Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies

Article metrics


Polymorphism in the apolipoprotein E (APOE) gene is a major genetic risk determinant of late-onset Alzheimer disease (AD), with the APOE*ε4 allele conferring an increased risk and the APOE*ε2 allele conferring a decreased risk relative to the common APOE*ε3 allele. Strong evidence from clinical and basic research suggests that a major pathway by which APOE4 increases the risk of AD is by driving earlier and more abundant amyloid pathology in the brains of APOE*ε4 carriers. The number of amyloid-β (Aβ)-dependent and Aβ-independent pathways that are known to be differentially modulated by APOE isoforms is increasing. For example, evidence is accumulating that APOE influences tau pathology, tau-mediated neurodegeneration and microglial responses to AD-related pathologies. In addition, APOE4 is either pathogenic or shows reduced efficiency in multiple brain homeostatic pathways, including lipid transport, synaptic integrity and plasticity, glucose metabolism and cerebrovascular function. Here, we review the recent progress in clinical and basic research into the role of APOE in AD pathogenesis. We also discuss how APOE can be targeted for AD therapy using a precision medicine approach.

Key points

  • The apolipoprotein E (APOE) gene has three major allelic variants, APOE*ε2, APOE*ε3 and APOE*ε4; APOE*ε4 is associated with an increased risk and lower age of onset of Alzheimer disease (AD), whereas APOE*ε2 seems to confer protection against AD.

  • Increasing evidence suggests that the effect of APOE*ε4 on AD risk is exerted through inhibition of amyloid-β (Aβ) clearance and promotion of Aβ aggregation.

  • APOE influences tau pathology and tau-mediated neurodegeneration in an isoform-dependent manner, although the relevance of this observation to AD pathogenesis requires further investigation.

  • APOE4 contributes to AD pathogenesis by impairing microglial responsiveness, lipid transport, synaptic integrity and plasticity, glucose metabolism and cerebrovascular integrity and function; some of these effects are independent of Aβ-related pathways.

  • Current research into APOE-targeted AD therapeutic strategies aims to modulate APOE quantity and lipidation, APOE structural properties, APOE–Aβ interaction and APOE receptor expression.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Structure of lipid-free and lipid-bound APOE3.
Fig. 2: Association of age with prevalence estimates of amyloid positivity according to cognitive status and apolipoprotein E (APOE) genotype.
Fig. 3: APOE isoforms and Aβ aggregation and clearance.
Fig. 4: Effects of APOE4 on AD pathogenesis pathways.
Fig. 5: Model of precision medicine based on APOE genotype.


  1. 1.

    Lambert, J. C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat. Genet. 45, 1452–1458 (2013).

  2. 2.

    Alzheimer’s Association. 2018 Alzheimer’s disease facts and figures. Alzheimers Dement. 14, 367–425 (2018).

  3. 3.

    Serrano-Pozo, A., Frosch, M. P., Masliah, E. & Hyman, B. T. Neuropathological alterations in Alzheimer disease. Cold Spring Harb. Perspect. Med. 1, a006189 (2011).

  4. 4.

    Corder, E. H. 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).

  5. 5.

    Saunders, A. M. et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43, 1467–1472 (1993).

  6. 6.

    Farrer, L. A. 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 278, 1349–1356 (1997).

  7. 7.

    Corder, E. H. et al. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat. Genet. 7, 180–184 (1994).

  8. 8.

    Neu, S. C. et al. Apolipoprotein E genotype and sex risk factors for Alzheimer disease — a meta-analysis. JAMA Neurol. 74, 1178–1189 (2017).

  9. 9.

    Genin, E. et al. APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol. Psychiatry 16, 903–907 (2011).

  10. 10.

    Sando, S. B. et al. APOE epsilon 4 lowers age at onset and is a high risk factor for Alzheimer’s disease; a case control study from central Norway. BMC Neurol. 8, 9 (2008).

  11. 11.

    Liu, C. C., Kanekiyo, T., Xu, H. & Bu, G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat. Rev. Neurol. 9, 106–118 (2013).

  12. 12.

    Shi, Y. et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549, 523–527 (2017).

  13. 13.

    Bras, J. et al. Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies. Hum. Mol. Genet. 23, 6139–6146 (2014).

  14. 14.

    Guerreiro, R. et al. Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study. Lancet Neurol. 17, 64–74 (2018).

  15. 15.

    Tsuang, D. et al. APOE epsilon4 increases risk for dementia in pure synucleinopathies. JAMA Neurol. 70, 223–228 (2013).

  16. 16.

    Huang, X., Chen, P., Kaufer, D. I., Troster, A. I. & Poole, C. Apolipoprotein E and dementia in Parkinson disease: a meta-analysis. Arch. Neurol. 63, 189–193 (2006).

  17. 17.

    Irwin, D. J. et al. Neuropathologic substrates of Parkinson disease dementia. Ann. Neurol. 72, 587–598 (2012).

  18. 18.

    Tropea, T. F. et al. APOE, thought disorder, and SPARE-AD predict cognitive decline in established Parkinson’s disease. Mov. Disord. 33, 289–297 (2018).

  19. 19.

    Josephs, K. A. et al. TDP-43 is a key player in the clinical features associated with Alzheimer’s disease. Acta Neuropathol. 127, 811–824 (2014).

  20. 20.

    Wennberg, A. M. et al. Association of apolipoprotein E epsilon4 with transactive response DNA-binding protein 43. JAMA Neurol. 75, 1347–1354 (2018).

  21. 21.

    Yang, H.-S. et al. Evaluation of TDP-43 proteinopathy and hippocampal sclerosis in relation to APOE ε4 haplotype status: a community-based cohort study. Lancet Neurol. 17, 773–781 (2018).

  22. 22.

    Mahley, R. W. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 240, 622–630 (1988).

  23. 23.

    Xu, Q. et al. 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, 4985–4994 (2006).

  24. 24.

    Kang, S. S. et al. Microglial translational profiling reveals a convergent APOE pathway from aging, amyloid, and tau. J. Exp. Med. 215, 2235–2245 (2018).

  25. 25.

    Wahrle, S. E. et al. ABCA1 is required for normal central nervous system ApoE levels and for lipidation of astrocyte-secreted apoE. J. Biol. Chem. 279, 40987–40993 (2004).

  26. 26.

    Karten, B., Campenot, R. B., Vance, D. E. & Vance, J. E. Expression of ABCG1, but not ABCA1, correlates with cholesterol release by cerebellar astroglia. J. Biol. Chem. 281, 4049–4057 (2006).

  27. 27.

    LaDu, M. J. et al. Nascent astrocyte particles differ from lipoproteins in CSF. J. Neurochem. 70, 2070–2081 (1998).

  28. 28.

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

  29. 29.

    Kanekiyo, T., Xu, H. & Bu, G. ApoE and Abeta in Alzheimer’s disease: accidental encounters or partners? Neuron 81, 740–754 (2014).

  30. 30.

    Dong, J. et al. Interaction of the N-terminal domain of apolipoprotein E4 with heparin. Biochemistry 40, 2826–2834 (2001).

  31. 31.

    Segelke, B. W. et al. Conformational flexibility in the apolipoprotein E amino-terminal domain structure determined from three new crystal forms: implications for lipid binding. Protein Sci. 9, 886–897 (2000).

  32. 32.

    Wilson, C. et al. Salt bridge relay triggers defective LDL receptor binding by a mutant apolipoprotein. Structure 2, 713–718 (1994).

