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Cited by 105Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

APOEε4 potentiates the relationship between amyloid-β and tau pathologies

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Therriault, Joseph, Benedet, Andrea L., Pascoal, Tharick A., Mathotaarachchi, Sulantha, Savard, Melissa, Chamoun, Mira, Thomas, Emilie, Kang, Min Su +10 more·2021·Molecular Psychiatry
DOI 10.1038/s41380-020-0688-6PMC PMC8758492
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Abstract

APOEε4 is the most well-established genetic risk factor for sporadic Alzheimer’s disease and is associated with cerebral amyloid-β. However, the association between APOEε4 and tau pathology, the other major proteinopathy of Alzheimer’s disease, has been controversial. Here, we sought to determine whether the relationship between APOEε4 and tau pathology is determined by local interactions with amyloid-β. We examined three independent samples of cognitively unimpaired, mild cognitive impairment and Alzheimer’s disease subjects: (1) 211 participants who underwent tau-PET with [ 18 F]MK6240 and amyloid-PET with [ 18 F]AZD4694, (2) 264 individuals who underwent tau-PET with [ 18 F]Flortaucipir and amyloid-PET with [ 18 F]Florbetapir and (3) 487 individuals who underwent lumbar puncture and amyloid-PET with [ 18 F]Florbetapir. Using a novel analytical framework, we applied voxel-wise regression models to assess the interactive effect of APOEε4 and amyloid-β on tau load, independently of age and clinical diagnosis. We found that the interaction effect between APOEε4 and amyloid-β, rather than the sum of their independent effects, was related to increased tau load in Alzheimer’s disease-vulnerable regions. The interaction between one APOEε4 allele and amyloid-β was related to increased tau load, while the interaction between amyloid-β and two APOEε4 alleles was related to a more widespread pattern of tau aggregation. Our results contribute to an emerging framework in which the elevated risk of developing dementia conferred by APOEε4 genotype involves mechanisms associated with both amyloid-β and tau aggregation. These results may have implications for future disease-modifying therapeutic trials targeting amyloid or tau pathologies.

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  • APOE4 exacerbates AD-related pathologies, including amyloid-beta plaques, Tau tangles, neurodegeneration and neuroinflammation.

    “It exacerbates AD-related pathologies, including amyloid-beta (Aβ) plaques, Tau tangles, neurodegeneration and neuroinflammation4–16.”

    From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [13]

    The Introduction links APOEε4 to increased amyloid-β burden and reports associations with inflammation and neurodegeneration in mouse models. The Results and Discussion support a stronger relationship between amyloid-β and tau pathology in APOEε4 carriers. The paper does not establish that APOEε4 exacerbates neuroinflammation or neurodegeneration generally; its statement about those outcomes is limited to an association reported in mouse models. Page numbers are unavailable in our copy. (LLM, conf=0.86)

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References 67 · Cited by 105

