the pathology of Alzheimer disease: the Hisayama study. Neurology 75, 764–770 (2010).

  70. 70.

    et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485, 512–516 (2012).

  71. 71.

    , & Apolipoprotein E in Alzheimer's disease and other neurological disorders. Lancet Neurol. 10, 241–252 (2011).

  72. 72.

    et al. Meta-analysis of APOE4 allele and outcome after traumatic brain injury. J. Neurotrauma 25, 279–290 (2008).

  73. 73.

    , , , & Head injury as a risk factor for Alzheimer's disease: the evidence 10 years on; a partial replication. J. Neurol. Neurosurg. Psychiatry 74, 857–862 (2003).

  74. 74.

    & New perspectives on amyloid-β dynamics after acute brain injury: moving between experimental approaches and studies in the human brain. Arch. Neurol. 67, 1068–1073 (2010).

  75. 75.

    , & Apolipoprotein E ε4 allele is associated with deposition of amyloid β-protein following head injury. Nat. Med. 1, 135–137 (1995).

  76. 76.

    Morphologic diagnosis of “vascular dementia”—a critical update. J. Neurol. Sci. 270, 1–12 (2008).

  77. 77.

    et al. Association between apolipoprotein E gene polymorphism and the risk of vascular dementia: a meta-analysis. Neurosci. Lett. 514, 6–11 (2012).

  78. 78.

    et al. The association between APOE and dementia does not seem to be mediated by vascular factors. Neurology 54, 397–402 (2000).

  79. 79.

    & Age-related differences in memory and executive functions in healthy APOE ε4 carriers: the contribution of individual differences in prefrontal volumes and systolic blood pressure. Neuropsychologia 50, 704–714 (2012).

  80. 80.

    et al. Meta-analysis of APOE genotype and subarachnoid hemorrhage. Neurology 69, 766–775 (2007).

  81. 81.

    et al. APOE genotype and extent of bleeding and outcome in lobar intracerebral haemorrhage: a genetic association study. Lancet Neurol. 10, 702–709 (2011).

  82. 82.

    , , & A large study reveals no association between APOE and Parkinson's disease. Neurobiol. Dis. 46, 389–392 (2012).

  83. 83.

    et al. Lack of association of APOE and tau polymorphisms with dementia in Parkinson's disease. Neurosci. Lett. 448, 20–23 (2008).

  84. 84.

    et al. Dementia with Lewy bodies. Semin. Clin. Neuropsychiatry 8, 46–57 (2003).

  85. 85.

    et al. Influence of apolipoprotein E genotype on senile dementia of the Alzheimer and Lewy body types. Significance for etiological theories of Alzheimer's disease. Am. J. Pathol. 145, 1472–1484 (1994).

  86. 86.

    , , , & Amyloid β protein (Aβ) deposition in dementia with Lewy bodies: predominance of Aβ42(43) and paucity of Aβ40 compared with sporadic Alzheimer's disease. Neuropathol. Appl. Neurobiol. 24, 187–194 (1998).

  87. 87.

    et al. Aβ deposition is associated with enhanced cortical α-synuclein lesions in Lewy body diseases. Neurobiol. Aging 26, 1183–1192 (2005).

  88. 88.

    et al. The APOE gene locus in frontotemporal dementia and primary progressive aphasia. Arch. Neurol. 68, 622–628 (2011).

  89. 89.

    et al. Apolipoprotein E genotypes do not influence the age of onset in Huntington's disease. J. Neurol. Neurosurg. Psychiatry 75, 1692–1696 (2004).

  90. 90.

    et al. Does apolipoprotein E genotype modify the clinical expression of ALS? Eur. J. Neurol. 18, 618–624 (2011).

  91. 91.

    et al. Human APOE isoform-dependent effects on brain β-amyloid levels in PDAPP transgenic mice. J. Neurosci. 29, 6771–6779 (2009).

  92. 92.