  33. 33.

    Dong, L. M. et al. Human apolipoprotein E. Role of arginine 61 in mediating the lipoprotein preferences of the E3 and E4 isoforms. J. Biol. Chem. 269, 22358–22365 (1994).

  34. 34.

    Wilson, C., Wardell, M. R., Weisgraber, K. H., Mahley, R. W. & Agard, D. A. Three-dimensional structure of the LDL receptor-binding domain of human apolipoprotein E. Science 252, 1817–1822 (1991).

  35. 35.

    Dong, L. M. et al. Novel mechanism for defective receptor binding of apolipoprotein E2 in type III hyperlipoproteinemia. Nat. Struct. Biol. 3, 718–722 (1996).

  36. 36.

    Guttman, M., Prieto, J. H., Handel, T. M., Domaille, P. J. & Komives, E. A. Structure of the minimal interface between ApoE and LRP. J. Mol. Biol. 398, 306–319 (2010).

  37. 37.

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

  38. 38.

    Richter, J. E. et al. Protein molecular modeling shows residue T599 is critical to wild-type function of POLG and description of a novel variant associated with the SANDO phenotype. Hum. Genome Var. 5, 18016 (2018).

  39. 39.

    Puschmann, A. et al. Heterozygous PINK1 p. G411S increases risk of Parkinson’s disease via a dominant-negative mechanism. Brain 140, 98–117 (2017).

  40. 40.

    Kayode, O. et al. An acrobatic substrate metamorphosis reveals a requirement for substrate conformational dynamics in trypsin proteolysis. J. Biol. Chem. 291, 26304–26319 (2016).

  41. 41.

    Caulfield, T. R., Fiesel, F. C. & Springer, W. Activation of the E3 ubiquitin ligase Parkin. Biochem. Soc. Trans. 43, 269–274 (2015).

  42. 42.

    Caulfield, T. R. et al. Phosphorylation by PINK1 releases the UBL domain and initializes the conformational opening of the E3 ubiquitin ligase parkin. PLOS Comput. Biol. 10, e1003935 (2014).

  43. 43.

    Zhang, Y. J. et al. The dual functions of the extreme N-terminus of TDP-43 in regulating its biological activity and inclusion formation. Hum. Mol. Genet. 22, 3112–3122 (2013).

  44. 44.

    Caulfield, T. & Devkota, B. Motion of transfer RNA from the A/T state into the A-site using docking and simulations. Proteins 80, 2489–2500 (2012).

  45. 45.

    Altschul, S. F. et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 25, 3389–3402 (1997).

  46. 46.

    Hooft, R. W., Sander, C., Scharf, M. & Vriend, G. The PDBFINDER database: a summary of PDB, DSSP and HSSP information with added value. Comput. Appl. Biosci. 12, 525–529 (1996).

  47. 47.

    Hooft, R. W., Vriend, G., Sander, C. & Abola, E. E. Errors in protein structures. Nature 381, 272 (1996).

  48. 48.

    Krieger, E. et al. Improving physical realism, stereochemistry, and side-chain accuracy in homology modeling: four approaches that performed well in CASP8. Proteins 77 (Suppl. 9), 114–122 (2009).

  49. 49.

    Frieden, C., Wang, H. & Ho, C. M. W. A mechanism for lipid binding to apoE and the role of intrinsically disordered regions coupled to domain-domain interactions. Proc. Natl Acad. Sci. USA 114, 6292–6297 (2017).

  50. 50.

    Mondal, T. et al. ApoE: in vitro studies of a small molecule effector. Biochemistry 55, 2613–2621 (2016).

  51. 51.

    Frieden, C. ApoE: the role of conserved residues in defining function. Protein Sci. 24, 138–144 (2015).

  52. 52.

    Garai, K., Verghese, P. B., Baban, B., Holtzman, D. M. & Frieden, C. The binding of apolipoprotein E to oligomers and fibrils of amyloid-beta alters the kinetics of amyloid aggregation. Biochemistry 53, 6323–6331 (2014).

  53. 53.

    Frieden, C. & Garai, K. Concerning the structure of apoE. Protein Sci. 22, 1820–1825 (2013).

  54. 54.

    Ji, Z. S., Dichek, H. L., Miranda, R. D. & Mahley, R. W. Heparan sulfate proteoglycans participate in hepatic lipase and apolipoprotein E-mediated binding and uptake of plasma lipoproteins, including high density lipoproteins. J. Biol. Chem. 272, 31285–31292 (1997).

  55. 55.

    Hatters, D. M., Peters-Libeu, C. A. & Weisgraber, K. H. Apolipoprotein E structure: insights into function. Trends Biochem. Sci. 31, 445–454 (2006).

  56. 56.

    Phillips, M. C. Apolipoprotein E isoforms and lipoprotein metabolism. IUBMB Life 66, 616–623 (2014).

  57. 57.

    Lane-Donovan, C. et al. Genetic restoration of plasma ApoE improves cognition and partially restores synaptic defects in ApoE-deficient mice. J. Neurosci. 36, 10141–10150 (2016).

  58. 58.

    Nielsen, H. M. et al. Peripheral apoE isoform levels in cognitively normal APOE epsilon3/epsilon4 individuals are associated with regional gray matter volume and cerebral glucose metabolism. Alzheimers Res. Ther. 9, 5 (2017).

  59. 59.

    Martinez-Morillo, E. et al. Total apolipoprotein E levels and specific isoform composition in cerebrospinal fluid and plasma from Alzheimer’s disease patients and controls. Acta Neuropathol. 127, 633–643 (2014).

  60. 60.

    Baker-Nigh, A. T. et al. Human central nervous system (CNS) ApoE isoforms are increased by age, differentially altered by amyloidosis, and relative amounts reversed in the CNS compared with plasma. J. Biol. Chem. 291, 27204–27218 (2016).

  61. 61.

    Christensen, D. Z., Schneider-Axmann, T., Lucassen, P. J., Bayer, T. A. & Wirths, O. Accumulation of intraneuronal Abeta correlates with ApoE4 genotype. Acta Neuropathol. 119, 555–566 (2010).

  62. 62.

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

  63. 63.

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

  64. 64.

    Schmechel, D. E. et al. Increased amyloid beta-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).

  65. 65.

    Tiraboschi, P. et al. Impact of APOE genotype on neuropathologic and neurochemical markers of Alzheimer disease. Neurology 62, 1977–1983 (2004).

  66. 66.

    Koffie, R. M. et al. Apolipoprotein E4 effects in Alzheimer’s disease are mediated by synaptotoxic oligomeric amyloid-beta. Brain 135, 2155–2168 (2012).

  67. 67.

    Rannikmae, K. et al. APOE associations with severe CAA-associated vasculopathic changes: collaborative meta-analysis. J. Neurol. Neurosurg. Psychiatry 85, 300–305 (2014).

  68. 68.

    Shinohara, M. et al. Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer’s disease. Acta Neuropathol. 132, 225–234 (2016).

  69. 69.

    Serrano-Pozo, A., Qian, J., Monsell, S. E., Betensky, R. A. & Hyman, B. T. APOEepsilon2 is associated with milder clinical and pathological Alzheimer disease. Ann. Neurol. 77, 917–929 (2015).

  70. 70.

    Nelson, P. T. et al. APOE-epsilon2 and APOE-epsilon4 correlate with increased amyloid accumulation in cerebral vasculature. J. Neuropathol. Exp. Neurol. 72, 708–715 (2013).

  71. 71.

