CoChat
Sign Up
Cited by 156Parkinson's Disease Mechanisms and TreatmentsAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

APOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid

Open access
Zhao, Na, Attrebi, Olivia N., Ren, Yingxue, Qiao, Wenhui, Sonustun, Berkiye, Martens, Yuka A., Meneses, Axel D., Li, Fuyao +16 more·2020·Science Translational Medicine
DOI 10.1126/scitranslmed.aay1809PMC PMC8309690
Open this paper in CoChat — free account

Abstract

APOE4 exacerbates α-synuclein pathology in a synucleinopathy mouse model, and APOE4 genotype associates with increased α-synuclein pathology in humans.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1126/scitranslmed.aay1809

Cites

8 of 8 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • APOEε4 has been associated with the burden of α-synuclein inclusions in Lewy body disease with minimal Alzheimer disease co-pathology, although other studies have only found an association between APOEε4 and Lewy body disease in the presence of Alzheimer disease neuropathology, but not in pure Lewy body disease.

    “APOEε4 has also been associated with the burden of α-synuclein inclusions in LBD with minimal AD co-pathology62,71, although other studies have only found an association between APOEε4 and LBD in the presence of AD neuropathology, but not in pure LBD72,73.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [71]

    Split into 2 atoms — 1 confirmed, 0 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 76

