Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Susceptibility to neurofibrillary tangles: role of the PTPRD locus and limited pleiotropy with other neuropathologies

Molecular Psychiatry volume 23, pages 1521–1529 (2018)Cite this article

Subjects

Abstract

Tauopathies, including Alzheimer’s disease (AD) and other neurodegenerative conditions, are defined by a pathological hallmark: neurofibrillary tangles (NFTs). NFT accumulation is thought to be closely linked to cognitive decline in AD. Here, we perform a genome-wide association study for NFT pathologic burden and report the association of the PTPRD locus (rs560380, P=3.8 × 10−8) in 909 prospective autopsies. The association is replicated in an independent data set of 369 autopsies. The association of PTPRD with NFT is not dependent on the accumulation of amyloid pathology. In contrast, we found that the ZCWPW1 AD susceptibility variant influences NFT accumulation and that this effect is mediated by an accumulation of amyloid β plaques. We also performed complementary analyses to identify common pathways that influence multiple neuropathologies that coexist with NFT and found suggestive evidence that certain loci may influence multiple different neuropathological traits, including tau, amyloid β plaques, vascular injury and Lewy bodies. Overall, these analyses offer an evaluation of genetic susceptibility to NFT, a common end point for multiple different pathologic processes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Johnson VE, Stewart W, Smith DH . Widespread Tau and amyloid‐beta pathology many years after a single traumatic brain injury in humans. Brain Pathol 2012; 22: 142–149.

    Article  CAS  PubMed  Google Scholar 

  2. Beecham GW, Hamilton K, Naj AC, Martin ER, Huentelman M, Myers AJ et al. Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias. PLOS Genet 2014; 10: e1004606.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Bennett DA, Schneider JA, Arvanitakis Z, Wilson RS . Overview and findings from the religious orders study. Curr Alzheimer Res 2012; 9: 628–645.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bennett DA, Schneider JA, Buchman AS, Barnes LL, Boyle PA, Wilson RS . Overview and findings from the Rush Memory and Aging Project. Curr Alzheimer Res 2012; 9: 646–663.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kukull WA, Higdon R, Bowen JD, McCormick WC, Teri L, Schellenberg GD et al. Dementia and Alzheimer disease incidence: a prospective cohort study. Arch Neurol 2002; 59: 1737–1746.

    Article  PubMed  Google Scholar 

  6. Sonnen JA, Larson EB, Haneuse S, Woltjer R, Li G, Crane PK et al. Neuropathology in the adult changes in thought study: a review. J Alzheimer's Dis 2009; 18: 703–711.

    Article  Google Scholar 

  7. Sonnen JA, Larson EB, Crane PK, Haneuse S, Li G, Schellenberg GD et al. Pathological correlates of dementia in a longitudinal, population-based sample of aging. Ann Neurol 2007; 62: 406–413.

    Article  PubMed  Google Scholar 

  8. Bennett DA, De Jager PL, Leurgans SE, Schneider JA . Neuropathologic intermediate phenotypes enhance association to Alzheimer susceptibility alleles. Neurology 2009; 72: 1495–1503.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Bennett DA, Schneider JA, Arvanitakis Z, Kelly JF, Aggarwal NT, Shah RC et al. Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology 2006; 66: 1837–1844.

    Article  CAS  PubMed  Google Scholar 

  10. Bennett DA, Wilson RS, Schneider JA, Evans DA, Beckett LA, Aggarwal NT et al. Natural history of mild cognitive impairment in older persons. Neurology 2002; 59: 198–205.

    Article  CAS  PubMed  Google Scholar 

  11. Bennett DA, Wilson RS, Schneider JA, Bienias JL, Arnold SE . Cerebral infarctions and the relationship of depression symptoms to level of cognitive functioning in older persons. Am J Geriatr Psychiatry 2004; 12: 211–219.

    Article  PubMed  Google Scholar 

  12. Barnes LL, Schneider JA, Boyle PA, Bienias JL, Bennett DA . Memory complaints are related to Alzheimer disease pathology in older persons. Neurology 2006; 67: 1581–1585.

    Article  CAS  PubMed  Google Scholar 

  13. Yu L, Boyle PA, Nag S, Leurgans S, Buchman AS, Wilson RS et al. APOE and cerebral amyloid angiopathy in community-dwelling older persons. Neurobiol Aging 2015; 36: 2946–2953.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. McKeith IG, Galasko D, Kosaka K, Perry EK, Dickson DW, Hansen LA et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 1996; 47: 1113–1124.

    Article  CAS  PubMed  Google Scholar 

  15. Arvanitakis Z, Leurgans SE, Barnes LL, Bennett DA, Schneider JA . Microinfarct pathology, dementia, and cognitive systems. Stroke 2011; 42: 722–727.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Braak H, Braak E . Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991; 82: 239–259.