    Nicoll, J. A. et al. High frequency of apolipoprotein E epsilon 2 allele in hemorrhage due to cerebral amyloid angiopathy. Ann. Neurol. 41, 716–721 (1997).

  72. 72.

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

  73. 73.

    Love, S. et al. Development, appraisal, validation and implementation of a consensus protocol for the assessment of cerebral amyloid angiopathy in post-mortem brain tissue. Am. J. Neurodegener. Dis. 3, 19–32 (2014).

  74. 74.

    Gonneaud, J. et al. Relative effect of APOE epsilon4 on neuroimaging biomarker changes across the lifespan. Neurology 87, 1696–1703 (2016).

  75. 75.

    Kantarci, K. et al. APOE modifies the association between Abeta load and cognition in cognitively normal older adults. Neurology 78, 232–240 (2012).

  76. 76.

    Sunderland, T. et al. Cerebrospinal fluid beta-amyloid1-42 and tau in control subjects at risk for Alzheimer’s disease: the effect of APOE epsilon4 allele. Biol. Psychiatry 56, 670–676 (2004).

  77. 77.

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

  78. 78.

    Jack, C. R. Jr. et al. Age, sex, and APOE epsilon4 effects on memory, brain structure, and beta-amyloid across the adult life span. JAMA Neurol. 72, 511–519 (2015).

  79. 79.

    Murphy, K. R. et al. Mapping the effects of ApoE4, age and cognitive status on 18F-florbetapir PET measured regional cortical patterns of beta-amyloid density and growth. Neuroimage 78, 474–480 (2013).

  80. 80.

    Fleisher, A. S. et al. Apolipoprotein E epsilon4 and age effects on florbetapir positron emission tomography in healthy aging and Alzheimer disease. Neurobiol. Aging 34, 1–12 (2013).

  81. 81.

    Mishra, S. et al. Longitudinal brain imaging in preclinical Alzheimer disease: impact of APOE epsilon4 genotype. Brain 141, 1828–1839 (2018).

  82. 82.

    Lim, Y. Y. & Mormino, E. C. APOE genotype and early beta-amyloid accumulation in older adults without dementia. Neurology 89, 1028–1034 (2017).

  83. 83.

    Grothe, M. J., Villeneuve, S., Dyrba, M., Bartres-Faz, D. & Wirth, M. Multimodal characterization of older APOE2 carriers reveals selective reduction of amyloid load. Neurology 88, 569–576 (2017).

  84. 84.

    Chiang, G. C. et al. Hippocampal atrophy rates and CSF biomarkers in elderly APOE2 normal subjects. Neurology 75, 1976–1981 (2010).

  85. 85.

    Jansen, W. J. et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA 313, 1924–1938 (2015).

  86. 86.

    Berlau, D. J., Corrada, M. M., Head, E. & Kawas, C. H. APOE epsilon2 is associated with intact cognition but increased Alzheimer pathology in the oldest old. Neurology 72, 829–834 (2009).

  87. 87.

    Shinohara, M. et al. APOE2 eases cognitive decline during aging: clinical and preclinical evaluations. Ann. Neurol. 79, 758–774 (2016).

  88. 88.

    Tarasoff-Conway, J. M. et al. Clearance systems in the brain-implications for Alzheimer disease. Nat. Rev. Neurol. 11, 457–470 (2015).

  89. 89.

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

  90. 90.

    Fitz, N. F. 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).

  91. 91.

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

  92. 92.

    Robert, J. et al. Clearance of beta-amyloid is facilitated by apolipoprotein E and circulating high-density lipoproteins in bioengineered human vessels. eLife 6, e29595 (2017).

  93. 93.

    Ma, Q. et al. Blood-brain barrier-associated pericytes internalize and clear aggregated amyloid-beta42 by LRP1-dependent apolipoprotein E isoform-specific mechanism. Mol. Neurodegener. 13, 57 (2018).

  94. 94.

    Lin, Y. T. et al. APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types. Neuron 98, 1294 (2018).

  95. 95.

    Koistinaho, M. et al. Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides. Nat. Med. 10, 719–726 (2004).

  96. 96.

    Basak, J. M., Verghese, P. B., Yoon, H., Kim, J. & Holtzman, D. M. Low-density lipoprotein receptor represents an apolipoprotein E-independent pathway of Abeta uptake and degradation by astrocytes. J. Biol. Chem. 287, 13959–13971 (2012).

  97. 97.

    Verghese, P. B. et al. ApoE influences amyloid-beta (Abeta) clearance despite minimal apoE/Abeta association in physiological conditions. Proc. Natl Acad. Sci. USA 110, E1807–E1816 (2013).

  98. 98.

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

  99. 99.

    Lee, C. Y. D., Tse, W., Smith, J. D. & Landreth, G. E. Apolipoprotein E promotes beta-amyloid trafficking and degradation by modulating microglial cholesterol levels. J. Biol. Chem. 287, 2032–2044 (2012).

  100. 100.

    Saido, T. & Leissring, M. A. Proteolytic degradation of amyloid beta-protein. Cold Spring Harb. Perspect. Med. 2, a006379 (2012).

  101. 101.

    Miners, J. S. et al. Decreased expression and activity of neprilysin in Alzheimer disease are associated with cerebral amyloid angiopathy. J. Neuropathol. Exp. Neurol. 65, 1012–1021 (2006).

  102. 102.

    Cook, D. G. et al. Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer’s disease is associated with the apolipoprotein E-epsilon4 allele. Am. J. Pathol. 162, 313–319 (2003).

  103. 103.

    Weller, R. O., Subash, M., Preston, S. D., Mazanti, I. & Carare, R. O. Perivascular drainage of amyloid-beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer’s disease. Brain Pathol. 18, 253–266 (2008).

  104. 104.

    Hawkes, C. A. et al. Disruption of arterial perivascular drainage of amyloid-beta from the brains of mice expressing the human APOE epsilon4 allele. PLOS ONE 7, e41636 (2012).

  105. 105.

    Louveau, A. et al. Understanding the functions and relationships of the glymphatic system and meningeal lymphatics. J. Clin. Invest. 127, 3210–3219 (2017).

  106. 106.

    Achariyar, T. M. et al. Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation. Mol. Neurodegener. 11, 74 (2016).

  107. 107.

    Arosio, P., Knowles, T. P. & Linse, S. On the lag phase in amyloid fibril formation. Phys. Chem. Chem. Phys. 17, 7606–7618 (2015).

  108. 108.

    Kim, J., Basak, J. M. & Holtzman, D. M. The role of apolipoprotein E in Alzheimer’s disease. Neuron 63, 287–303 (2009).

  109. 109.

    Liu, C. C. et al. ApoE4 accelerates early seeding of amyloid pathology. Neuron 96, 1024–1032 (2017).

  110. 110.

    Huynh, T. P. V. et al. Age-dependent effects of apoE reduction using antisense oligonucleotides in a model of beta-amyloidosis. Neuron 96, 1013–1023 (2017).

  111. 111.

    O’Brien, R. J. & Wong, P. C. Amyloid precursor protein processing and Alzheimer’s disease. Annu. Rev. Neurosci. 34, 185–204 (2011).

  112. 112.

    Huang, Y. A., Zhou, B., Wernig, M. & Sudhof, T. C. ApoE2, ApoE3, and ApoE4 differentially stimulate APP transcription and Abeta secretion. Cell 168, 427–441 (2017).

  113. 113.

    Wang, C. et al. Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. Nat. Med. 24, 647–657 (2018).