  1. [1]Rahkonen T, Dementia with Lewy bodies according to the consensus criteria in a general population aged 75 years or older. J Neurol Neurosurg Psychiatry 74, 720– 724 (2003). 12754338 PMC1738491
  2. [2]Emre M, Dementia associated with Parkinson’s disease. Lancet Neurol 2, 229– 237 (2003). 12849211
  3. [3]Lippa CF, DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers. Neurology 68, 812– 819 (2007). 17353469
  4. [4]McKeith IG, Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology 89, 88– 100 (2017). 28592453 PMC5496518
  5. [5]Siddiqui IJ, Pervaiz N, Abbasi AA, The Parkinson Disease gene SNCA: Evolutionary and structural insights with pathological implication. Sci Rep 6, 24475 (2016). 27080380 PMC4832246
  6. [6]Sidransky E, Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med 361, 1651– 1661 (2009). 19846850 PMC2856322
  7. [7]Berge G, Sando SB, Rongve A, Aarsland D, White LR, Apolipoprotein E epsilon2 genotype delays onset of dementia with Lewy bodies in a Norwegian cohort. J Neurol Neurosurg Psychiatry 85, 1227– 1231 (2014). 24639435 PMC4215279
  8. [8]Bras J, Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies. Hum Mol Genet 23, 6139– 6146 (2014). 24973356 PMC4222357
  9. [9]Guerreiro R, Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study. The Lancet Neurology 17, 64– 74 (2018). 29263008 PMC5805394
  10. [10]Tsuang D, APOE epsilon4 increases risk for dementia in pure synucleinopathies. JAMA Neurol 70, 223– 228 (2013). 23407718 PMC3580799
  11. [11]Huang X, Chen P, Kaufer DI, Troster AI, Poole C, Apolipoprotein E and dementia in Parkinson disease: a meta-analysis. Arch Neurol 63, 189– 193 (2006). 16476806
  12. [12]Irwin DJ, Neuropathologic substrates of Parkinson disease dementia. Ann Neurol 72, 587– 598 (2012). 23037886 PMC3484250
  13. [13]Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G, Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9, 106– 118 (2013). 23296339 PMC3726719
  14. [14]Bu G, Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat Rev Neurosci 10, 333– 344 (2009). 19339974 PMC2908393
  15. [15]Zhao N, Liu CC, Qiao W, Bu G, Apolipoprotein E, Receptors, and Modulation of Alzheimer’s Disease. Biol Psychiatry, (2017). PMC5599322 28434655
  16. [16]Spillantini MG, Alpha-synuclein in Lewy bodies. Nature 388, 839– 840 (1997). 9278044
  17. [17]Vekrellis K, Xilouri M, Emmanouilidou E, Rideout HJ, Stefanis L, Pathological roles of alpha-synuclein in neurological disorders. Lancet Neurol 10, 1015– 1025 (2011). 22014436
  18. [18]Lashuel HA, Overk CR, Oueslati A, Masliah E, The many faces of alpha-synuclein: from structure and toxicity to therapeutic target. Nat Rev Neurosci 14, 38– 48 (2013). 23254192 PMC4295774
  19. [20]Kruger R, Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet 18, 106– 108 (1998). 9462735
  20. [21]Fredenburg RA, The impact of the E46K mutation on the properties of alpha-synuclein in its monomeric and oligomeric states. Biochemistry 46, 7107– 7118 (2007). 17530780
  21. [22]Chartier-Harlin MC, Alpha-synuclein locus duplication as a cause of familial Parkinson’s disease. Lancet 364, 1167– 1169 (2004). 15451224
  22. [23]Singleton AB, alpha-Synuclein locus triplication causes Parkinson’s disease. Science 302, 841 (2003). 14593171
  23. [24]Visanji NP, alpha-Synuclein-Based Animal Models of Parkinson’s Disease: Challenges and Opportunities in a New Era. Trends Neurosci 39, 750– 762 (2016). 27776749
  24. [25]Kirik D, Parkinson-like neurodegeneration induced by targeted overexpression of alpha-synuclein in the nigrostriatal system. J Neurosci 22, 2780– 2791 (2002). 11923443 PMC6758323
  25. [27]Delenclos M, Neonatal AAV delivery of alpha-synuclein induces pathology in the adult mouse brain. Acta Neuropathol Commun 5, 51 (2017). 28645308 PMC5481919
  26. [28]Sullivan PM, Reduced levels of human apoE4 protein in an animal model of cognitive impairment. Neurobiol Aging 32, 791– 801 (2011). 19577821
  27. [29]Kovacs GG, Intracellular processing of disease-associated alpha-synuclein in the human brain suggests prion-like cell-to-cell spread. Neurobiol Dis 69, 76– 92 (2014). 24878508
  28. [30]Kovacs GG, An antibody with high reactivity for disease-associated alpha-synuclein reveals extensive brain pathology. Acta Neuropathol 124, 37– 50 (2012). 22370907
  29. [31]Fujiwara H, alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 4, 160– 164 (2002). 11813001
  30. [32]Magen I, Chesselet MF, Mouse models of cognitive deficits due to alpha-synuclein pathology. J Parkinsons Dis 1, 217– 227 (2011). 23939303
  31. [33]Aarsland D, Beyer MK, Kurz MW, Dementia in Parkinson’s disease. Curr Opin Neurol 21, 676– 682 (2008). 18989112
  32. [34]Burn DJ, Cortical Lewy body disease. J Neurol Neurosurg Psychiatry 75, 175– 178 (2004). 14742580 PMC1738936
  33. [35]Jellinger K, Overview of morphological changes in Parkinson’s disease. Adv Neurol 45, 1– 18 (1987). 3825687
  34. [36]Cookson MR, alpha-Synuclein and neuronal cell death. Mol Neurodegener 4, 9 (2009). 19193223 PMC2646729
  35. [38]Burda JE, Sofroniew MV, Reactive gliosis and the multicellular response to CNS damage and disease. Neuron 81, 229– 248 (2014). 24462092 PMC3984950
  36. [39]Dickson DW, APOE epsilon4 is associated with severity of Lewy body pathology independent of Alzheimer pathology. Neurology 91, e1182– e1195 (2018). 30143564 PMC6161556
  37. [40]Robinson JL, Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated. Brain 141, 2181– 2193 (2018). 29878075 PMC6022546
  38. [41]Beecham GW, Genome-wide association meta-analysis of neuropathologic features of Alzheimer’s disease and related dementias. PLoS Genet 10, e1004606 (2014). 25188341 PMC4154667
  39. [42]Tropea TF, APOE, thought disorder, and SPARE-AD predict cognitive decline in established Parkinson’s disease. Mov Disord 33, 289– 297 (2018). 29168904 PMC5809205
  40. [43]Apaydin H, Ahlskog JE, Parisi JE, Boeve BF, Dickson DW, Parkinson disease neuropathology: later-developing dementia and loss of the levodopa response. Arch. Neurol. 59, 102– 112 (2002). 11790237