    Article  CAS  PubMed  Google Scholar 

  17. Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K . Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 2006; 112: 389–404.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Sonnen JA, Larson EB, Crane PK, Haneuse S, Li G, Schellenberg GD et al. Pathological correlates of dementia in a longitudinal, population-based sample of aging. Ann Neurol 2007; 62: 406–413.

    Article  PubMed  Google Scholar 

  19. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D . Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 2006; 38: 904–909.

    Article  CAS  PubMed  Google Scholar 

  20. Shulman JM, Chen K, Keenan BT, Chibnik LB, Fleisher A, Thiyyagura P et al. Genetic susceptibility for Alzheimer disease neuritic plaque pathology. JAMA Neurol 2013; 70: 1150–1157.

    Article  PubMed  PubMed Central  Google Scholar 

  21. De Jager PL, Shulman JM, Chibnik LB, Keenan BT, Raj T, Wilson RS et al. A genome-wide scan for common variants affecting the rate of age-related cognitive decline. Neurobiol Aging 2012; 33: 1017, e1011–e1015.

    Article  Google Scholar 

  22. Venables WN, Ripley BD . Modern Applied Statistics with S. 4th edn. Springer: New York, 2002.

    Book  Google Scholar 

  23. Willer CJ, Li Y, Abecasis GR . METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 2010; 26: 2190–2191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. O'Reilly PF, Hoggart CJ, Pomyen Y, Calboli FC, Elliott P, Jarvelin MR et al. MultiPhen: joint model of multiple phenotypes can increase discovery in GWAS. PLOS One 2012; 7: e34861.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D . Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 2006; 38: 904–909.

    Article  CAS  PubMed  Google Scholar 

  26. Cruchaga C, Kauwe JS, Harari O, Jin SC, Cai Y, Karch CM et al. GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer's disease. Neuron 2013; 78: 256–268.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Jack CR Jr, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol 2010; 9: 119–128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bennett DA, Schneider JA, Wilson RS, Bienias JL, Berry-Kravis E, Arnold SE . Amyloid mediates the association of apolipoprotein E e4 allele to cognitive function in older people. J Neurol Neurosurg Psychiatry 2005; 76: 1194–1199.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Raj T, Rothamel K, Mostafavi S, Ye C, Lee MN, Replogle JM et al. Polarization of the effects of autoimmune and neurodegenerative risk alleles in leukocytes. Science 2014; 344: 519–523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bennett DA, Wilson RS, Schneider JA, Evans DA, Aggarwal NT, Arnold SE et al. Apolipoprotein E epsilon4 allele, AD pathology, and the clinical expression of Alzheimer's disease. Neurology 2003; 60: 246–252.

    Article  CAS  PubMed  Google Scholar 

  31. Snow AD, Mar H, Nochlin D, Kimata K, Kato M, Suzuki S et al. The presence of heparan sulfate proteoglycans in the neuritic plaques and congophilic angiopathy in Alzheimer's disease. Am J Pathol 1988; 133: 456–463.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Perry G, Siedlak SL, Richey P, Kawai M, Cras P, Kalaria RN et al. Association of heparan sulfate proteoglycan with the neurofibrillary tangles of Alzheimer's disease. J Neurosci 1991; 11: 3679–3683.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. van Horssen J, Wesseling P, van den Heuvel LP, de Waal RM, Verbeek MM . Heparan sulphate proteoglycans in Alzheimer's disease and amyloid-related disorders. Lancet Neurol 2003; 2: 482–492.

    Article  CAS  PubMed  Google Scholar 

  34. Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet 2013; 45: 1452–1458.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet 2009; 41: 1094–1099.

    Article  CAS  PubMed  Google Scholar 

  36. Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, Carrasquillo MM et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat Genet 2011; 43: 429–435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Naj AC, Jun G, Beecham GW, Wang LS, Vardarajan BN, Buros J et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat Genet 2011; 43: 436–441.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Shulman JM, Imboywa S, Giagtzoglou N, Powers MP, Hu Y, Devenport D et al. Functional screening in Drosophila identifies Alzheimer's disease susceptibility genes and implicates Tau-mediated mechanisms. Hum Mol Genet 2013; 23: 870–877.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Yang Q, Li L, Yang R, Shen GQ, Chen Q, Foldvary-Schaefer N et al. Family-based and population-based association studies validate PTPRD as a risk factor for restless legs syndrome. Mov Disord 2011; 26: 516–519.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Schormair B, Kemlink D, Roeske D, Eckstein G, Xiong L, Lichtner P et al. PTPRD (protein tyrosine phosphatase receptor type delta) is associated with restless legs syndrome. Nat Genet 2008; 40: 946–948.