  114. 114.

    Nuriel, T. et al. The endosomal-lysosomal pathway is dysregulated by APOE4 expression in vivo. Front. Neurosci. 11, 702 (2017).

  115. 115.

    Wang, Y. & Mandelkow, E. Tau in physiology and pathology. Nat. Rev. Neurosci. 17, 5–21 (2016).

  116. 116.

    Leyns, C. E. G. & Holtzman, D. M. Glial contributions to neurodegeneration in tauopathies. Mol. Neurodegener. 12, 50 (2017).

  117. 117.

    Farfel, J. M., Yu, L., De Jager, P. L., Schneider, J. A. & Bennett, D. A. Association of APOE with tau-tangle pathology with and without beta-amyloid. Neurobiol. Aging 37, 19–25 (2016).

  118. 118.

    Crary, J. F. et al. Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol. 128, 755–766 (2014).

  119. 119.

    Tsuboi, Y., Josephs, K. A., Cookson, N. & Dickson, D. W. APOE E4 is a determinant for Alzheimer type pathology in progressive supranuclear palsy. Neurology 60, 240–245 (2003).

  120. 120.

    Tabaton, M. et al. Apolipoprotein E epsilon 4 allele frequency is not increased in progressive supranuclear palsy. Neurology 45, 1764–1765 (1995).

  121. 121.

    Ikeda, K. et al. A subset of senile dementia with high incidence of the apolipoprotein E epsilon2 allele. Ann. Neurol. 41, 693–695 (1997).

  122. 122.

    Zhao, N. et al. APOE ε2 is associated with increased tau pathology in primary tauopathy. Nat. Commun. 9, 4388 (2018).

  123. 123.

    Ossenkoppele, R. et al. Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer’s disease. Brain 139, 1551–1567 (2016).

  124. 124.

    Brier, M. R. et al. Tau and Abeta imaging, CSF measures, and cognition in Alzheimer’s disease. Sci. Transl Med. 8, 338ra66 (2016).

  125. 125.

    Josephs, K. A. et al. Beta-amyloid burden is not associated with rates of brain atrophy. Ann. Neurol. 63, 204–212 (2008).

  126. 126.

    Arriagada, P. V., Growdon, J. H., Hedley-Whyte, E. T. & Hyman, B. T. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology 42, 631–639 (1992).

  127. 127.

    Brecht, W. J. et al. Neuron-specific apolipoprotein e4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J. Neurosci. 24, 2527–2534 (2004).

  128. 128.

    Federoff, M., Jimenez-Rolando, B., Nalls, M. A. & Singleton, A. B. A large study reveals no association between APOE and Parkinson’s disease. Neurobiol. Dis. 46, 389–392 (2012).

  129. 129.

    Spatola, M. & Wider, C. Genetics of Parkinson’s disease: the yield. Parkinsonism Relat. Disord. 20 (Suppl. 1), 35–38 (2014).

  130. 130.

    Spillantini, M. G. et al. Alpha-synuclein in Lewy bodies. Nature 388, 839–840 (1997).

  131. 131.

    Lashuel, H. A., Overk, C. R., Oueslati, A. & Masliah, E. The many faces of alpha-synuclein: from structure and toxicity to therapeutic target. Nat. Rev. Neurosci. 14, 38–48 (2013).

  132. 132.

    Apaydin, H., Ahlskog, J. E., Parisi, J. E., Boeve, B. F. & Dickson, D. W. Parkinson disease neuropathology: later-developing dementia and loss of the levodopa response. Arch. Neurol. 59, 102–112 (2002).

  133. 133.

    McKeith, I. G. et al. Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB Consortium. Neurology 89, 88–100 (2017).

  134. 134.

    Olichney, J. M. et al. Cognitive decline is faster in Lewy body variant than in Alzheimer’s disease. Neurology 51, 351–357 (1998).

  135. 135.

    Selkoe, D. J. & Hardy, J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol. Med. 8, 595–608 (2016).

  136. 136.

    Gallardo, G., Schluter, O. M. & Sudhof, T. C. A molecular pathway of neurodegeneration linking alpha-synuclein to ApoE and Abeta peptides. Nat. Neurosci. 11, 301–308 (2008).

  137. 137.

    Dickson, D. W. et al. APOE epsilon4 is associated with severity of Lewy body pathology independent of Alzheimer pathology. Neurology 91, e1182–e1195 (2018).

  138. 138.

    Sugiyama, T. et al. A novel low-density lipoprotein receptor-related protein mediating cellular uptake of apolipoprotein E-enriched beta-VLDL in vitro. Biochemistry 39, 15817–15825 (2000).

  139. 139.

    Brodeur, J. et al. LDLR-related protein 10 (LRP10) regulates amyloid precursor protein (APP) trafficking and processing: evidence for a role in Alzheimer’s disease. Mol. Neurodegener. 7, 31 (2012).

  140. 140.

    Quadri, M. et al. LRP10 genetic variants in familial Parkinson’s disease and dementia with Lewy bodies: a genome-wide linkage and sequencing study. Lancet Neurol. 17, 597–608 (2018).

  141. 141.

    Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130–133 (2006).

  142. 142.

    Itagaki, S., McGeer, P. L., Akiyama, H., Zhu, S. & Selkoe, D. Relationship of microglia and astrocytes to amyloid deposits of Alzheimer disease. J. Neuroimmunol. 24, 173–182 (1989).

  143. 143.

    Song, W. M. & Colonna, M. The identity and function of microglia in neurodegeneration. Nat. Immunol. 19, 1048–1058 (2018).

  144. 144.

    Deczkowska, A. et al. Disease-associated microglia: a universal immune sensor of neurodegeneration. Cell 173, 1073–1081 (2018).

  145. 145.

    Rangaraju, S. et al. Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer’s disease. Mol. Neurodegener. 13, 24 (2018).

  146. 146.

    Krasemann, S. et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566–581 (2017).

  147. 147.

    Ulrich, J. D. et al. ApoE facilitates the microglial response to amyloid plaque pathology. J. Exp. Med. 215, 1047–1058 (2018).

  148. 148.

    Keene, C. D., Cudaback, E., Li, X., Montine, K. S. & Montine, T. J. 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).

  149. 149.

    Rodriguez, G. A., Tai, L. M., LaDu, M. J. & Rebeck, G. W. Human APOE4 increases microglia reactivity at Abeta plaques in a mouse model of Abeta deposition. J. Neuroinflamm. 11, 111 (2014).

  150. 150.

    Shi, Y. & Holtzman, D. M. Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight. Nat. Rev. Immunol. 18, 759–772 (2018).

  151. 151.

    Yeh, F. L., Wang, Y., Tom, I., Gonzalez, L. C. & Sheng, M. TREM2 binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-beta by microglia. Neuron 91, 328–340 (2016).

  152. 152.

    Atagi, Y. et al. Apolipoprotein E is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2). J. Biol. Chem. 290, 26043–26050 (2015).

  153. 153.

    Bailey, C. C., DeVaux, L. B. & Farzan, M. The triggering receptor expressed on myeloid cells 2 binds apolipoprotein E. J. Biol. Chem. 290, 26033–26042 (2015).

  154. 154.

    Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl. J. Med. 368, 107–116 (2013).

  155. 155.

    Guerreiro, R. et al. TREM2 variants in Alzheimer’s disease. N. Engl. J. Med. 368, 117–127 (2013).

  156. 156.

