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Primary age-related tauopathy (PART): a common pathology associated with human aging

Acta Neuropathologica volume 128, pages 755–766 (2014)Cite this article

Abstract

We recommend a new term, “primary age-related tauopathy” (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer’s disease (AD), in the absence of amyloid (Aβ) plaques. For these “NFT+/Aβ−” brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as “tangle-only dementia” and “tangle-predominant senile dementia”, are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.

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References

  1. Ahmed Z, Bigio EH, Budka H et al (2013) Globular glial tauopathies (GGT): consensus recommendations. Acta Neuropathol 126:537–544. doi:10.1007/s00401-013-1171-0

    PubMed Central  PubMed  Google Scholar 

  2. Alafuzoff I (2013) Alzheimer’s disease-related lesions. J Alzheimers Dis 33(Suppl 1):S173–S179. doi:10.3233/JAD-2012-129024

    PubMed  Google Scholar 

  3. Andrade-Moraes CH, Oliveira-Pinto AV, Castro-Fonseca E et al (2013) Cell number changes in Alzheimer’s disease relate to dementia, not to plaques and tangles. Brain 136:3738–3752. doi:10.1093/brain/awt273

    PubMed  Google Scholar 

  4. Arai T, Ikeda K, Akiyama H et al (2001) Distinct isoforms of tau aggregated in neurons and glial cells in brains of patients with Pick’s disease, corticobasal degeneration and progressive supranuclear palsy. Acta Neuropathol 101:167–173

    CAS  PubMed  Google Scholar 

  5. Arnold SE, Hyman BT, Flory J, Damasio AR, Van Hoesen GW (1991) The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer’s disease. Cereb Cortex 1:103–116

    CAS  PubMed  Google Scholar 

  6. Arriagada PV, Marzloff K, Hyman BT (1992) Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer’s disease. Neurology 42:1681–1688

    CAS  PubMed  Google Scholar 

  7. Attems J, Jellinger KA (2006) Olfactory tau pathology in Alzheimer disease and mild cognitive impairment. Clin Neuropathol 25:265–271

    CAS  PubMed  Google Scholar 

  8. Attems J, Lintner F, Jellinger KA (2005) Olfactory involvement in aging and Alzheimer’s disease: an autopsy study. J Alzheimers Dis 7:149–157 (discussion 173–180)

    CAS  PubMed  Google Scholar 

  9. Attems J, Thal DR, Jellinger KA (2012) The relationship between subcortical tau pathology and Alzheimer’s disease. Biochem Soc Trans 40:711–715. doi:10.1042/BST20120034

    CAS  PubMed  Google Scholar 

  10. Baborie A, Griffiths TD, Jaros E et al (2012) Frontotemporal dementia in elderly individuals. Arch Neurol 69:1052–1060. doi:10.1001/archneurol.2011.3323

    PubMed  Google Scholar 

  11. Ball MJ (1978) Topographic distribution of neurofibrillary tangles and granulovacuolar degeneration in hippocampal cortex of aging and demented patients. A quantitative study. Acta Neuropathol 42:73–80

    CAS  PubMed  Google Scholar 

  12. Ball MJ, Nuttall K (1981) Topography of neurofibrillary tangles and granulovacuoles in hippocampi of patients with Down’s syndrome: quantitative comparison with normal ageing and Alzheimer’s disease. Neuropathol Appl Neurobiol 7:13–20

    CAS  PubMed  Google Scholar 

  13. Bancher C, Egensperger R, Kosel S, Jellinger K, Graeber MB (1997) Low prevalence of apolipoprotein E epsilon 4 allele in the neurofibrillary tangle predominant form of senile dementia. Acta Neuropathol 94:403–409

    CAS  PubMed  Google Scholar 

  14. Bancher C, Jellinger KA (1994) Neurofibrillary tangle predominant form of senile dementia of Alzheimer type: a rare subtype in very old subjects. Acta Neuropathol 88:565–570