    , , , & Direct and potent regulation of γ-secretase by its lipid microenvironment. J. Biol. Chem. 283, 22529–22540 (2008).

  93. 93.

    et al. Impact of apolipoprotein E (apoE) polymorphism on brain ApoE levels. J. Neurosci. 28, 11445–11453 (2008).

  94. 94.

    et al. Reduced levels of human apoE4 protein in an animal model of cognitive impairment. Neurobiol. Aging 32, 791–801 (2011).

  95. 95.

    et al. Apolipoprotein E levels in cerebrospinal fluid and the effects of ABCA1 polymorphisms. Mol. Neurodegener. 2, 7 (2007).

  96. 96.

    et al. Apolipoprotein E and β-amyloid levels in the hippocampus and frontal cortex of Alzheimer's disease subjects are disease-related and apolipoprotein E genotype dependent. Brain Res. 843, 87–94 (1999).

  97. 97.

    et al. ApoE and clusterin cooperatively suppress Aβ levels and deposition: evidence that ApoE regulates extracellular Aβ metabolism in vivo. Neuron 41, 193–202 (2004).

  98. 98.

    et al. The LXR agonist TO901317 selectively lowers hippocampal Aβ42 and improves memory in the Tg2576 mouse model of Alzheimer's disease. Mol. Cell Neurosci. 34, 621–628 (2007).

  99. 99.

    et al. Liver X receptor activation restores memory in aged AD mice without reducing amyloid. Neurobiol. Aging 32, 1262–1272 (2011).

  100. 100.

    et al. ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models. Science 335, 1503–1506 (2012).

  101. 101.

    et al. Abca1 deficiency affects Alzheimer's disease-like phenotype in human ApoE4 but not in ApoE3-targeted replacement mice. J. Neurosci. 32, 13125–13136 (2012).

  102. 102.

    , & The role of apolipoprotein E in Alzheimer's disease. Neuron 63, 287–303 (2009).

  103. 103.

    et al. Isoform-specific binding of apolipoprotein E to β-amyloid. J. Biol. Chem. 269, 23403–23406 (1994).

  104. 104.

    et al. ApoE isoform-specific disruption of amyloid β peptide clearance from mouse brain. J. Clin. Invest. 118, 4002–4013 (2008).

  105. 105.

    et al. ApoE promotes the proteolytic degradation of Aβ. Neuron 58, 681–693 (2008).

  106. 106.

    et al. Lack of apolipoprotein E dramatically reduces amyloid β-peptide deposition. Nat. Genet. 17, 263–264 (1997).

  107. 107.

    et al. Magnetic resonance imaging characterization of brain structure and function in mild cognitive impairment: a review. J. Am. Geriatr. Soc. 56, 920–934 (2008).

  108. 108.

    , & Advances in the early detection of Alzheimer's disease. Nat. Med. 10 (Suppl.), S34–S41 (2004).

  109. 109.

    , , & Medial temporal lobe atrophy on MRI predicts dementia in patients with mild cognitive impairment. Neurology 63, 94–100 (2004).

  110. 110.

    et al. Apolipoprotein E ε4 and the pattern of regional brain atrophy in Alzheimer's disease. Neurology 57, 1461–1466 (2001).

  111. 111.

    et al. Accelerated age-related cortical thinning in healthy carriers of apolipoprotein E ε4. Neurobiol. Aging 29, 329–340 (2008).

  112. 112.

    et al. Hippocampal volumes in cognitively normal persons at genetic risk for Alzheimer's disease. Ann. Neurol. 44, 288–291 (1998).

  113. 113.

    et al. Presence of APOE ε4 allele associated with thinner frontal cortex in middle age. J. Alzheimers Dis. 26, 49–60 (2011).

  114. 114.

    et al. APOE4 allele disrupts resting state fMRI connectivity in the absence of amyloid plaques or decreased CSF Aβ42. J. Neurosci. 30, 17035–17040 (2010).