Research works printed but not linked: 52

  1. [1]Zhao N Liu CC Qiao W Bu G Apolipoprotein E, receptors, and modulation of Alzheimer’s Disease Biol Psychiatry. 2017 83 347 57 28434655 PMC5599322
  2. [3]Pietrzik CU Yoon I-S Jaeger S Busse T Weggen S Koo EH FE65 constitutes the functional link between the low-density lipoprotein receptor-related protein and the amyloid precursor protein J Neurosci 2004 24 4259 65 15115822 PMC6729272
  3. [4]Liu CC Zhao N Yamaguchi Y Cirrito JR Kanekiyo T Holtzman DM Neuronal heparan sulfates promote amyloid pathology by modulating brain amyloid-β clearance and aggregation in Alzheimer’s disease Sci Transl Med 2016 8 332ra44 332ra44 27030596 PMC5512541
  4. [5]Fu Y, Zhao J, Atagi Y, Nielsen HM, Liu CC, Zheng H, et al. Apolipoprotein e lipoprotein particles inhibit amyloid-β uptake through cell surface heparan sulphate proteoglycan. Mol Neurodegener. 2016;11. PMC4857252 27151330
  5. [6]Gonneaud J Arenaza-Urquijo EM Fouquet M Perrotin A Fradin S De La Sayette V Relative effect of APOE ϵ4 on neuroimaging biomarker changes across the lifespan Neurology. 2016 87 1696 703 27683850
  6. [7]Fleisher AS Chen K Liu X Ayutyanont N Roontiva A Thiyyagura P Apolipoprotein E ε4 and age effects on florbetapir positron emission tomography in healthy aging and Alzheimer disease Neurobiol Aging 2013 34 1 12 22633529
  7. [8]Hardy J Selkow D The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics Science. 2002 297 353 6 12130773
  8. [10]Mormino E Betensky RA Hedden T Schultz AP Ward AM Huijbers W Amyloid and APOE4 interact to influence short-term decline in preclinical Alzheimer’s disease Neurology 2014 82 1 25 PMC4035706 24748674
  9. [11]Kantarci K Lowe V Przybelski SA Weigand SD Senjem ML Ivnik RJ APOE modifies the association between Aβ load and cognition in cognitively normal older adults Neurology. 2012 78 232 40 22189452 PMC3280056
  10. [12]Lim YY Villemagne VL Pietrzak RH Ames D Ellis KA Harrington K APOE ε4 moderates amyloid-related memory decline in preclinical Alzheimer’s disease Neurobiol Aging 2015 36 1239 44 25559335
  11. [13]Lim YY Villemagne VL Laws SM Pietrzak RH Snyder PJ Ames D APOE and BDNF polymorphisms moderate amyloid β-related cognitive decline in preclinical Alzheimer’s disease Mol Psychiatry. 2015 20 1322 8 25288138 PMC4759101
  12. [14]Johnson KA Schultz A Betensky RA Becker JA Sepulcre J Rentz D Tau positron emission tomographic imaging in aging and early Alzheimer disease Ann Neurol 2016 79 110 9 26505746 PMC4738026
  13. [15]Ossenkoppele R Schonhaut DR Schöll M Lockhart SN Ayakta N Baker SL Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer’s disease Brain. 2016 139 1551 67 26962052 PMC5006248
  14. [17]Beffert U Poirier J Apolipoprotein E, plaques, tangles and cholinergic dysfunction in Alzheimer’s Disease Ann N. Y. Acad Sci 1996 777 166 74 8624080
  15. [18]Cho H Choi J Hwang M Lee J Kim Y Lee H Tau PET in Alzheimer disease and mild cognitive impairment Neurology. 2016 87 375 83 27358341
  16. [19]Hachinski VC, Iliff LD, Zilhka E, Boulay GH, McAllister VL, Marshall J, et al. Cerebral blood flow in dementia. Arch Neurol. 1975. 10.1001/archneur.1975.00490510088009. 1164215 · DOI · Paper page
  17. [20]McKhann G Drachman D Folstein M Katzman R Price D Stadlan EM Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA Work Group* under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease Neurology. 1984 34 939 44 6610841
  18. [21]Saykin AJ, Shen L, Yao X, Kim S, Nho K, Risacher SL, et al. Genetic studies of quantitative MCI and AD phenotypes in ADNI: progress, opportunities, and plans. Alzheimer’s and Dement. 2015. 10.1016/j.jalz.2015.05.009. PMC4510473 26194313 · DOI