    CAS  PubMed  Google Scholar 

  15. Bancher C, Paulus W, Paukner K, Jellinger K (1997) Neuropathologic diagnosis of Alzheimer disease: consensus between practicing neuropathologists? Alzheimer Dis Assoc Disord 11:207–219

    CAS  PubMed  Google Scholar 

  16. Beekly DL, Ramos EM, Lee WW et al (2007) The National Alzheimer’s Coordinating Center (NACC) database: the uniform data set. Alzheimer Dis Assoc Disord 21:249–258. doi:10.1097/WAD.0b013e318142774e

    PubMed  Google Scholar 

  17. Berg L, McKeel DW Jr, Miller JP et al (1998) Clinicopathologic studies in cognitively healthy aging and Alzheimer’s disease: relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype. Arch Neurol 55:326–335

    CAS  PubMed  Google Scholar 

  18. Bondareff W, Mountjoy CQ, Roth M et al (1987) Age and histopathologic heterogeneity in Alzheimer’s disease. Evidence for subtypes. Arch Gen Psychiatry 44:412–417

    CAS  PubMed  Google Scholar 

  19. Bondareff W, Mountjoy CQ, Roth M et al (1987) Neuronal degeneration in locus coeruleus and cortical correlates of Alzheimer disease. Alzheimer Dis Assoc Disord 1:256–262

    CAS  PubMed  Google Scholar 

  20. Bondareff W, Mountjoy CQ, Wischik CM et al (1993) Evidence of subtypes of Alzheimer’s disease and implications for etiology. Arch Gen Psychiatry 50:350–356

    CAS  PubMed  Google Scholar 

  21. Bouras C, Hof PR, Giannakopoulos P, Michel JP, Morrison JH (1994) Regional distribution of neurofibrillary tangles and senile plaques in the cerebral cortex of elderly patients: a quantitative evaluation of a one-year autopsy population from a geriatric hospital. Cereb Cortex 4:138–150

    CAS  PubMed  Google Scholar 

  22. Bouras C, Hof PR, Morrison JH (1993) Neurofibrillary tangle densities in the hippocampal formation in a non-demented population define subgroups of patients with differential early pathologic changes. Neurosci Lett 153:131–135

    CAS  PubMed  Google Scholar 

  23. Boutajangout A, Wisniewski T (2014) Tau-based therapeutic approaches for Alzheimer’s disease—a mini-review. Gerontology 60(5):381–385. doi:10.1159/000358875

    CAS  PubMed  Google Scholar 

  24. Bowler JV, Hachinski V (1995) Vascular cognitive impairment: a new approach to vascular dementia. Bailliere’s Clin Neurol 4:357–376

    CAS  Google Scholar 

  25. Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K (2006) Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 112:389–404. doi:10.1007/s00401-006-0127-z

    PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  27. Braak H, Braak E (1995) Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging 16:271–278 (discussion 278–284)

    CAS  PubMed  Google Scholar 

  28. Braak H, Braak E, Bohl J (1993) Staging of Alzheimer-related cortical destruction. Eur Neurol 33:403–408

    CAS  PubMed  Google Scholar 

  29. Braak H, Del Tredici K (2004) Alzheimer’s disease: intraneuronal alterations precede insoluble amyloid-beta formation. Neurobiol Aging 25:713–718. doi:10.1016/j.neurobiolaging.2003.12.015 (discussion 743–716)

    PubMed  Google Scholar 

  30. Braak H, Del Tredici K (2011) The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathol 121:171–181. doi:10.1007/s00401-010-0789-4

    PubMed  Google Scholar 

  31. Braak H, Del Tredici K (2012) Where, when, and in what form does sporadic Alzheimer’s disease begin? Curr Opin Neurol 25:708–714. doi:10.1097/WCO.0b013e32835a3432

    CAS  PubMed  Google Scholar 

  32. Braak H, Thal DR, Ghebremedhin E, Del Tredici K (2011) Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol 70:960–969. doi:10.1097/NEN.0b013e318232a379