    Pimenova, A. A., Marcora, E. & Goate, A. M. A tale of two genes: microglial Apoe and Trem2. Immunity 47, 398–400 (2017).

  157. 157.

    Jay, T. R., von Saucken, V. E. & Landreth, G. E. TREM2 in neurodegenerative diseases. Mol. Neurodegener. 12, 56 (2017).

  158. 158.

    Efthymiou, A. G. & Goate, A. M. Late onset Alzheimer’s disease genetics implicates microglial pathways in disease risk. Mol. Neurodegener. 12, 43 (2017).

  159. 159.

    Parhizkar, S. et al. Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat. Neurosci. 22, 191–204 (2019).

  160. 160.

    Arendt, T. et al. Plastic neuronal remodeling is impaired in patients with Alzheimer’s disease carrying apolipoprotein epsilon 4 allele. J. Neurosci. 17, 516–529 (1997).

  161. 161.

    Ji, Y. 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).

  162. 162.

    Sweet, R. A. et al. Apolipoprotein E*4 (APOE*4) genotype is associated with altered levels of glutamate signaling proteins and synaptic coexpression networks in the prefrontal cortex in mild to moderate Alzheimer disease. Mol. Cell. Proteomics 15, 2252–2262 (2016).

  163. 163.

    Love, S. et al. Premorbid effects of APOE on synaptic proteins in human temporal neocortex. Neurobiol. Aging 27, 797–803 (2006).

  164. 164.

    Liraz, O., Boehm-Cagan, A. & Michaelson, D. M. ApoE4 induces Abeta42, tau, and neuronal pathology in the hippocampus of young targeted replacement apoE4 mice. Mol. Neurodegener. 8, 16 (2013).

  165. 165.

    Yong, S. M., Lim, M. L., Low, C. M. & Wong, B. S. Reduced neuronal signaling in the ageing apolipoprotein-E4 targeted replacement female mice. Sci. Rep. 4, 6580 (2014).

  166. 166.

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

  167. 167.

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

  168. 168.

    Klein, R. C., Mace, B. E., Moore, S. D. & Sullivan, P. M. Progressive loss of synaptic integrity in human apolipoprotein E4 targeted replacement mice and attenuation by apolipoprotein E2. Neuroscience 171, 1265–1272 (2010).

  169. 169.

    Chen, Y., Durakoglugil, M. S., Xian, X. & Herz, J. ApoE4 reduces glutamate receptor function and synaptic plasticity by selectively impairing ApoE receptor recycling. Proc. Natl Acad. Sci. USA 107, 12011–12016 (2010).

  170. 170.

    Lane-Donovan, C. & Herz, J. The ApoE receptors Vldlr and Apoer2 in central nervous system function and disease. J. Lipid Res. 58, 1036–1043 (2017).

  171. 171.

    Andrews-Zwilling, Y. 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).

  172. 172.

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

  173. 173.

    Tensaouti, Y., Stephanz, E. P., Yu, T. S. & Kernie, S. G. ApoE regulates the development of adult newborn hippocampal neurons. eNeuro 5, ENEURO.0155-18.2018 (2018).

  174. 174.

    Kara, E. et al. Isoform- and cell type-specific structure of apolipoprotein E lipoparticles as revealed by a novel Forster resonance energy transfer assay. J. Biol. Chem. 292, 14720–14729 (2017).

  175. 175.

    Fu, Y. et al. Apolipoprotein E lipoprotein particles inhibit amyloid-beta uptake through cell surface heparan sulphate proteoglycan. Mol. Neurodegener. 11, 37 (2016).

  176. 176.

    Zhao, J. et al. APOE epsilon4/epsilon4 diminishes neurotrophic function of human iPSC-derived astrocytes. Hum. Mol. Genet. 26, 2690–2700 (2017).

  177. 177.

    Heinsinger, N. M., Gachechiladze, M. A. & Rebeck, G. W. Apolipoprotein E genotype affects size of ApoE complexes in cerebrospinal fluid. J. Neuropathol. Exp. Neurol. 75, 918–924 (2016).

  178. 178.

    Yassine, H. N. et al. ABCA1-mediated cholesterol efflux capacity to cerebrospinal fluid is reduced in patients with mild cognitive impairment and Alzheimer’s disease. J. Am. Heart Assoc. 5, e002886 (2016).

  179. 179.

    Hanson, A. J. et al. Effect of apolipoprotein E genotype and diet on apolipoprotein E lipidation and amyloid peptides: randomized clinical trial. JAMA Neurol. 70, 972–980 (2013).

  180. 180.

    Rebeck, G. W. The role of APOE on lipid homeostasis and inflammation in normal brains. J. Lipid Res. 58, 1493–1499 (2017).

  181. 181.

    Fryer, J. D. et al. The low density lipoprotein receptor regulates the level of central nervous system human and murine apolipoprotein E but does not modify amyloid plaque pathology in PDAPP mice. J. Biol. Chem. 280, 25754–25759 (2005).

  182. 182.

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

  183. 183.

    Ulrich, J. D. et al. In vivo measurement of apolipoprotein E from the brain interstitial fluid using microdialysis. Mol. Neurodegener. 8, 13 (2013).

  184. 184.

    Petersen, R. C. et al. Association of elevated amyloid levels with cognition and biomarkers in cognitively normal people from the community. JAMA Neurol. 73, 85–92 (2016).

  185. 185.

    Jack, C. R. Jr & Holtzman, D. M. Biomarker modeling of Alzheimer’s disease. Neuron 80, 1347–1358 (2013).

  186. 186.

    Bertens, D., Knol, D. L., Scheltens, P. & Visser, P. J. Temporal evolution of biomarkers and cognitive markers in the asymptomatic, MCI, and dementia stage of Alzheimer’s disease. Alzheimers Dement. 11, 511–522 (2015).

  187. 187.

    Willette, A. A. et al. Association of insulin resistance with cerebral glucose uptake in late middle-aged adults at risk for Alzheimer disease. JAMA Neurol. 72, 1013–1020 (2015).

  188. 188.

    Craft, S. Alzheimer disease: insulin resistance and AD—extending the translational path. Nat. Rev. Immunol. 8, 360–362 (2012).

  189. 189.

    Craft, S., Cholerton, B. & Baker, L. D. Insulin and Alzheimer’s disease: untangling the web. J. Alzheimers Dis. 33 (Suppl. 1), 263–275 (2013).

  190. 190.

    Hoyer, S. Glucose metabolism and insulin receptor signal transduction in Alzheimer disease. Eur. J. Pharmacol. 490, 115–125 (2004).

  191. 191.

    Steen, E. et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease—is this type 3 diabetes? J. Alzheimers Dis. 7, 63–80 (2005).

  192. 192.

    Ekblad, L. L. et al. Midlife insulin resistance, APOE genotype, and late-life brain amyloid accumulation. Neurology 90, e1150–e1157 (2018).

  193. 193.

    Jagust, W. J. & Landau, S. M. Apolipoprotein E,not fibrillar beta-amyloid, reduces cerebral glucose metabolism in normal aging. J. Neurosci. 32, 18227–18233 (2012).

  194. 194.

    Zhao, N. et al. Apolipoprotein E4 impairs neuronal insulin signaling by trapping insulin receptor in the endosomes. Neuron 96, 115–129 (2017).

  195. 195.

    Reiman, E. M. et al. Preclinical evidence of Alzheimer’s disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. N. Engl. J. Med. 334, 752–758 (1996).

  196. 196.

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

  197. 197.

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

  198. 198.