  115. 115.

    et al. Effect of APOE ε4 status on intrinsic network connectivity in cognitively normal elderly subjects. Arch. Neurol. 68, 1131–1136 (2011).

  116. 116.

    et al. Patterns of brain activation in people at risk for Alzheimer's disease. N. Engl. J. Med. 343, 450–456 (2000).

  117. 117.

    et al. Distinct patterns of brain activity in young carriers of the APOE-ε4 allele. Proc. Natl Acad. Sci. USA 106, 7209–7214 (2009).

  118. 118.

    , , & fMRI evidence of compensatory mechanisms in older adults at genetic risk for Alzheimer disease. Neurology 64, 501–508 (2005).

  119. 119.

    et al. Neuronal activity regulates the regional vulnerability to amyloid-β deposition. Nat. Neurosci. 14, 750–756 (2011).

  120. 120.

    et al. Synaptic activity regulates interstitial fluid amyloid-β levels in vivo. Neuron 48, 913–922 (2005).

  121. 121.

    et al. Hippocampal hyperactivation associated with cortical thinning in Alzheimer's disease signature regions in non-demented elderly adults. J. Neurosci. 31, 17680–17688 (2011).

  122. 122.

    et al. Longitudinal fMRI in elderly reveals loss of hippocampal activation with clinical decline. Neurology 74, 1969–1976 (2010).

  123. 123.

    et al. Pre-clinical detection of Alzheimer's disease using FDG-PET, with or without amyloid imaging. J. Alzheimers Dis. 20, 843–854 (2010).

  124. 124.

    et al. Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease. JAMA 273, 942–947 (1995).

  125. 125.

    et al. Preclinical evidence of Alzheimer's disease in persons homozygous for the ε4 allele for apolipoprotein E. N. Engl. J. Med. 334, 752–758 (1996).

  126. 126.

    et al. Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease. Proc. Natl Acad. Sci. USA 97, 6037–6042 (2000).

  127. 127.

    et al. Correlations between apolipoprotein E ε4 gene dose and brain-imaging measurements of regional hypometabolism. Proc. Natl Acad. Sci. USA 102, 8299–8302 (2005).

  128. 128.

    Aβ-independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer's disease. Trends Mol. Med. 16, 287–294 (2010).

  129. 129.

    et al. Increased expression of neuronal apolipoprotein E in human brain with cerebral infarction. Stroke 34, 875–880 (2003).

  130. 130.

    et al. Neuron-specific apolipoprotein E4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J. Neurosci. 24, 2527–2534 (2004).

  131. 131.

    , & Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer's disease. Proc. Natl Acad. Sci. USA 103, 5644–5651 (2006).

  132. 132.

    , , & Apolipoprotein epsilon 3 alleles are associated with indicators of neuronal resilience. BMC Med. 10, 35 (2012).

  133. 133.

    et al. Cellular source of apolipoprotein E4 determines neuronal susceptibility to excitotoxic injury in transgenic mice. Am. J. Pathol. 177, 563–569 (2010).

  134. 134.

    et al. CNS synaptogenesis promoted by glia-derived cholesterol. Science 294, 1354–1357 (2001).

  135. 135.

    Cholesterol homeostasis and function in neurons of the central nervous system. Cell Mol. Life Sci. 60, 1158–1171 (2003).

  136. 136.

    & Membrane lipids, selectively diminished in Alzheimer brains, suggest synapse loss as a primary event in early-onset form (Type I) and demyelination in late-onset form (Type II). J. Neurochem. 62, 1039–1047 (1994).

  137. 137.

    , & Implication of apoE isoforms in cholesterol metabolism by primary rat hippocampal neurons and astrocytes. Biochimie 88, 473–483 (2006).

  138. 138.

    et al. Altered cholesterol metabolism in human apolipoprotein E4 knock-in mice. Hum. Mol. Genet. 9, 353–361 (2000).

  139. 139.

    Alzheimer's disease is a synaptic failure. Science 298, 789–791 (2002).

  140. 140.

