Skip to main content
SpringerLink
Log in

Associations Between APOE Variants, Tau and α-Synuclein

  • Chapter
  • First Online:
Tau Biology

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1184))

Abstract

Neurodegenerative diseases are characterized by the aggregation and deposition of misfolded proteins in the brain, most prominently amyloid-β (Aβ), tau and α-synuclein (α-syn), and are thus referred to as proteinopathies. While tau is a hallmark of Alzheimer’s disease (AD) and other non-AD tauopathies, and α-synuclein is the pathological feature of the spectrum of synucleinopathies including Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB), the presence of co-pathologies is very frequent in all these diseases. Positive and synergistic associations between the different types of protein deposits have been reported, leading to worse prognosis and cognitive decline. A large variation in phenotypic clinical presentation of these diseases, largely due to the frequent presence of co-pathologies, makes differential diagnosis challenging. The observed clinico-pathological overlaps suggest common underlying mechanisms, in part due to shared genetic risk factors. The ε4 allele of the apolipoprotein (APOE) gene is one of the major genetic risk factors for the sporadic forms of proteinopathies, but the biological mechanisms linking APOE, tau and α-syn are not fully understood. This chapter describes current experimental evidence on the relationships between APOE variants, tau and α-syn, from clinical studies on fluid biomarkers and positron emission tomography (PET) imaging, and from basic experimental studies in cellular/molecular biology and animal models. The chapter focuses on recent advances and identifies knowledge gaps. In particular, no PET tracer for assessment of brain α-syn deposits is yet available, although it is subject of intense research and development, therefore experimental evidence on in vivo α-syn levels is based on measures in the cerebrospinal fluid (CSF) and plasma. Moreover, tau PET imaging studies comparing the patterns of tracer retention in synucleinopathies versus in other proteinopathies are scarce and much is still unknown regarding the relationships between APOE variants and fluid and/or imaging biomarkers of tau and α-syn. Further research incorporating multimodal imaging, fluid biomarkers and genetic factors will help elucidate the biological mechanisms underlying these proteinopathies, and contribute to differential diagnosis and patient stratification for clinical trials.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Robinson JL, et al. Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated. Brain. 2018;141(7):2181–93.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Irwin DJ, et al. Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis. Lancet Neurol. 2017;16(1):55–65.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Villemagne VL, et al. Imaging tau and amyloid-beta proteinopathies in Alzheimer disease and other conditions. Nat Rev Neurol. 2018;14(4):225–36.

    Article  CAS  PubMed  Google Scholar 

  4. Villemagne VL, et al. Tau imaging: early progress and future directions. Lancet Neurol. 2015;14(1):114–24.

    Article  PubMed  Google Scholar 

  5. Clinton LK, et al. Synergistic interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline. J Neurosci. 2010;30(21):7281–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Van Cauwenberghe C, Van Broeckhoven C, Sleegers K. The genetic landscape of Alzheimer disease: clinical implications and perspectives. Genet Med. 2016;18(5):421–30.

    Article  PubMed  Google Scholar 

  7. Shi Y, Holtzman DM. Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight. Nat Rev Immunol. 2018;18:759–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Corbo RM, Scacchi R. Apolipoprotein E (APOE) allele distribution in the world. Is APOE∗4 a ‘thrifty’ allele? Ann Hum Genet. 1999;63(Pt 4):301–10.

    Article  CAS  PubMed  Google Scholar 

  9. Raichlen DA, Alexander GE. Exercise, APOE genotype, and the evolution of the human lifespan. Trends Neurosci. 2014;37(5):247–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Leduc V, et al. Function and comorbidities of apolipoprotein e in Alzheimer’s disease. Int J Alzheimers Dis. 2011;2011:974361.