    CAS  PubMed  Google Scholar 

  33. Cairns NJ, Bigio EH, Mackenzie IR et al (2007) Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol (Berl) 114:5–22

    Google Scholar 

  34. Clavaguera F, Akatsu H, Fraser G et al (2013) Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc Natl Acad Sci USA 110:9535–9540. doi:10.1073/pnas.1301175110

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Clavaguera F, Bolmont T, Crowther RA et al (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11:909–913. doi:10.1038/ncb1901

    CAS  PubMed Central  PubMed  Google Scholar 

  36. 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  PubMed  Google Scholar 

  37. Dawe RJ, Bennett DA, Schneider JA, Arfanakis K (2011) Neuropathologic correlates of hippocampal atrophy in the elderly: a clinical, pathologic, postmortem MRI study. PLoS One 6:e26286. doi:10.1371/journal.pone.0026286

    CAS  PubMed Central  PubMed  Google Scholar 

  38. de Calignon A, Polydoro M, Suarez-Calvet M et al (2012) Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron 73:685–697. doi:10.1016/j.neuron.2011.11.033

    PubMed Central  PubMed  Google Scholar 

  39. Dickson DW, Kouri N, Murray ME, Josephs KA (2011) Neuropathology of frontotemporal lobar degeneration-tau (FTLD-tau). J Mol Neurosci 45(3):384–389. doi:10.1007/s12031-011-9589-0

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Dugger BN, Hidalgo JA, Chiarolanza G et al (2013) The distribution of phosphorylated tau in spinal cords of Alzheimer’s disease and non-demented individuals. J Alzheimers Dis 34:529–536. doi:10.3233/JAD-121864

    CAS  PubMed Central  PubMed  Google Scholar 

  41. Dugger BN, Tu M, Murray ME, Dickson DW (2011) Disease specificity and pathologic progression of tau pathology in brainstem nuclei of Alzheimer’s disease and progressive supranuclear palsy. Neurosci Lett 491(2):122–126. doi:10.1016/j.neulet.2011.01.020

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Elobeid A, Soininen H, Alafuzoff I (2012) Hyperphosphorylated tau in young and middle-aged subjects. Acta Neuropathol 123:97–104. doi:10.1007/s00401-011-0906-z

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Feany MB, Dickson DW (1996) Neurodegenerative disorders with extensive tau pathology: a comparative study and review. Ann Neurol 40:139–148. doi:10.1002/ana.410400204

    CAS  PubMed  Google Scholar 

  44. Ferrer I, Lopez-Gonzalez I, Carmona M et al (2014) Glial and neuronal tau pathology in tauopathies: characterization of disease-specific phenotypes and tau pathology progression. J Neuropathol Exp Neurol 73:81–97. doi:10.1097/NEN.0000000000000030

    CAS  PubMed  Google Scholar 

  45. Ferrer I, Santpere G, van Leeuwen FW (2008) Argyrophilic grain disease. Brain 131:1416–1432. doi:10.1093/brain/awm305

    PubMed  Google Scholar 

  46. Frost B, Diamond MI (2010) Prion-like mechanisms in neurodegenerative diseases. Nat Rev Neurosci 11:155–159. doi:10.1038/nrn2786

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Frost B, Jacks RL, Diamond MI (2009) Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem 284:12845–12852. doi:10.1074/jbc.M808759200

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Fukutani Y, Kobayashi K, Nakamura I et al (1995) Neurons, intracellular and extracellular neurofibrillary tangles in subdivisions of the hippocampal cortex in normal ageing and Alzheimer’s disease. Neurosci Lett 200:57–60 (0304-3940(95)12083-G [pii])

    CAS  PubMed  Google Scholar 

  49. Garcia-Sierra F, Hauw JJ, Duyckaerts C et al (2000) The extent of neurofibrillary pathology in perforant pathway neurons is the key determinant of dementia in the very old. Acta Neuropathol 100:29–35