    , & Alzheimer's disease: synapses gone cold. Mol. Neurodegener. 6, 63 (2011).

  141. 141.

    , , & ApoE4 reduces glutamate receptor function and synaptic plasticity by selectively impairing ApoE receptor recycling. Proc. Natl Acad. Sci. USA .

  142. 142.

    et al. Modulation of Alzheimer-like synaptic and cholinergic deficits in transgenic mice by human apolipoprotein E depends on isoform, aging, and overexpression of amyloid β peptides but not on plaque formation. J. Neurosci. 22, 10539–10548 (2002).

  143. 143.

    et al. Apolipoprotein E isoform-specific regulation of dendritic spine morphology in apolipoprotein E transgenic mice and Alzheimer's disease patients. Neuroscience 122, 305–315 (2003).

  144. 144.

    et al. ApoE4 decreases spine density and dendritic complexity in cortical neurons in vivo. J. Neurosci. 29, 15317–15322 (2009).

  145. 145.

    et al. Human apoE4-targeted replacement mice display synaptic deficits in the absence of neuropathology. Neurobiol. Dis. 18, 390–398 (2005).

  146. 146.

    , & Apolipoprotein E3 (ApoE3) but not ApoE4 protects against synaptic loss through increased expression of protein kinase Cε. J. Biol. Chem. 287, 15947–15958 (2012).

  147. 147.

    , , & Progressive loss of synaptic integrity in human apolipoprotein E4 targeted replacement mice and attenuation by apolipoprotein E2. Neuroscience 171, 1265–1272 (2010).

  148. 148.

    , , , & Neuroinflammation and Alzheimer's disease: critical roles for cytokine/Aβ-induced glial activation, NF-κB, and apolipoprotein E. Neurobiol. Aging 21, 427–432 (2000).

  149. 149.

    et al. Apolipoprotein E and apolipoprotein E receptors modulate Aβ-induced glial neuroinflammatory responses. Neurochem. Int. 39, 427–434 (2001).

  150. 150.

    , , , & Apolipoprotein E modulates glial activation and the endogenous central nervous system inflammatory response. J. Neuroimmunol. 114, 107–113 (2001).

  151. 151.

    , , , & Apolipoprotein E isoforms and regulation of the innate immune response in brain of patients with Alzheimer's disease. Curr. Opin. Neurobiol. 21, 920–928 (2011).

  152. 152.

    et al. APOE genotype and an ApoE-mimetic peptide modify the systemic and central nervous system inflammatory response. J. Biol. Chem. 278, 48529–48533 (2003).

  153. 153.

    et al. Plasma signaling proteins in persons at genetic risk for Alzheimer disease: influence of APOE genotype. Arch. Neurol. 69, 757–764 (2012).

  154. 154.

    et al. NSAID use and dementia risk in the Cardiovascular Health Study: role of APOE and NSAID type. Neurology 70, 17–24 (2008).

  155. 155.

    & Adult hippocampal neurogenesis and its role in Alzheimer's disease. Mol. Neurodegener. 6, 85 (2011).

  156. 156.

    , , & ApoE is required for maintenance of the dentate gyrus neural progenitor pool. Development 138, 4351–4362 (2011).

  157. 157.

    et al. Apolipoprotein E4 causes age- and Tau-dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice. J. Neurosci. 30, 13707–13717 (2010).

  158. 158.

    et al. GABAergic interneuron dysfunction impairs hippocampal neurogenesis in adult apolipoprotein E4 knockin mice. Cell Stem Cell 5, 634–645 (2009).

  159. 159.

    et al. A randomized, double-blind, placebo-controlled clinical trial of intravenous bapineuzumab in patients with Alzheimer's disease who are apolipoprotein E ε4 non-carriers. Presented at the 16th meeting of the European Federation of Neurological Societies (Stockholm, Sweden, 2012).