    Article  CAS  PubMed  Google Scholar 

  41. Winkelmann J, Czamara D, Schormair B, Knauf F, Schulte EC, Trenkwalder C et al. Genome-wide association study identifies novel restless legs syndrome susceptibility loci on 2p14 and 16q12.1. PLOS Genet 2011; 7: e1002171.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Mattheisen M, Samuels JF, Wang Y, Greenberg BD, Fyer AJ, McCracken JT et al. Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS. Mol Psychiatry 2014; 20: 337–344.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Krueger NX, Streuli M, Saito H . Structural diversity and evolution of human receptor-like protein tyrosine phosphatases. EMBO J 1990; 9: 3241–3252.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Takahashi H, Craig AM . Protein tyrosine phosphatases PTPdelta, PTPsigma, and LAR: presynaptic hubs for synapse organization. Trends Neurosci 2013; 36: 522–534.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Uetani N, Kato K, Ogura H, Mizuno K, Kawano K, Mikoshiba K et al. Impaired learning with enhanced hippocampal long-term potentiation in PTPdelta-deficient mice. EMBO J 2000; 19: 2775–2785.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Consensus Recommendations for the Postmortem Diagnosis of Alzheimer's Disease. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's Disease. Neurobiol Aging 1997; 18 (Suppl.): S1–S2.

    Google Scholar 

  47. Shulman JM, Chipendo P, Chibnik LB, Aubin C, Tran D, Keenan BT et al. Functional screening of Alzheimer pathology genome-wide association signals in Drosophila. Am J Hum Genet 2011; 88: 232–238.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Holmes BB, DeVos SL, Kfoury N, Li M, Jacks R, Yanamandra K et al. Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathicseeds. Proc Natl Acad Sci USA 2013; 110: E3138–E3147.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Debette S, Ibrahim Verbaas CA, Bressler J, Schuur M, Smith A, Bis JC et al. Genome-wide studies of verbal declarative memory in nondemented older people: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Biol Psychiatry 2015; 77: 749–763.

    Article  PubMed  Google Scholar 

  50. Hoglinger GU, Melhem NM, Dickson DW, Sleiman PM, Wang LS, Klei L et al. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet 2011; 43: 699–705.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank all the participants of the Religious Orders Study the Rush Memory and Aging Project and the Adult Changes in Thought, as well as the staff at the Rush Alzheimer’s Disease Center for this work. This work was supported by the National Institutes of Health (Grants P30AG10161, R01AG15819, R01AG17917, R01AG36042, R01AG36836, K25AG041906 and U01AG46152).

Author contributions

CDK, JS and JAS collected, prepared and generated data from the samples. LBC, CCW, TR and LY performed analyses on the resulting data. SM, EBL, TJM, CDK, JS and PKC generated and analyzed the replication data. EBL, TJM and PKC designed the replication study. PLD and DAB designed the primary study. PLD, CCW, JMS and LBC wrote the manuscript. All of the authors critically reviewed the manuscript.

Author information

Author notes

  1. D A Bennett and P L De Jager: These authors contributed equally to this work.

Authors and Affiliations

  1. Departments of Neurology and Psychiatry, Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Brigham and Women’s Hospital, Boston, MA, USA

    L B Chibnik, C C White, T Raj & P L De Jager

  2. Department of Neurology, Harvard Medical School, Boston, MA, USA

    L B Chibnik & P L De Jager

  3. Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    L B Chibnik, C C White, T Raj & P L De Jager

  4. Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA

    L B Chibnik

  5. Department of Medicine, University of Washington, Seattle, WA, USA

    S Mukherjee & P K Crane

  6. Department of Neurology, Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA

    L Yu, J A Schneider & D A Bennett

  7. Group Health Research Institute, Seattle, WA, USA

    E B Larson

  8. Department of Pathology, University of Washington, Seattle, WA, USA

    T J Montine & C D Keene

  9. Department of Pathology, University of Utah, Salt Lake City, UT, USA

    J Sonnen

  10. Departments of Neurology, Molecular and Human Genetics, Neuroscience and Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA

    J M Shulman

  11. Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, USA

    J M Shulman

Authors
  1. L B Chibnik
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C C White
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Mukherjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T Raj
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E B Larson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T J Montine
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C D Keene
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J Sonnen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J A Schneider
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. P K Crane
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. J M Shulman
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. D A Bennett
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. P L De Jager
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P L De Jager.

Ethics declarations

Competing interests

Dr Schneider is a consultant for Navidea Biopharmaceuticals and an advisor to Eli Lilly and Genetech. The remaining authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chibnik, L., White, C., Mukherjee, S. et al. Susceptibility to neurofibrillary tangles: role of the PTPRD locus and limited pleiotropy with other neuropathologies. Mol Psychiatry 23, 1521–1529 (2018). https://doi.org/10.1038/mp.2017.20

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2017.20

This article is cited by

Search

Advanced search

Quick links