Skip to main content

TDP-43 is a key player in the clinical features associated with Alzheimer’s disease

Abstract

The aim of this study was to determine whether the TAR DNA-binding protein of 43 kDa (TDP-43) has any independent effect on the clinical and neuroimaging features typically ascribed to Alzheimer’s disease (AD) pathology, and whether TDP-43 pathology could help shed light on the phenomenon of resilient cognition in AD. Three-hundred and forty-two subjects pathologically diagnosed with AD were screened for the presence, burden and distribution of TDP-43. All had been classified as cognitively impaired or normal, prior to death. Atlas-based parcellation and voxel-based morphometry were used to assess regional atrophy on MRI. Regression models controlling for age at death, apolipoprotein ε4 and other AD-related pathologies were utilized to explore associations between TDP-43 and cognition or brain atrophy, stratified by Braak stage. In addition, we determined whether the effects of TDP-43 were mediated by hippocampal sclerosis. One-hundred and ninety-five (57 %) cases were TDP-positive. After accounting for age, apolipoprotein ε4 and other pathologies, TDP-43 had a strong effect on cognition, memory loss and medial temporal atrophy in AD. These effects were not mediated by hippocampal sclerosis. TDP-positive subjects were 10× more likely to be cognitively impaired at death compared to TDP-negative subjects. Greater cognitive impairment and medial temporal atrophy were associated with greater TDP-43 burden and more extensive TDP-43 distribution. TDP-43 is an important factor in the manifestation of the clinico-imaging features of AD. TDP-43 also appears to be able to overpower what has been termed resilient brain aging. TDP-43 therefore should be considered a potential therapeutic target for the treatment of AD.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

References

  1. Agresti A, Coull BA (1998) Approximate is better than "exact" for interval estimation of binomial proportions. Am Stat 52:119–126

    Google Scholar 

  2. Alzheimer A (1907) Über eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrift für Psychiatrie und Psychisch-Gerichtliche Medizin 64:146–148

    Google Scholar 

  3. Amador-Ortiz C, Lin WL, Ahmed Z et al (2007) TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer’s disease. Ann Neurol 61:435–445. doi:10.1002/ana.21154

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  4. Arai T, Mackenzie IR, Hasegawa M et al (2009) Phosphorylated TDP-43 in Alzheimer’s disease and dementia with Lewy bodies. Acta Neuropathol 117:125–136. doi:10.1007/s00401-008-0480-1

    CAS  Article  PubMed  Google Scholar 

  5. Arnold SE, Louneva N, Cao K et al (2013) Cellular, synaptic, and biochemical features of resilient cognition in Alzheimer’s disease. Neurobiol Aging 34:157–168. doi:10.1016/j.neurobiolaging.2012.03.004

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  6. Ashburner J, Friston KJ (2000) Voxel-based morphometry—the methods. NeuroImage 11:805–821

    CAS  Article  PubMed  Google Scholar 

  7. Ashburner J, Friston KJ (2005) Unified segmentation. NeuroImage 26:839–851

    Article  PubMed  Google Scholar 

  8. Bigio EH, Mishra M, Hatanpaa KJ et al (2010) TDP-43 pathology in primary progressive aphasia and frontotemporal dementia with pathologic Alzheimer disease. Acta Neuropathol 120:43–54. doi:10.1007/s00401-010-0681-2

    PubMed Central  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  10. Brenowitz WD, Monsell SE, Schmitt FA, Kukull WA, Nelson PT (2014) Hippocampal sclerosis of aging is a key Alzheimer’s Disease mimic: clinical-pathologic correlations and comparisons with both Alzheimer’s Disease and non-tauopathic frontotemporal lobar degeneration. J Alzheimers Dis 39:691–702. doi:10.3233/JAD-131880

    PubMed  Google Scholar 

  11. Buratti E, Brindisi A, Pagani F, Baralle FE (2004) Nuclear factor TDP-43 binds to the polymorphic TG repeats in CFTR intron 8 and causes skipping of exon 9: a functional link with disease penetrance. Am J Hum Genet 74:1322–1325. doi:10.1086/420978

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  12. Corder EH, Saunders AM, Strittmatter WJ et al (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923

    CAS  Article  PubMed  Google Scholar 

  13. Crook R, Hardy J, Duff K (1994) Single-day apolipoprotein E genotyping. J Neurosci Methods 53:125–127

    CAS  Article  PubMed  Google Scholar 

  14. Davidson YS, Raby S, Foulds PG et al (2011) TDP-43 pathological changes in early onset familial and sporadic Alzheimer’s disease, late onset Alzheimer’s disease and Down’s syndrome: association with age, hippocampal sclerosis and clinical phenotype. Acta Neuropathol 122:703–713. doi:10.1007/s00401-011-0879-y