    PubMed  PubMed Central  Google Scholar 

  11. Kraft HG, et al. Changes of genetic apolipoprotein phenotypes caused by liver-transplantation – implications for apolipoprotein synthesis. J Clin Investig. 1989;83(1):137–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Linton MF, et al. Phenotypes of apolipoprotein B and apolipoprotein E after liver transplantation. J Clin Invest. 1991;88(1):270–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kockx M, Traini M, Kritharides L. Cell-specific production, secretion, and function of apolipoprotein E. J Mol Med (Berl). 2018;96(5):361–71.

    Article  CAS  Google Scholar 

  14. Pitas RE, et al. Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins. Biochim Biophys Acta. 1987;917(1):148–61.

    Article  CAS  PubMed  Google Scholar 

  15. Bu G. Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat Rev Neurosci. 2009;10(5):333–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gregg RE, et al. Abnormal in vivo metabolism of apolipoprotein E4 in humans. J Clin Invest. 1986;78(3):815–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wildsmith KR, et al. In vivo human apolipoprotein E isoform fractional turnover rates in the CNS. PLoS One. 2012;7(6):e38013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ikewaki K, et al. Comparative in vivo metabolism of apolipoproteins E2 and E4 in heterozygous apoE2/4 subjects. J Lab Clin Med. 2002;140(5):369–74.

    Article  CAS  PubMed  Google Scholar 

  19. 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. 2014;127(5):633–43.

    Article  CAS  PubMed  Google Scholar 

  20. Rasmussen KL, et al. Plasma levels of apolipoprotein E and risk of dementia in the general population. Ann Neurol. 2015;77(2):301–11.

    Article  CAS  PubMed  Google Scholar 

  21. Berge G, et al. Apolipoprotein E epsilon2 genotype delays onset of dementia with Lewy bodies in a Norwegian cohort. J Neurol Neurosurg Psychiatry. 2014;85(11):1227–31.

    Article  PubMed  Google Scholar 

  22. Li YJ, et al. Apolipoprotein E controls the risk and age at onset of Parkinson disease. Neurology. 2004;62(11):2005–9.

    Article  CAS  PubMed  Google Scholar 

  23. Tsuang D, et al. APOE epsilon4 increases risk for dementia in pure synucleinopathies. JAMA Neurol. 2013;70(2):223–8.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Verghese PB, Castellano JM, Holtzman DM. Apolipoprotein E in Alzheimer’s disease and other neurological disorders. Lancet Neurol. 2011;10(3):241–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ogaki K, et al. Multiple system atrophy and apolipoprotein E. Mov Disord. 2018;33:647–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhao N, et al. APOE epsilon2 is associated with increased tau pathology in primary tauopathy. Nat Commun. 2018;9(1):4388.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Cruchaga C, et al. Cerebrospinal fluid APOE levels: an endophenotype for genetic studies for Alzheimer’s disease. Hum Mol Genet. 2012;21(20):4558–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Darreh-Shori T, et al. Differential levels of apolipoprotein E and butyrylcholinesterase show strong association with pathological signs of Alzheimer’s disease in the brain in vivo. Neurobiol Aging. 2011;32(12):2320 e15-32.

    Article  PubMed  CAS  Google Scholar 

  29. Riddell DR, et al. Impact of apolipoprotein E (ApoE) polymorphism on brain ApoE levels. J Neurosci. 2008;28(45):11445–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Simon R, et al. Total ApoE and ApoE4 isoform assays in an Alzheimer’s disease case-control study by targeted mass spectrometry (n=669): a pilot assay for methionine-containing proteotypic peptides. Mol Cell Proteomics. 2012;11(11):1389–403.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Song F, et al. Plasma apolipoprotein levels are associated with cognitive status and decline in a community cohort of older individuals. PLoS One. 2012;7(6):e34078.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Martinez-Morillo E, et al. Assessment of peptide chemical modifications on the development of an accurate and precise multiplex selected reaction monitoring assay for apolipoprotein e isoforms. J Proteome Res. 2014;13(2):1077–87.