  19. [23]Toledo JB, Xie SX, Trojanowski JQ, Shaw LM. Longitudinal change in CSF Tau and Aβ biomarkers for up to 48 months in ADNI. Acta Neuropathol. 2013. 10.1007/s00401-013-1151-4. PMC3875373 23812320 · DOI · Paper page
  20. [24]Pascoal TA Shin M Kang MS Chamoun M Chartrand D Mathotaarachchi S In vivo quantification of neurofibrillary tangles with [18F]MK-6240 Alzheimer’s Res Ther 2018 10 1 14. 30064520 PMC6069775
  21. [25]Cselényi Z Jönhagen ME Forsberg A Halldin C Julin P Schou M Clinical validation of 18F-AZD4694, an amyloid-β-specific PET radioligand J Nucl Med 2012 53 415 24 22323782
  22. [26]Thomas BA, Cuplov V, Bousse A, Mendes A, Thielemans K, Hutton BF, et al. PETPVC: a toolbox for performing partial volume correction techniques in positron emission tomography. Phys Med Biol. 2016. 10.1088/0031-9155/61/22/7975. 27779136 · DOI
  23. [27]Therriault J, Benedet AL, Pascoal TA, Mathotaarachchi S, Chamoun M, Savard M, et al. Association of apolipoprotein e ϵ4 with medial temporal tau independent of amyloid-β. JAMA Neurol. 2019:1–10. [Epub ahead of print]. PMC6990684 31860000
  24. [28]Maass A Landau S Horng A Lockhart SN Rabinovici GD Jagust WJ Comparison of multiple tau-PET measures as biomarkers in aging and Alzheimer’s disease NeuroImage. 2017 157 448 63 28587897 PMC5814575
  25. [29]Mattsson N Smith R Strandberg O Palmqvist S Schöll M Insel PS Comparing 18F-AV-1451 with CSF t-tau and p-tau for diagnosis of Alzheimer disease Neurology. 2018 90 e388 e395. 29321235 PMC5791788
  26. [30]La Joie R, Bejanin A, Fagan AM, Ayakta N, Baker SL, Bourakova V, et al. Associations between [18F]AV1451 tau PET and CSF measures of tau pathology in a clinical sample. Neurology. 2017. 10.1212/WNL.0000000000004860. PMC5798657 29282337 · DOI · Paper page
  27. [31]Chhatwal JP Schultz AP Marshall GA Boot B Gomez-Isla T Dumurgier J Temporal T807 binding correlates with CSF tau and phospho-tau in normal elderly Neurology. 2016 87 920 6 27473132 PMC5035159
  28. [32]Berrington de González A Cox DR Interpretation of interaction: a review Ann Appl Stat 2007 1 371 85
  29. [33]Slinker BK The statistics of synergism J Mol Cell Cardiol 1998 30 723 31 9602421
  30. [34]Mathotaarachchi S, Wang S, Shin M, Pascoal TA, Rosa-neto P. VoxelStats: a MATLAB package for multi-modal voxel-wise brain image analysis. Front Neuroinform. 2016;10. PMC4908129 27378902
  31. [37]Worsley KJ Taylor JE Tomaiuolo F Lerch J Unified univariate and multivariate random field theory NeuroImage 2004 23 189 95 15501088
  32. [38]Chiotis K Leuzy A Almkvist O Savitcheva I Jonasson M Lubberink M Longitudinal changes of tau PET imaging in relation to hypometabolism in prodromal and Alzheimer’ s disease dementia Mol Psychiatry 2017 23 1 8 28507319
  33. [39]Aghourian M Legault-Denis C Soucy J-P Rosa-Neto P Gauthier S Kostikov A Quantification of brain cholinergic denervation in Alzheimer’s disease using PET imaging with [18F]-FEOBV Mol Psychiatry. 2017 22 1531 8 28894304
  34. [40]Therriault J Ng KP Pascoal TA Mathotaarachchi S Kang MS Struyfs H Anosognosia predicts default mode network hypometabolism and clinical progression to dementia Neurology. 2018 90 e932 39. 29444971 PMC5858945
  35. [41]Hanseeuw BJ Betensky RA Jacobs HIL Schultz AP Sepulcre J Becker JA Association of amyloid and tau with cognition in preclinical Alzheimer disease: a longitudinal study JAMA Neurol 2019 02114 915 24. PMC6547132 31157827
  36. [42]Tiraboschi P, Hansen LA, Masliah E, Alford M, Thal LJ, Corey-Bloom J. Impact of APOE genotype on neuropathologic and neurochemical markers of Alzheimer disease. Neurology. 2004. 10.1212/01.WNL.0000128091.92139.0F. 15184600 · DOI · Paper page