    CAS  PubMed  Google Scholar 

  50. Geser F, Winton MJ, Kwong LK et al (2008) Pathological TDP-43 in parkinsonism–dementia complex and amyotrophic lateral sclerosis of Guam. Acta Neuropathol 115:133–145. doi:10.1007/s00401-007-0257-y

    CAS  PubMed  Google Scholar 

  51. Giannakopoulos P, Hof PR, Mottier S, Michel JP, Bouras C (1994) Neuropathological changes in the cerebral cortex of 1258 cases from a geriatric hospital: retrospective clinicopathological evaluation of a 10-year autopsy population. Acta Neuropathol 87:456–468

    CAS  PubMed  Google Scholar 

  52. Goodman L (1953) Alzheimer’s disease: a clinico-pathologic analysis of twenty-three cases with a theory on pathogenesis. J Nerv Ment Dis 117:97–130

    Google Scholar 

  53. Grinberg LT, Rub U, Ferretti RE et al (2009) The dorsal raphe nucleus shows phospho-tau neurofibrillary changes before the transentorhinal region in Alzheimer’s disease. A precocious onset? Neuropathol Appl Neurobiol 35:406–416. doi:10.1111/j.1365-2990.2009.00997.x

    CAS  PubMed  Google Scholar 

  54. Grinberg LT, Wang X, Wang C et al (2013) Argyrophilic grain disease differs from other tauopathies by lacking tau acetylation. Acta Neuropathol 125:581–593. doi:10.1007/s00401-013-1080-2

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Grudzien A, Shaw P, Weintraub S et al (2007) Locus coeruleus neurofibrillary degeneration in aging, mild cognitive impairment and early Alzheimer’s disease. Neurobiol Aging 28:327–335. doi:10.1016/j.neurobiolaging.2006.02.007

    CAS  PubMed  Google Scholar 

  56. Guillozet AL, Weintraub S, Mash DC, Mesulam MM (2003) Neurofibrillary tangles, amyloid, and memory in aging and mild cognitive impairment. Arch Neurol 60:729–736

    PubMed  Google Scholar 

  57. Guo JL, Lee VM (2011) Seeding of normal tau by pathological tau conformers drives pathogenesis of Alzheimer-like tangles. J Biol Chem 286(17):15317–15331. doi:10.1074/jbc.M110.209296

    CAS  PubMed Central  PubMed  Google Scholar 

  58. Hauw JJ, Vignolo P, Duyckaerts C et al (1986) Neuropathological study of 12 centenarians: the incidence of Alzheimer type senile dementia is not particularly increased in this group of very old patients. Rev Neurol 142:107–115

    CAS  PubMed  Google Scholar 

  59. Hof PR, Archin N, Osmand AP et al (1993) Posterior cortical atrophy in Alzheimer’s disease: analysis of a new case and re-evaluation of a historical report. Acta Neuropathol 86:215–223

    CAS  PubMed  Google Scholar 

  60. Hof PR, Bouras C, Buée L et al (1992) Differential distribution of neurofibrillary tangles in the cerebral cortex of dementia pugilistica and Alzheimer’s disease cases. Acta Neuropathol 85:23–30

    CAS  PubMed  Google Scholar 

  61. Hof PR, Perl DP, Loerzel AJ, Morrison JH (1991) Neurofibrillary tangle distribution in the cerebral cortex of parkinsonism-dementia cases from Guam: differences with Alzheimer’s disease. Brain Res 564:306–313 (0006-8993(91)91467-F [pii])

    CAS  PubMed  Google Scholar 

  62. Hof PR, Vogt BA, Bouras C, Morrison JH (1997) Atypical form of Alzheimer’s disease with prominent posterior cortical atrophy: a review of lesion distribution and circuit disconnection in cortical visual pathways. Vision Res 37:3609–3625. doi:10.1016/S0042-6989(96)00240-4

    CAS  PubMed  Google Scholar 

  63. Hutton M, Lendon CL, Rizzu P et al (1998) Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393:702–705. doi:10.1038/31508