    Article  CAS  PubMed  Google Scholar 

  33. Nielsen HM, 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. 2017;9(1):5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Toledo JB, et al. CSF Apo-E levels associate with cognitive decline and MRI changes. Acta Neuropathol. 2014;127:621–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Koch G, et al. CSF tau is associated with impaired cortical plasticity, cognitive decline and astrocyte survival only in APOE4-positive Alzheimer’s disease. Sci Rep. 2017;7(1):13728.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Twohig D, et al. The relevance of cerebrospinal fluid alpha-synuclein levels to sporadic and familial Alzheimer’s disease. Acta Neuropathol Commun. 2018;6(130):1–19.

    Google Scholar 

  37. Vergallo A, et al. Association of cerebrospinal fluid alpha-synuclein with total and phospho-tau181 protein concentrations and brain amyloid load in cognitively normal subjective memory complainers stratified by Alzheimer’s disease biomarkers. Alzheimers Dement. 2018;14:1623–31.

    Article  PubMed  Google Scholar 

  38. Veitch DP, et al. Understanding disease progression and improving Alzheimer’s disease clinical trials: recent highlights from the Alzheimer’s disease neuroimaging initiative. Alzheimers Dement. 2019;15:106–52.

    Article  PubMed  Google Scholar 

  39. Morris JC, et al. APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann Neurol. 2010;67(1):122–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Risacher SL, et al. The role of apolipoprotein E (APOE) genotype in early mild cognitive impairment (E-MCI). Front Aging Neurosci. 2013;5:11.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Grothe MJ, et al. Multimodal characterization of older APOE2 carriers reveals selective reduction of amyloid load. Neurology. 2017;88(6):569–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Suri S, et al. The forgotten APOE allele: a review of the evidence and suggested mechanisms for the protective effect of APOE varepsilon2. Neurosci Biobehav Rev. 2013;37(10 Pt 2):2878–86.

    Article  CAS  PubMed  Google Scholar 

  43. Mathis CA, et al. Small-molecule PET tracers for imaging proteinopathies. Semin Nucl Med. 2017;47(5):553–75.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Lee SH, et al. Distinct patterns of amyloid-dependent tau accumulation in Lewy body diseases. Mov Disord. 2018;33(2):262–72.

    Article  CAS  PubMed  Google Scholar 

  45. Kantarci K, et al. AV-1451 tau and beta-amyloid positron emission tomography imaging in dementia with Lewy bodies. Ann Neurol. 2017;81(1):58–67.

    Article  CAS  PubMed  Google Scholar 

  46. Mattsson N, et al. Greater tau load and reduced cortical thickness in APOE epsilon4-negative Alzheimer’s disease: a cohort study. Alzheimers Res Ther. 2018;10(1):77.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Rabinovici GD, et al. Increased metabolic vulnerability in early-onset Alzheimer’s disease is not related to amyloid burden. Brain. 2010;133(Pt 2):512–28.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Johnson KA, et al. Tau positron emission tomographic imaging in aging and early Alzheimer disease. Ann Neurol. 2016;79(1):110–9.

    Article  PubMed  Google Scholar 

  49. Whitwell JL, et al. [(18) F]AV-1451 clustering of entorhinal and cortical uptake in Alzheimer’s disease. Ann Neurol. 2018;83(2):248–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ossenkoppele R, et al. Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer’s disease. Brain. 2016;139(Pt 5):1551–67.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Harris FM, et al. Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer’s disease-like neurodegeneration and behavioral deficits in transgenic mice. Proc Natl Acad Sci U S A. 2003;100(19):10966–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kanekiyo T, Xu H, Bu G. ApoE and Abeta in Alzheimer’s disease: accidental encounters or partners? Neuron. 2014;81(4):740–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kok E, et al. Apolipoprotein E-dependent accumulation of Alzheimer disease-related lesions begins in middle age. Ann Neurol. 2009;65(6):650–7.

    Article  CAS  PubMed  Google Scholar 

  54. Pletnikova O, et al. The spectrum of preclinical Alzheimer’s disease pathology and its modulation by ApoE genotype. Neurobiol Aging. 2018;71:72–80.