  41. [44]Olichney JM, Cognitive decline is faster in Lewy body variant than in Alzheimer’s disease. Neurology 51, 351– 357 (1998). 9710002
  42. [45]Zhao N, Liu CC, Qiao W, Bu G, Apolipoprotein E, Receptors, and Modulation of Alzheimer’s Disease. Biol Psychiatry 83, 347– 357 (2018). 28434655 PMC5599322
  43. [46]Davidson WS, Jonas A, Clayton DF, George JM, Stabilization of alpha-synuclein secondary structure upon binding to synthetic membranes. J Biol Chem 273, 9443– 9449 (1998). 9545270
  44. [47]Petrucci S, Ginevrino M, Valente EM, Phenotypic spectrum of alpha-synuclein mutations: New insights from patients and cellular models. Parkinsonism Relat Disord 22 Suppl 1, S16– 20 (2016). 26341711
  45. [49]Galvagnion C, The Role of Lipids Interacting with alpha-Synuclein in the Pathogenesis of Parkinson’s Disease. J Parkinsons Dis 7, 433– 450 (2017). 28671142
  46. [50]Mahley RW, Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 240, 622– 630 (1988). 3283935
  47. [51]Shinohara M, APOE2 eases cognitive decline during Aging: Clinical and preclinical evaluations. Ann Neurol 79, 758– 774 (2016). 26933942 PMC5010530
  48. [52]Beach TG, Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol 119, 689– 702 (2010). 20306269 PMC2866090
  49. [53]Emamzadeh FN, Allsop D, alpha-Synuclein Interacts with Lipoproteins in Plasma. J Mol Neurosci 63, 165– 172 (2017). 28887769 PMC5674120
  50. [54]Emamzadeh FN, Role of Apolipoproteins and alpha-Synuclein in Parkinson’s Disease. J Mol Neurosci 62, 344– 355 (2017). 28695482 PMC5541107
  51. [55]Emamzadeh FN, Aojula H, McHugh PC, Allsop D, Effects of different isoforms of apoE on aggregation of the alpha-synuclein protein implicated in Parkinson’s disease. Neurosci Lett 618, 146– 151 (2016). 26921451
  52. [56]Lee HJ, Bae EJ, Lee SJ, Extracellular alpha--synuclein-a novel and crucial factor in Lewy body diseases. Nat Rev Neurol 10, 92– 98 (2014). 24468877
  53. [57]Ulrich JD, In vivo measurement of apolipoprotein E from the brain interstitial fluid using microdialysis. Mol Neurodegener 8, 13 (2013). 23601557 PMC3640999
  54. [58]Achariyar TM, Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation. Mol Neurodegener 11, 74 (2016). 27931262 PMC5146863
  55. [59]Dzeja P, Terzic A, Adenylate kinase and AMP signaling networks: metabolic monitoring, signal communication and body energy sensing. Int J Mol Sci 10, 1729– 1772 (2009). 19468337 PMC2680645
  56. [60]Fernandez-Gonzalez A, Kourembanas S, Wyatt TA, Mitsialis SA, Mutation of murine adenylate kinase 7 underlies a primary ciliary dyskinesia phenotype. Am J Respir Cell Mol Biol 40, 305– 313 (2009). 18776131 PMC2645528
  57. [61]Miyamoto Y, Possible existence of lysosome-like organella within mitochondria and its role in mitochondrial quality control. PLoS One 6, e16054 (2011). 21264221 PMC3022026
  58. [62]Kitamura N, Mieap, a p53-inducible protein, controls mitochondrial quality by repairing or eliminating unhealthy mitochondria. PLoS One 6, e16060 (2011). 21264228 PMC3022033
  59. [63]Nakamura Y, BNIP3 and NIX mediate Mieap-induced accumulation of lysosomal proteins within mitochondria. PLoS One 7, e30767 (2012). 22292033 PMC3266916
  60. [64]Roesler R, Schwartsmann G, Gastrin-releasing peptide receptors in the central nervous system: role in brain function and as a drug target. Front Endocrinol (Lausanne) 3, 159 (2012). 23251133 PMC3523293
  61. [66]Wennberg AM, Association of Apolipoprotein E epsilon4 With Transactive Response DNA-Binding Protein 43. JAMA Neurol. 75, 1347– 1354 (2018). 30422173 PMC6248121
  62. [67]Yang H-S, 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). 30093249 PMC6154505
  63. [68]Koriath C, ApoE4 lowers age at onset in patients with frontotemporal dementia and tauopathy independent of amyloid-beta copathology. Alzheimers Dement (Amst) 11, 277– 280 (2019). 30949567 PMC6430720
  64. [69]Dickson DW, Immunoreactivity profile of hippocampal CA2/3 neurites in diffuse Lewy body disease. Acta Neuropathol 87, 269– 276 (1994). 7912027
  65. [70]Adamowicz DH, Hippocampal alpha-Synuclein in Dementia with Lewy Bodies Contributes to Memory Impairment and Is Consistent with Spread of Pathology. J Neurosci 37, 1675– 1684 (2017). 28039370 PMC5320602
  66. [71]Riekkinen M, Kejonen K, Jakala P, Soininen H, Riekkinen P Jr., Reduction of noradrenaline impairs attention and dopamine depletion slows responses in Parkinson’s disease. Eur J Neurosci 10, 1429– 1435 (1998). 9749797
  67. [72]Sawamoto N, Cognitive deficits and striato-frontal dopamine release in Parkinson’s disease. Brain 131, 1294– 1302 (2008). 18362097
  68. [73]Halliday GM, Leverenz JB, Schneider JS, Adler CH, The neurobiological basis of cognitive impairment in Parkinson’s disease. Mov Disord 29, 634– 650 (2014). 24757112 PMC4049032
  69. [75]Liu CC, Neuronal heparan sulfates promote amyloid pathology by modulating brain amyloid-beta clearance and aggregation in Alzheimer’s disease. Sci Transl Med 8, 332ra344 (2016). PMC5512541 27030596
  70. [76]Shinohara M, Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer’s disease. Acta Neuropathol 132, 225– 234 (2016). 27179972 PMC4947445
  71. [79]Maejima T, Postnatal loss of P/Q-type channels confined to rhombic-lip-derived neurons alters synaptic transmission at the parallel fiber to purkinje cell synapse and replicates genomic Cacna1a mutation phenotype of ataxia and seizures in mice. J Neurosci 33, 5162– 5174 (2013). 23516282 PMC3641643
  72. [80]Guyenet SJ, A simple composite phenotype scoring system for evaluating mouse models of cerebellar ataxia. J Vis Exp, (2010). PMC3121238 20495529
  73. [81]Zhu JW, Li YF, Wang ZT, Jia WQ, Xu RX, Toll-Like Receptor 4 Deficiency Impairs Motor Coordination. Front Neurosci 10, 33 (2016). 26909014 PMC4754460
  74. [82]Kalari KR, MAP-RSeq: Mayo Analysis Pipeline for RNA sequencing. BMC Bioinformatics 15, 224 (2014). 24972667 PMC4228501
  75. [84]Langfelder P, Horvath S, WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics 9, 559 (2008). 19114008 PMC2631488
  76. [85]Hu Z, VisANT 4.0: Integrative network platform to connect genes, drugs, diseases and therapies. Nucleic Acids Res 41, W225– 231 (2013). 23716640 PMC3692070