  37. [43]Crary JF Trojanowski JQ Schneider JA Abisambra JF Erin L Alafuzoff I Primary age-related tauopathy (PART): a common pathology associated with human aging Acta Neuropathol. 2014 128 755 66 25348064 PMC4257842
  38. [44]Farfel JM Yu L De Jager PL Schneider JA Bennett DA Association of APOE with tau-tangle pathology with and without β-amyloid Neurobiol Aging 2016 37 19 25 26481403 PMC4716785
  39. [45]Pascoal TA Mathotaarachchi S Mohades S Benedet AL Chung C-O Shin M Amyloid-β and hyperphosphorylated tau synergy drives metabolic decline in preclinical Alzheimer’s disease Mol Psychiatry. 2016 23 1 6 PMC5262471 27021814
  40. [46]Pascoal TA Mathotaarachchi S Shin M Benedet AL Mohades S Wang S Synergistic interaction between amyloid and tau predicts the progression to dementia Alzheimer’s Dement 2016 23 1 10 28024995
  41. [47]Braak H Braak E Staging of alzheimer’s disease-related neurofibrillary changes Neurobiol Aging 1995 16 271 8 7566337
  42. [48]Hostetler ED Walji AM Zeng Z Miller P Bennacef I Salinas C Preclinical characterization of 18F-MK-6240, a promising PET tracer for in vivo quantification of human neurofibrillary tangles J Nucl Med 2016 57 1599 606 27230925
  43. [50]Huang Y Liu XQ Wyss-Coray T Brecht WJ Sanan DA Mahley RW Apolipoprotein E fragments present in Alzheimer’s disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons Proc Natl Acad Sci. 2001 98 8838 43 11447277 PMC37522
  44. [51]Brecht WJ Harris FM Chang S Tesseur I Yu G-Q Xu Q Neuron-specific apolipoprotein E4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice J Neurosci 2004 24 2527 34 15014128 PMC6729489
  45. [52]Tesseur I, Van Dorpe J, Spittaels K, Van den Haute C, Moechars D, Van Leuven F. Expression of human apolipoprotein E4 in neurons causes hyperphosphorylation of protein tau in the brains of transgenic mice. Am J Pathol. 2000. 10.1016/S0002-9440(10)64963-2. PMC1876840 10702411 · DOI
  46. [53]Tesseur I, Van Dorpe J, Bruynseels K, Bronfman F, Sciot R, Van Lommel A, et al. Prominent axonopathy and disruption of axonal transport in transgenic mice expressing human apolipoprotein E4 in neurons of brain and spinal cord. Am J Pathol. 2000. 10.1016/S0002-9440(10)64788-8. PMC1885744 11073810 · DOI
  47. [54]Wille H, Drewes G, Biernat J, Mandelkow EM, Mandelkow E. Alzheimer-like paired helical filaments and antiparallel dimers formed from microtubule-associated protein tau in vitro. J Cell Biol. 1992. 10.1083/jcb.118.3.573. PMC2289542 1639844 · DOI
  48. [55]Strittmatter WJ Huang DY Goedert M Jakes R Weisgraber KH Garner CC Isoform-specific interactions of apolipoprotein E with the microtubule-associated protein MAP2c: implications for Alzheimer’s disease Proc Natl Acad Sci USA 1994 182 11183 6 PMC45191 7972031
  49. [56]Huang Y. Abeta-independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer’s disease. Trends Mol Med. 2010. 10.1016/j.molmed.2010.04.004. 20537952 · DOI · Paper page
  50. [57]Mahley RW, Weisgraber KH, Huang Y. Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease. Proc Natl Acad Sci. 2006. 10.1073/pnas.0600549103. PMC1414631 16567625 · DOI · Paper page
  51. [58]Jagust WJ Landau SM Apolipoprotein E Not fibrillar B-amyloid, reduces cerebral glucose metabolism in normal aging J Neurosc 2012 32 18227 33 PMC3537830 23238736
  52. [59]Leuzy A, Chiotis K, Lemoine L, Gillberg PG, Almkvist O, Rodriguez-Vieitez E, et al. Tau PET imaging in neurodegenerative tauopathies—still a challenge. Mol Psychiatry. 2019. 10.1038/s41380-018-0342-8. PMC6756230 30635637 · DOI · Paper page