    Reiman, E. M. et al. Correlations between apolipoprotein E epsilon4 gene dose and brain-imaging measurements of regional hypometabolism. Proc. Natl Acad. Sci. USA 102, 8299–8302 (2005).

  199. 199.

    Small, G. W. 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).

  200. 200.

    Mosconi, L. et al. MCI conversion to dementia and the APOE genotype: a prediction study with FDG-PET. Neurology 63, 2332–2340 (2004).

  201. 201.

    Drzezga, A. et al. Cerebral glucose metabolism in patients with AD and different APOE genotypes. Neurology 64, 102–107 (2005).

  202. 202.

    Mosconi, L. et al. Brain metabolic decreases related to the dose of the ApoE e4 allele in Alzheimer’s disease. J. Neurol. Neurosurg. Psychiatry 75, 370–376 (2004).

  203. 203.

    Pardo, J. V. & Lee, J. T. Atypical localization and dissociation between glucose uptake and amyloid deposition in cognitively normal APOE*E4 homozygotic elders compared with patients with late-onset Alzheimer’s disease. eNeuro ENEURO. 5, ENEURO.0396-17.2018 (2018).

  204. 204.

    Reger, M. A. et al. Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol. Aging 27, 451–458 (2006).

  205. 205.

    Claxton, A. et al. Sex and ApoE genotype differences in treatment response to two doses of intranasal insulin in adults with mild cognitive impairment or Alzheimer’s disease. J. Alzheimers Dis. 35, 789–797 (2013).

  206. 206.

    Claxton, A. et al. Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer’s disease dementia. J. Alzheimers Dis. 44, 897–906 (2015).

  207. 207.

    Geijselaers, S. L. C. et al. Association of cerebrospinal fluid (CSF) insulin with cognitive performance and CSF biomarkers of Alzheimer’s disease. J. Alzheimers Dis. 61, 309–320 (2018).

  208. 208.

    Morris, J. K. et al. Effect of APOE epsilon4 genotype on metabolic biomarkers in aging and Alzheimer’s disease. J. Alzheimers Dis. 58, 1129–1135 (2017).

  209. 209.

    Wu, L., Zhang, X. & Zhao, L. Human ApoE isoforms differentially modulate brain glucose and ketone body metabolism: implications for Alzheimer’s disease risk reduction and early intervention. J. Neurosci. 38, 6665–6681 (2018).

  210. 210.

    Johnson, L. A. et al. Apolipoprotein E4 mediates insulin resistance-associated cerebrovascular dysfunction and the post-prandial response. J. Cereb. Blood Flow Metab. 39, 770–781 (2017).

  211. 211.

    Liu, C. C. et al. Neuronal LRP1 regulates glucose metabolism and insulin signaling in the brain. J. Neurosci. 35, 5851–5859 (2015).

  212. 212.

    Sun, J. H. et al. Genetics of vascular dementia: systematic review and meta-analysis. J. Alzheimers Dis. 46, 611–629 (2015).

  213. 213.

    Davidson, Y. et al. Apolipoprotein E epsilon4 allele frequency in vascular dementia. Dement. Geriatr. Cogn. Disord. 22, 15–19 (2006).

  214. 214.

    Sudre, C. H. et al. APOE epsilon4 status is associated with white matter hyperintensities volume accumulation rate independent of AD diagnosis. Neurobiol. Aging 53, 67–75 (2017).

  215. 215.

    Schilling, S. et al. APOE genotype and MRI markers of cerebrovascular disease: systematic review and meta-analysis. Neurology 81, 292–300 (2013).

  216. 216.

    Halliday, M. R. et al. Relationship between cyclophilin A levels and matrix metalloproteinase 9 activity in cerebrospinal fluid of cognitively normal apolipoprotein E4 carriers and blood-brain barrier breakdown. JAMA Neurol. 70, 1198–1200 (2013).

  217. 217.

    Halliday, M. R. et al. Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease. J. Cereb. Blood Flow Metab. 36, 216–227 (2016).

  218. 218.

    Alata, W., Ye, Y., St-Amour, I., Vandal, M. & Calon, F. Human apolipoprotein E epsilon4 expression impairs cerebral vascularization and blood-brain barrier function in mice. J. Cereb. Blood Flow Metab. 35, 86–94 (2015).

  219. 219.

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

  220. 220.

    Koizumi, K. et al. Apoepsilon4 disrupts neurovascular regulation and undermines white matter integrity and cognitive function. Nat. Commun. 9, 3816 (2018).

  221. 221.

    Bien-Ly, N. et al. Lack of widespread BBB disruption in Alzheimer’s disease models: focus on therapeutic antibodies. Neuron 88, 289–297 (2015).

  222. 222.

    Iturria-Medina, Y. et al. Early role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis. Nat. Commun. 7, 11934 (2016).

  223. 223.

    Janelidze, S. et al. CSF biomarkers of neuroinflammation and cerebrovascular dysfunction in early Alzheimer disease. Neurology 91, e867–e877 (2018).

  224. 224.

    Yamazaki, Y. et al. Selective loss of cortical endothelial tight junction proteins during Alzheimer’s disease progression. Brain 142, 1077–1092 (2019).

  225. 225.

    Nation, D. A. et al. Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat. Med. 25, 270–276 (2019).

  226. 226.

    Ulrich, V. et al. Genetic variants of ApoE and ApoER2 differentially modulate endothelial function. Proc. Natl Acad. Sci. USA 111, 13493–13498 (2014).

  227. 227.

    Tai, L. M. et al. The role of APOE in cerebrovascular dysfunction. Acta Neuropathol. 131, 709–723 (2016).

  228. 228.

    Groot, C. et al. Clinical phenotype, atrophy, and small vessel disease in APOE epsilon 2 carriers eth Alzheimer disease. Neurology 91, e1851–e1859 (2018).

  229. 229.

    Hong, C. & Tontonoz, P. Liver X receptors in lipid metabolism: opportunities for drug discovery. Nat. Rev. Drug Discov. 13, 433–444 (2014).

  230. 230.

    Burns, M. P. et al. The effects of ABCA1 on cholesterol efflux and Abeta levels in vitro and in vivo. J. Neurochem. 98, 792–800 (2006).

  231. 231.

    Donkin, J. J. 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).

  232. 232.

    Koldamova, R. P. et al. The liver X receptor ligand T0901317 decreases amyloid beta production in vitro and in a mouse model of Alzheimer’s disease. J. Biol. Chem. 280, 4079–4088 (2005).

  233. 233.

    Riddell, D. R. et al. The LXR agonist TO901317 selectively lowers hippocampal Abeta42 and improves memory in the Tg2576 mouse model of Alzheimer’s disease. Mol. Cell. Neurosci. 34, 621–628 (2007).

  234. 234.

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

  235. 235.

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

  236. 236.

    Fitz, N. F., Cronican, A. A., Lefterov, I. & Koldamova, R. Comment on “ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models”. Science 340, 924-c (2013).

  237. 237.

    Boehm-Cagan, A. & Michaelson, D. M. Reversal of apoE4-driven brain pathology and behavioral deficits by bexarotene. J. Neurosci. 34, 7293–7301 (2014).

  238. 238.

    Tachibana, M. et al. Rescuing effects of RXR agonist bexarotene on aging-related synapse loss depend on neuronal LRP1. Exp. Neurol. 277, 1–9 (2016).

  239. 239.

    Veeraraghavalu, K. et al. Comment on “ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models”. Science 340, 924-f (2013).

  240. 240.