    Article  CAS  PubMed  Google Scholar 

  55. Nielsen HM, et al. Astrocytic Abeta1-42 uptake is determined by Abeta-aggregation state and the presence of amyloid-associated proteins. Glia. 2010;58(10):1235–46.

    Article  PubMed  Google Scholar 

  56. Mulder SD, et al. Apolipoproteins E and J interfere with amyloid-beta uptake by primary human astrocytes and microglia in vitro. Glia. 2014;62(4):493–503.

    Article  PubMed  Google Scholar 

  57. Verghese PB, et al. ApoE influences amyloid-beta (Abeta) clearance despite minimal apoE/Abeta association in physiological conditions. Proc Natl Acad Sci U S A. 2013;110(19):E1807–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Fu Y, et al. Apolipoprotein E lipoprotein particles inhibit amyloid-beta uptake through cell surface heparan sulphate proteoglycan. Mol Neurodegener. 2016;11(1):37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Holmes BB, et al. Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc Natl Acad Sci U S A. 2013;110(33):E3138–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Gassowska M, et al. Extracellular alpha-synuclein leads to microtubule destabilization via GSK-3beta-dependent Tau phosphorylation in PC12 cells. PLoS One. 2014;9(4):e94259.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Namba Y, et al. Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer’s disease and kuru plaque amyloid in Creutzfeldt-Jakob disease. Brain Res. 1991;541(1):163–6.

    Article  CAS  PubMed  Google Scholar 

  62. Rohn TT, et al. Identification of an amino-terminal fragment of apolipoprotein E4 that localizes to neurofibrillary tangles of the Alzheimer’s disease brain. Brain Res. 2012;1475:106–15.

    Article  CAS  PubMed  Google Scholar 

  63. Rohn TT, et al. Immunolocalization of an amino-terminal fragment of apolipoprotein E in the Pick’s disease brain. PLoS One. 2013;8(12):e80180.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Huang Y, et al. Apolipoprotein E fragments present in Alzheimer’s disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons. Proc Natl Acad Sci U S A. 2001;98(15):8838–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Brecht WJ, et al. Neuron-specific apolipoprotein e4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J Neurosci. 2004;24(10):2527–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Zhou J, Chen J, Feng Y. Effect of truncated-ApoE4 overexpression on tau phosphorylation in cultured N2a cells. J Huazhong Univ Sci Technolog Med Sci. 2006;26(3):272–4.

    Article  CAS  PubMed  Google Scholar 

  67. Tesseur I, et al. Expression of human apolipoprotein E4 in neurons causes hyperphosphorylation of protein tau in the brains of transgenic mice. Am J Pathol. 2000;156(3):951–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Shi Y, et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017;549(7673):523–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Leuzy A, et al. Tau PET imaging in neurodegenerative tauopathies—still a challenge. Mol Psychiatry. 2019;24(8):1112–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden

    Elena Rodriguez-Vieitez

  2. Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden

    Henrietta M. Nielsen

Authors
  1. Elena Rodriguez-Vieitez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Henrietta M. Nielsen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Henrietta M. Nielsen .

Editor information

Editors and Affiliations

  1. Department of Life Sciences, Gakushuin University, Tokyo, Japan

    Akihiko Takashima

  2. Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA

    Benjamin Wolozin

  3. University of Lille, INSERM, CHU-Lille, Alzheimer & Tauopathies, LabEx DISTALZ, Lille, France

    Luc Buee

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Rodriguez-Vieitez, E., Nielsen, H.M. (2019). Associations Between APOE Variants, Tau and α-Synuclein. In: Takashima, A., Wolozin, B., Buee, L. (eds) Tau Biology. Advances in Experimental Medicine and Biology, vol 1184. Springer, Singapore. https://doi.org/10.1007/978-981-32-9358-8_15

Download citation

Publish with us

Policies and ethics

Search

Navigation