Authors
Therriault, J., Benedet, A. L., Pascoal, T. A., Mathotaarachchi, S., Savard, M., Chamoun, M., Thomas, E., Kang, M. S., Lussier, F., Tissot, C., Soucy, J.-P., Massarweh, G., Rej, S., Saha-Chaudhuri, P., Poirier, J., Gauthier, S., Rosa-Neto, P., & Initiative, F. T. A. D. N.
Affiliations
  • Montreal Neurological Institute and Hospital (CA)
  • Douglas Mental Health University Institute (CA)
  • McGill University (CA)
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2020-03-11
Volume
26
Issue
10
Pages
5977-5988
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-020-0688-6
PMC
PMC8758492
OpenAlex
W3012279716
Cited by
105
References
67
Citations by year
2026: 18 · 2025: 23 · 2024: 11 · 2023: 21 · 2022: 11 · 2021: 17 · 2020: 4
FWCI
7.97
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Defense (U01 AG024904, W81XWH, W81XWH-12-2-, W81XWH-12, W81XWH1220012, AG024904)
  • Foundation for the National Institutes of Health (W81XWH-12-2-0012, U01AG024904, Grant U01 AG024904, AG024904)
  • Alzheimer's Association (MOP-11-51-31, NIRP-12-259245, NIRG1292090, NIRP12259245, #NIRG‐12‐92090, U01 AG024904, W81XWH-12-2-0012)
  • Bristol-Myers Squibb (U01 AG024904, AG024904, W81XWH-12-2-0012)
  • Eli Lilly and Company (U01 AG024904, AG024904, W81XWH-12-2-0012)
  • Pfizer (AG024904, W81XWH-12-2-0012, U01 AG024904)
  • Biogen (W81XWH-12-2-0012, U01 AG024904, AG024904)
  • University of Southern California (W81XWH-12-2-0012, U01 AG024904)
  • F. Hoffmann-La Roche (W81XWH-12-2-0012, AG024904, U01 AG024904)
  • Meso Scale Diagnostics (U01 AG024904, AG024904, W81XWH-12-2-0012)
  • Alzheimer's Disease Neuroimaging Initiative (W81XWH-12-2–0012, U01AG024904, AG024904, W81XWH-12-2-, Department of Defense award number W81XWH-12-2-0012)
  • BioClinica (U01 AG024904, W81XWH-12-2-0012, AG024904)
  • Novartis Pharmaceuticals Corporation (W81XWH-12-2-0012, U01 AG024904, AG024904)
  • McGill University (MOP-11-51-31)
  • Northern California Institute for Research and Education (U01 AG024904, W81XWH-12-2-0012)
  • Weston Brain Institute (MOP-11-51-31, NIRP‐12‐259245)
  • Consortium canadien en neurodégénérescence associée au vieillissement (MOP-11-51-31)
  • Alzheimer Society
  • Eisai (W81XWH-12-2-0012, U01 AG024904, AG024904)
  • Servier (AG024904, W81XWH-12-2-0012, U01 AG024904)
  • H. Lundbeck A/S (U01 AG024904, AG024904, W81XWH-12-2-0012)
  • IXICO (AG024904, W81XWH-12-2-0012, U01 AG024904)
  • National Institutes of Health (3u01ag024904-10s2, W81XWH, W81XWH-12-2-0012, U01-AG024904, Grant U01 AG024904, AG024904)
  • Genentech (W81XWH-12-2-0012, AG024904, U01 AG024904)
  • Alzheimer Society Research Program
  • Canadian Institutes of Health Research (#MOP-11-51-31, NIRP-12-259245, NIRG-12-92090, U01 AG024904, W81XWH-12-2-0012, 92090)
  • National Institute on Aging (U01-AG-024904, W81XWH-12-2–0012, AG 024904)
  • National Institute of Biomedical Imaging and Bioengineering (W81XWH-12-2-0012, U01 AG024904, AG024904)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
amyloid-beta, tau pathology, Alzheimer's disease, gene-environment interaction, mild cognitive impairment, tau PET, amyloid PET, dementia risk, disease-modifying therapy
MeSH terms
Alzheimer Disease, Humans, Amyloid beta-Peptides, tau Proteins, Positron-Emission Tomography, Cognitive Dysfunction

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