    Article  PubMed  Google Scholar 

  15. Davis DG, Schmitt FA, Wekstein DR, Markesbery WR (1999) Alzheimer neuropathologic alterations in aged cognitively normal subjects. J Neuropathol Exp Neurol 58:376–388

    CAS  Article  PubMed  Google Scholar 

  16. Dickson DW, Davies P, Bevona C et al (1994) Hippocampal sclerosis: a common pathological feature of dementia in very old (≥80 years of age) humans. Acta Neuropathol 88:212–221

    CAS  Article  PubMed  Google Scholar 

  17. Folstein MF, Folstein SE, McHugh PR (1975) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198

    CAS  Article  PubMed  Google Scholar 

  18. Gosche KM, Mortimer JA, Smith CD, Markesbery WR, Snowdon DA (2002) Hippocampal volume as an index of Alzheimer neuropathology: findings from the Nun Study. Neurology 58:1476–1482

    CAS  Article  PubMed  Google Scholar 

  19. Hu WT, Josephs KA, Knopman DS et al (2008) Temporal lobar predominance of TDP-43 neuronal cytoplasmic inclusions in Alzheimer disease. Acta Neuropathol 116:215–220. doi:10.1007/s00401-008-0400-4

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  20. Jack CR Jr, Dickson DW, Parisi JE et al (2002) Antemortem MRI findings correlate with hippocampal neuropathology in typical aging and dementia. Neurology 58:750–757

    PubMed Central  Article  PubMed  Google Scholar 

  21. Jack CR Jr, Lowe VJ, Senjem ML et al (2008) 11C PiB and structural MRI provide complementary information in imaging of Alzheimer’s disease and amnestic mild cognitive impairment. Brain J Neurol 131:665–680. doi:10.1093/brain/awm336

    Article  Google Scholar 

  22. Janocko NJ, Brodersen KA, Soto-Ortolaza AI et al (2012) Neuropathologically defined subtypes of Alzheimer’s disease differ significantly from neurofibrillary tangle-predominant dementia. Acta Neuropathol 124:681–692. doi:10.1007/s00401-012-1044-y

    PubMed Central  Article  PubMed  Google Scholar 

  23. Josephs KA, Tsuboi Y, Cookson N, Watt H, Dickson DW (2004) Apolipoprotein E epsilon 4 is a determinant for Alzheimer-type pathologic features in tauopathies, synucleinopathies, and frontotemporal degeneration. Arch Neurol 61:1579–1584. doi:10.1001/archneur.61.10.1579

    Article  PubMed  Google Scholar 

  24. Josephs KA, Whitwell JL, Knopman DS et al (2008) Abnormal TDP-43 immunoreactivity in AD modifies clinicopathologic and radiologic phenotype. Neurology 70:1850–1857. doi:10.1212/01.wnl.0000304041.09418.b1

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  25. Josephs KA, Whitwell JL, Parisi JE et al (2008) Argyrophilic grains: a distinct disease or an additive pathology? Neurobiol Aging 29:566–573. doi:10.1016/j.neurobiolaging.2006.10.032

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  26. Josephs KA, Murray ME, Whitwell JL et al (2014) Staging TDP-43 pathology in Alzheimer’s disease. Acta Neuropathol 127:441–450. doi:10.1007/s00401-013-1211-9

    CAS  Article  PubMed  Google Scholar 

  27. Kaplan E, Goodglass H, Weintraub S (1983) The Boston Naming Test. Lea & Febiger, Philadelphia

    Google Scholar 

  28. Kaufer DI, Cummings JL, Ketchel P et al (2000) Validation of the NPI-Q, a brief clinical form of the Neuropsychiatric Inventory. J Neuropsychiatry Clin Neurosci 12:233–239

    CAS  Article  PubMed  Google Scholar 

  29. Mattis S (1988) Dementia Rating Scale. Psychological Assessment Resources, City

  30. Mirra SS, Heyman A, McKeel D et al (1991) The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41:479–486

    CAS  Article  PubMed  Google Scholar 

  31. Morris JC (1993) The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 43:2412–2414

    CAS  Article  PubMed  Google Scholar 

  32. Murray ME, Graff-Radford NR, Ross OA, Petersen RC, Duara R, Dickson DW (2011) Neuropathologically defined subtypes of Alzheimer’s disease with distinct clinical characteristics: a retrospective study. Lancet Neurol 10:785–796

    PubMed Central  Article  PubMed  Google Scholar 

  33. Nelson PT, Schmitt FA, Lin Y et al (2011) Hippocampal sclerosis in advanced age: clinical and pathological features. Brain J Neurol 134:1506–1518. doi:10.1093/brain/awr053