    Tesseur, I. et al. Comment on “ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models”. Science 340, 924-e (2013).

  241. 241.

    Price, A. R. et al. Comment on “ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models”. Science 340, 924-d (2013).

  242. 242.

    Tai, L. M. et al. Amyloid-beta pathology and APOE genotype modulate retinoid X receptor agonist activity in vivo. J. Biol. Chem. 289, 30538–30555 (2014).

  243. 243.

    Cummings, J. L. et al. Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer’s disease. Alzheimers Res. Ther. 8, 4 (2016).

  244. 244.

    Ghosal, K. et al. A randomized controlled study to evaluate the effect of bexarotene on amyloid-beta and apolipoprotein E metabolism in healthy subjects. Alzheimers Dement. 2, 110–120 (2016).

  245. 245.

    Lalloyer, F. et al. Rexinoid bexarotene modulates triglyceride but not cholesterol metabolism via gene-specific permissivity of the RXR/LXR heterodimer in the liver. Arterioscler. Thromb. Vasc. Biol. 29, 1488–1495 (2009).

  246. 246.

    Finan, G. M. et al. Bioactive compound screen for pharmacological enhancers of apolipoprotein E in primary human astrocytes. Cell Chem. Biol. 23, 1526–1538 (2016).

  247. 247.

    Dodart, J. C. et al. Gene delivery of human apolipoprotein E alters brain Abeta burden in a mouse model of Alzheimer’s disease. Proc. Natl Acad. Sci. USA 102, 1211–1216 (2005).

  248. 248.

    Zhao, L. et al. Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer’s disease mouse models. Neurobiol. Aging 44, 159–172 (2016).

  249. 249.

    Hudry, E. et al. Gene transfer of human Apoe isoforms results in differential modulation of amyloid deposition and neurotoxicity in mouse brain. Sci. Transl Med. 5, 212ra161 (2013).

  250. 250.

    Hu, J. et al. Opposing effects of viral mediated brain expression of apolipoprotein E2 (apoE2) and apoE4 on apoE lipidation and Abeta metabolism in apoE4-targeted replacement mice. Mol. Neurodegener. 10, 6 (2015).

  251. 251.

    Bien-Ly, N., Gillespie, A. K., Walker, D., Yoon, S. Y. & Huang, Y. Reducing human apolipoprotein E levels attenuates age-dependent Abeta accumulation in mutant human amyloid precursor protein transgenic mice. J. Neurosci. 32, 4803–4811 (2012).

  252. 252.

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

  253. 253.

    Youmans, K. L. et al. APOE4-specific changes in Abeta accumulation in a new transgenic mouse model of Alzheimer disease. J. Biol. Chem. 287, 41774–41786 (2012).

  254. 254.

    Koldamova, R., Staufenbiel, M. & Lefterov, I. Lack of ABCA1 considerably decreases brain ApoE level and increases amyloid deposition in APP23 mice. J. Biol. Chem. 280, 43224–43235 (2005).

  255. 255.

    Wahrle, S. E. et al. Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease. J. Biol. Chem. 280, 43236–43242 (2005).

  256. 256.

    Wahrle, S. E. et al. Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease. J. Clin. Invest. 118, 671–682 (2008).

  257. 257.

    Liao, F. et al. Anti-ApoE antibody given after plaque onset decreases Abeta accumulation and improves brain function in a mouse model of Abeta amyloidosis. J. Neurosci. 34, 7281–7292 (2014).

  258. 258.

    Kim, J. et al. Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Abeta amyloidosis. J. Exp. Med. 209, 2149–2156 (2012).

  259. 259.

    Liao, F. et al. Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation. J. Clin. Invest. 128, 2144–2155 (2018).

  260. 260.

    Vitek, M. P. et al. APOE-mimetic peptides reduce behavioral deficits, plaques and tangles in Alzheimer’s disease transgenics. Neurodegener. Dis. 10, 122–126 (2012).

  261. 261.

    Handattu, S. P. et al. In vivo and in vitro effects of an apolipoprotein e mimetic peptide on amyloid-beta pathology. J. Alzheimers Dis. 36, 335–347 (2013).

  262. 262.

    Ghosal, K. et al. 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 (2013).

  263. 263.

    Mahley, R. W. Central nervous system lipoproteins ApoE and regulation of cholesterol metabolism. Arterioscler. Thromb. Vasc. Biol. 36, 1305–1315 (2016).

  264. 264.

    Mahley, R. W. & Huang, Y. Small-molecule structure correctors target abnormal protein structure and function: structure corrector rescue of apolipoprotein E4-associated neuropathology. J. Med. Chem. 55, 8997–9008 (2012).

  265. 265.

    Chen, H. K. et al. Apolipoprotein E4 domain interaction mediates detrimental effects on mitochondria and is a potential therapeutic target for Alzheimer disease. J. Biol. Chem. 286, 5215–5221 (2011).

  266. 266.

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

  267. 267.

    Brodbeck, J. et al. Structure-dependent impairment of intracellular apolipoprotein E4 trafficking and its detrimental effects are rescued by small-molecule structure correctors. J. Biol. Chem. 286, 17217–17226 (2011).

  268. 268.

    Sadowski, M. et al. A synthetic peptide blocking the apolipoprotein E/beta-amyloid binding mitigates beta-amyloid toxicity and fibril formation in vitro and reduces beta-amyloid plaques in transgenic mice. Am. J. Pathol. 165, 937–948 (2004).

  269. 269.

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

  270. 270.

    Liu, S. et al. Blocking the apolipoprotein E/amyloid beta interaction in triple transgenic mice ameliorates Alzheimer’s disease related amyloid beta and tau pathology. J. Neurochem. 128, 577–591 (2014).

  271. 271.

    Kuszczyk, M. A. et al. Blocking the interaction between apolipoprotein E and Abeta reduces intraneuronal accumulation of Abeta and inhibits synaptic degeneration. Am. J. Pathol. 182, 1750–1768 (2013).

  272. 272.

    Pankiewicz, J. E. et al. Blocking the apoE/Abeta interaction ameliorates Abeta-related pathology in APOE epsilon2 and epsilon4 targeted replacement Alzheimer model mice. Acta Neuropathol. Commun. 2, 75 (2014).

  273. 273.

    Zhao, N., Liu, C. C., Qiao, W. & Bu, G. Apolipoprotein E, receptors, and modulation of Alzheimer’s disease. Biol. Psychiatry 83, 347–357 (2018).

  274. 274.

    Cao, D., Fukuchi, K., Wan, H., Kim, H. & Li, L. Lack of LDL receptor aggravates learning deficits and amyloid deposits in Alzheimer transgenic mice. Neurobiol. Aging 27, 1632–1643 (2006).

  275. 275.

    Katsouri, L. & Georgopoulos, S. Lack of LDL receptor enhances amyloid deposition and decreases glial response in an Alzheimer’s disease mouse model. PLOS ONE 6, e21880 (2011).

  276. 276.

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

  277. 277.

    Kanekiyo, T. et al. Neuronal clearance of amyloid-beta by endocytic receptor LRP1. J. Neurosci. 33, 19276–19283 (2013).

  278. 278.

    Liu, C. C. et al. Astrocytic LRP1 mediates brain Abeta clearance and impacts amyloid deposition. J. Neurosci. 37, 4023–4031 (2017).

  279. 279.

    Kanekiyo, T., Liu, C. C., Shinohara, M., Li, J. & Bu, G. LRP1 in brain vascular smooth muscle cells mediates local clearance of Alzheimer’s amyloid-beta. J. Neurosci. 32, 16458–16465 (2012).