Cited by

Sorted by citations

Authors
Zhao, N., Attrebi, O. N., Ren, Y., Qiao, W., Sonustun, B., Martens, Y. A., Meneses, A. D., Li, F., Shue, F., Zheng, J., Van Ingelgom, A. J., Davis, M. D., Kurti, A., Knight, J. A., Linares, C., Chen, Y., Delenclos, M., Liu, C.-C., Fryer, J. D., Asmann, Y. W., McLean, P. J., Dickson, D. W., Ross, O. A., & Bu, G.
Affiliations
  • Mayo Clinic (US)
  • Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Corresponding author
Bu, Guojun
ORCID
Venue
Science Translational Medicine
Publisher
American Association for the Advancement of Science (AAAS)
Published
2020-02-05
Volume
12
Issue
529
ISSN
  • 1946-6234 (ISSN-L)
  • 1946-6242
DOI
10.1126/scitranslmed.aay1809
PMC
PMC8309690
OpenAlex
W3004824376
Cited by
156
References
8
Citations by year
2026: 16 · 2025: 27 · 2024: 29 · 2023: 19 · 2022: 23 · 2021: 21 · 2020: 21
FWCI
9.09
Type
journal article
Language
en
Open access
Locations
  • Science Translational Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
Funders
  • National Institutes of Health (R37AG027924, RF1AG057181, R01AG035355, RF1AG046205, RF1AG051504, P01NS074969, U54NS110435)
  • Mayo Foundation for Medical Education and Research
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
APOE ε4, alpha-synuclein, synucleinopathies, alpha-synuclein toxicity, genetic risk factors, Parkinson's disease, dementia with Lewy bodies
MeSH terms
Mice, Knockout, ApoE, Synucleinopathies, Animals, Amyloid beta-Peptides, Lewy Body Disease, Mice, alpha-Synuclein, Apolipoprotein E4

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review