  160. 160.

    et al. A randomized, double-blind, placebo-controlled clinical trial of intravenous bapineuzumab in patients with Alzheimer's disease who are apolipoprotein E ε4 carriers. Presented at the 16th meeting of the European Federation of Neurological Societies (Stockholm, Sweden, 2012).

  161. 161.

    et al. How can elderly apolipoprotein E ε4 carriers remain free from dementia? Neurobiol. Aging .

  162. 162.

    et al. Measurement of apolipoprotein E (apoE) in cerebrospinal fluid. Neurochem. Res. 25, 511–517 (2000).

  163. 163.

    et al. Plasma apolipoprotein E and Alzheimer disease risk. Neurology 76, 1091–1098 (2011).

  164. 164.

    et al. A PPARγ-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol. Cell 7, 161–171 (2001).

  165. 165.

    & Oxysterols, cholesterol homeostasis, and Alzheimer disease. J. Neurochem. 102, 1727–1737 (2007).

  166. 166.

    et al. 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, 34144–34154 (2010).

  167. 167.

    et al. Human apolipoprotein E4 alters the amyloid-β 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model. J. Neurosci. 25, 2803–2810 (2005).

  168. 168.

    et al. Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of amyloid-β amyloidosis. J. Neurosci. 31, 18007–18012 (2011).

  169. 169.

    , , , & Reducing human apolipoprotein E levels attenuates age-dependent Aβ accumulation in mutant human amyloid precursor protein transgenic mice. J. Neurosci. 32, 4803–4811 (2012).

  170. 170.

    et al. Blocking the apolipoprotein E/amyloid-β interaction as a potential therapeutic approach for Alzheimer's disease. Proc. Natl Acad. Sci. USA 103, 18787–18792 (2006).

  171. 171.

    et al. Small molecule structure correctors abolish detrimental effects of apolipoprotein E4 in cultured neurons. J. Biol. Chem. 287, 5253–5266 (2012).

  172. 172.

    et al. Protective effect of apolipoprotein E-mimetic peptides on N-methyl-D-aspartate excitotoxicity in primary rat neuronal-glial cell cultures. Neuroscience 116, 437–445 (2003).

  173. 173.

    et al. Apolipoprotein E-derived peptides ameliorate clinical disability and inflammatory infiltrates into the spinal cord in a murine model of multiple sclerosis. J. Pharmacol. Exp. Ther. 318, 956–965 (2006).

  174. 174.

    , , , & An apolipoprotein E-mimetic stimulates axonal regeneration and remyelination after peripheral nerve injury. J. Pharmacol. Exp. Ther. 334, 106–115 (2010).

  175. 175.

    et al. Heparan sulphate proteoglycan and the low-density lipoprotein receptor-related protein 1 constitute major pathways for neuronal amyloid-β uptake. J. Neurosci. 31, 1644–1651 (2011).

  176. 176.

    et al. Neuronal LRP1 knockout in adult mice leads to impaired brain lipid metabolism and progressive, age-dependent synapse loss and neurodegeneration. J. Neurosci. 30, 17068–17078 (2010).

  177. 177.

    et al. Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular Aβ clearance. Neuron 64, 632–644 (2009).

  178. 178.

    & Reelin, lipoprotein receptors and synaptic plasticity. Nat. Rev. Neurosci. 7, 850–859 (2006).

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Acknowledgements

Work in authors' laboratories is supported by the NIH, the Alzheimer's Association, the American Health Assistance Foundation, and Xiamen University Research Funds. We thank C. Stetler and O. Ross for critical reading of the manuscript before submission.

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Affiliations

  1. Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361005, China

    • Chia-Chen Liu
    • , Huaxi Xu
    •  & Guojun Bu
  2.  Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA

    • Takahisa Kanekiyo

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Contributions

All authors contributed to researching data for the article, discussion of the content, writing the article, and to review and/or editing of the manuscript before submission.

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The authors declare no competing financial interests.

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Correspondence to Guojun Bu.

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DOI

https://doi.org/10.1038/nrneurol.2012.263