  280. 280.

    Qosa, H., Abuznait, A. H., Hill, R. A. & Kaddoumi, A. Enhanced brain amyloid-beta clearance by rifampicin and caffeine as a possible protective mechanism against Alzheimer’s disease. J. Alzheimers Dis. 31, 151–165 (2012).

  281. 281.

    Shinohara, M. et al. Reduction of brain beta-amyloid (A beta) by fluvastatin, a hydroxymethylglutaryl-CoA reductase inhibitor, through increase in degradation of amyloid precursor protein C-terminal fragments (APP-CTFs) and A beta clearance. J. Biol. Chem. 285, 22091–22102 (2010).

  282. 282.

    Mak, A. C. et al. Effects of the absence of apolipoprotein e on lipoproteins, neurocognitive function, and retinal function. JAMA Neurol. 71, 1228–1236 (2014).

  283. 283.

    Centeno, E. G. Z., Cimarosti, H. & Bithell, A. 2D versus 3D human induced pluripotent stem cell-derived cultures for neurodegenerative disease modelling. Mol. Neurodegener. 13, 27 (2018).

  284. 284.

    Karch, C. M. & Goate, A. M. Alzheimer’s disease risk genes and mechanisms of disease pathogenesis. Biol. Psychiatry 77, 43–51 (2015).

  285. 285.

    Carmona, S., Hardy, J. & Guerreiro, R. The genetic landscape of Alzheimer disease. Handb. Clin. Neurol. 148, 395–408 (2018).

  286. 286.

    Alzgene. Meta-analysis of all published AD association studies (case-control only) APOE_E2/3/4. Alzgene http://www.alzgene.org/Meta.asp?GeneID=83 (2010).

  287. 287.

    Mattsson, N. et al. Prevalence of the apolipoprotein E epsilon4 allele in amyloid beta positive subjects across the spectrum of Alzheimer’s disease. Alzheimers Dement. 14, 913–924 (2018).

  288. 288.

    Cacace, R., Sleegers, K. & Van Broeckhoven, C. Molecular genetics of early-onset Alzheimer’s disease revisited. Alzheimers Dement. 12, 733–748 (2016).

  289. 289.

    van Duijn, C. M. et al. Apolipoprotein E4 allele in a population-based study of early-onset Alzheimer’s disease. Nat. Genet. 7, 74–78 (1994).

  290. 290.

    Chartier-Harlin, M. C. et al. Apolipoprotein E, epsilon 4 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).

  291. 291.

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

  292. 292.

    Sorbi, S. et al. Epistatic effect of APP717 mutation and apolipoprotein E genotype in familial Alzheimer’s disease. Ann. Neurol. 38, 124–127 (1995).

  293. 293.

    Pastor, P. et al. Apolipoprotein Eepsilon4 modifies Alzheimer’s disease onset in an E280A PS1 kindred. Ann. Neurol. 54, 163–169 (2003).

  294. 294.

    Wijsman, E. M. et al. APOE and other loci affect age-at-onset in Alzheimer’s disease families with PS2 mutation. Am. J. Med. Genet. 132B, 14–20 (2005).

  295. 295.

    Velez, J. I. et al. APOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer’s disease. Mol. Psychiatry 21, 916–924 (2016).

  296. 296.

    Ryman, D. C. et al. Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology 83, 253–260 (2014).

  297. 297.

    Altmann, A., Tian, L., Henderson, V. W. & Greicius, M. D. Sex modifies the APOE-related risk of developing Alzheimer disease. Ann. Neurol. 75, 563–573 (2014).

  298. 298.

    Buckley, R. F. et al. Sex, amyloid, and APOE epsilon4 and risk of cognitive decline in preclinical Alzheimer’s disease: findings from three well-characterized cohorts. Alzheimers Dement. 14, 1193–1203 (2018).

  299. 299.

    Deming, Y. et al. Sex-specific genetic predictors of Alzheimer’s disease biomarkers. Acta Neuropathol. 136, 857–872 (2018).

  300. 300.

    Hohman, T. J. et al. Sex-specific association of apolipoprotein E with cerebrospinal fluid levels of tau. JAMA Neurol. 75, 989–998 (2018).

  301. 301.

    Buckley, R. F. et al. Sex differences in the association of global amyloid and regional tau deposition measured by positron emission tomography in clinically normal older adults. JAMA Neurol. 76, 542–551 (2019).

  302. 302.

    Sundermann, E. E., Tran, M., Maki, P. M. & Bondi, M. W. Sex differences in the association between apolipoprotein E epsilon4 allele and Alzheimer’s disease markers. Alzheimers Dement. 10, 438–447 (2018).

  303. 303.

    Caselli, R. J. et al. Longitudinal modeling of age-related memory decline and the APOE epsilon4 effect. N. Engl. J. Med. 361, 255–263 (2009).

  304. 304.

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

  305. 305.

    Caselli, R. J. et al. Longitudinal modeling of frontal cognition in APOE epsilon4 homozygotes, heterozygotes, and noncarriers. Neurology 76, 1383–1388 (2011).

  306. 306.

    Bonham, L. W. et al. Age-dependent effects of APOE epsilon4 in preclinical Alzheimer’s disease. Ann. Clin. Transl Neurol. 3, 668–677 (2016).

  307. 307.

    Ferrari, C. et al. How can elderly apolipoprotein E epsilon 4 carriers remain free from dementia? Neurobiol. Aging 34, 13–21 (2013).

  308. 308.

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

  309. 309.

    Stocker, H., Mollers, T., Perna, L. & Brenner, H. The genetic risk of Alzheimer’s disease beyond APOE epsilon4: systematic review of Alzheimer’s genetic risk scores. Transl Psychiatry 8, 166 (2018).

  310. 310.

    Escott-Price, V., Myers, A. J., Huentelman, M. & Hardy, J. Polygenic risk score analysis of pathologically confirmed Alzheimer disease. Ann. Neurol. 82, 311–314 (2017).

  311. 311.

    Montine, T. J. & Montine, K. S. Precision medicine: clarity for the clinical and biological complexity of Alzheimer’s and Parkinson’s diseases. J. Exp. Med. 212, 601–605 (2015).

  312. 312.

    Salloway, S. et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N. Engl. J. Med. 370, 322–333 (2014).

  313. 313.

    Craft, S. et al. Insulin effects on glucose metabolism, memory, and plasma amyloid precursor protein in Alzheimer’s disease differ according to apolipoprotein-E genotype. Ann. NY Acad. Sci. 903, 222–228 (2000).

  314. 314.

    Reger, M. A. et al. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J. Alzheimers Dis. 13, 323–331 (2008).

  315. 315.

    Petersen, R. C. et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N. Engl. J. Med. 352, 2379–2388 (2005).

Download references


Support for work conducted in the authors’ laboratory was provided by the National Institutes of Health, the Cure Alzheimer’s Fund, the BrightFocus Foundation, the Alzheimer’s Association, the American Heart Association, the MetLife Foundation for Medical Awards Program and the Mayo Foundation for Medical Education and Research. The authors also thank C. Stetler for critical reading and editing of the manuscript.

Author information

All authors contributed to all aspects of the article.

Correspondence to Guojun Bu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yamazaki, Y., Zhao, N., Caulfield, T.R. et al. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol 15, 501–518 (2019) doi:10.1038/s41582-019-0228-7

Download citation

Further reading