    Article  Google Scholar 

  34. Neumann M, Sampathu DM, Kwong LK et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133. doi:10.1126/science.1134108

    CAS  Article  PubMed  Google Scholar 

  35. Pao WC, Dickson DW, Crook JE, Finch NA, Rademakers R, Graff-Radford NR (2011) Hippocampal sclerosis in the elderly: genetic and pathologic findings, some mimicking Alzheimer disease clinically. Alzheimer Dis Assoc Disord 25:364–368. doi:10.1097/WAD.0b013e31820f8f50

    PubMed Central  Article  PubMed  Google Scholar 

  36. Pavlopoulos E, Jones S, Kosmidis S et al (2013) Molecular mechanism for age-related memory loss: the histone-binding protein RbAp48. Sci Transl Med 5:200ra115. doi:10.1126/scitranslmed.3006373

    PubMed  Google Scholar 

  37. Perez-Nievas BG, Stein TD, Tai HC et al (2013) Dissecting phenotypic traits linked to human resilience to Alzheimer’s pathology. Brain J Neurol 136:2510–2526. doi:10.1093/brain/awt171

    Article  Google Scholar 

  38. Rojo MG, Garcia GB, Mateos CP, Garcia JG, Vicente MC (2006) Critical comparison of 31 commercially available digital slide systems in pathology. Int J Surg Pathol 14:285–305. doi:10.1177/1066896906292274

    Article  PubMed  Google Scholar 

  39. Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR (1997) Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA 277:813–817

    CAS  Article  PubMed  Google Scholar 

  40. Sullivan SG, Greenland S (2013) Bayesian regression in SAS software. Int J Epidemiol 42:308–317. doi:10.1093/ije/dys213

    Article  PubMed  Google Scholar 

  41. Thal DR, Schultz C, Botez G et al (2005) The impact of argyrophilic grain disease on the development of dementia and its relationship to concurrent Alzheimer’s disease-related pathology. Neuropathol Appl Neurobiol 31:270–279. doi:10.1111/j.1365-2990.2005.00635.x

    CAS  Article  PubMed  Google Scholar 

  42. Tzourio-Mazoyer N, Landeau B, Papathanassiou D et al (2002) Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. NeuroImage 15:273–289

    CAS  Article  PubMed  Google Scholar 

  43. Uryu K, Nakashima-Yasuda H, Forman MS et al (2008) Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies. J Neuropathol Exp Neurol 67:555–564. doi:10.1097/NEN.0b013e31817713b5

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  44. Whitwell JL, Josephs KA, Murray ME et al (2008) MRI correlates of neurofibrillary tangle pathology at autopsy: a voxel-based morphometry study. Neurology 71:743–749

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  45. Whitwell JL, Jack CR, Jr., Przybelski SA et al. (2011) Temporoparietal atrophy: A marker of AD pathology independent of clinical diagnosis. Neurobiol Aging 32:1531–1541

    PubMed Central  Article  PubMed  Google Scholar 

  46. Whitwell JL, Dickson DW, Murray ME et al (2012) Neuroimaging correlates of pathologically defined subtypes of Alzheimer’s disease: a case-control study. Lancet Neurol 11:868–877. doi:10.1016/S1474-4422(12)70200-4

    PubMed Central  Article  PubMed  Google Scholar 

  47. WorkingGroup (1997) Consensus recommendation for the postmortem diagnosis of Alzheimer’s disease. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for Neuropathologic Assessment of Alzheimer’s Disease. Neurobiol Aging 18:S1–S2

    Article  Google Scholar 

  48. Zhang YJ, Xu YF, Cook C et al (2009) Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity. Proc Natl Acad Sci USA 106:7607–7612. doi:10.1073/pnas.0900688106

    CAS  PubMed Central  Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was funded by the US National Institute of Heath (NIA) Grants R01-AG037491 (to KAJ), R21-AG038736 (to JLW), P50-AG016574 (to RCP) and R01-AG011378 (to CRJ). We wish to thank the families of the patients who donated their brains to science allowing completion of this study. We further wish to thank Kris Johnson, Linda Rousseau, Virginia Phillips and Monica Casey-Castanedes for pathological support.

Conflict of interest

The authors declare that they have no conflicts of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Keith A. Josephs.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Josephs, K.A., Whitwell, J.L., Weigand, S.D. et al. TDP-43 is a key player in the clinical features associated with Alzheimer’s disease. Acta Neuropathol 127, 811–824 (2014). https://doi.org/10.1007/s00401-014-1269-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-014-1269-z

Keywords

  • TDP-43
  • Alzheimer disease
  • Resilience
  • APOE ε4
  • Braak stage
  • MRI