    CAS  PubMed  Google Scholar 

  64. Hyman BT, Phelps CH, Beach TG et al (2012) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement 8:1–13. doi:10.1016/j.jalz.2011.10.007

    PubMed Central  PubMed  Google Scholar 

  65. Ikeda K, Akiyama H, Arai T, Nishimura T (1998) Glial tau pathology in neurodegenerative diseases: their nature and comparison with neuronal tangles. Neurobiol Aging 19:S85–S91

    CAS  PubMed  Google Scholar 

  66. Ikeda K, Akiyama H, Arai T et al (1999) Clinical aspects of ‘senile dementia of the tangle type’—a subset of dementia in the senium separable from late-onset Alzheimer’s disease. Dement Geriatr Cogn Disord 10:6–11

    CAS  PubMed  Google Scholar 

  67. Ikeda K, Akiyama H, Arai T et al (1997) A subset of senile dementia with high incidence of the apolipoprotein E epsilon2 allele. Ann Neurol 41:693–695. doi:10.1002/ana.410410522

    CAS  PubMed  Google Scholar 

  68. Ikeda K, Akiyama H, Kondo H et al (1995) Thorn-shaped astrocytes: possibly secondarily induced tau-positive glial fibrillary tangles. Acta Neuropathol 90:620–625

    CAS  PubMed  Google Scholar 

  69. Ikeda K, Kondo H, Fujishima T, Kase K, Mizutani Y (1993) A case of atypical senile dementia of Alzheimer type. No To Shinkei 45:455–460

    CAS  PubMed  Google Scholar 

  70. Iseki E, Tsunoda S, Suzuki K et al (2002) Regional quantitative analysis of NFT in brains of non-demented elderly persons: comparisons with findings in brains of late-onset Alzheimer’s disease and limbic NFT dementia. Neuropathology 22:34–39

    PubMed  Google Scholar 

  71. Ishizawa T, Ko LW, Cookson N et al (2002) Selective neurofibrillary degeneration of the hippocampal CA2 sector is associated with four-repeat tauopathies. J Neuropathol Exp Neurol 61:1040–1047

    CAS  PubMed  Google Scholar 

  72. Itoh Yamada M, Yoshida R et al (1996) Dementia characterized by abundant neurofibrillary tangles and scarce senile plaques: a quantitative pathological study. Eur Neurol 36:94–97

    CAS  PubMed  Google Scholar 

  73. Itoh Y, Yamada M, Suematsu N, Matsushita M, Otomo E (1998) An immunohistochemical study of centenarian brains: a comparison. J Neurol Sci 157:73–81

    CAS  PubMed  Google Scholar 

  74. Jack CR Jr, Albert MS, Knopman DS et al (2011) Introduction to the recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:257–262. doi:10.1016/j.jalz.2011.03.004

    PubMed Central  PubMed  Google Scholar 

  75. Jack CR Jr, Knopman DS, Weigand SD et al (2012) An operational approach to National Institute on Aging-Alzheimer’s Association criteria for preclinical Alzheimer disease. Ann Neurol 71:765–775. doi:10.1002/ana.22628

    PubMed Central  PubMed  Google Scholar 

  76. 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  PubMed  Google Scholar 

  77. Jellinger KA (2013) Challenges in the neuropathological diagnosis of dementias. Int J Neuropathol 1:44

    Google Scholar 

  78. Jellinger KA (2012) Neuropathological subtypes of Alzheimer’s disease. Acta Neuropathol 123:153–154. doi:10.1007/s00401-011-0889-9

    PubMed  Google Scholar 

  79. Jellinger KA, Attems J (2007) Neurofibrillary tangle-predominant dementia: comparison with classical Alzheimer disease. Acta Neuropathol 113:107–117. doi:10.1007/s00401-006-0156-7

    CAS  PubMed  Google Scholar 

  80. Jellinger KA, Attems J (2010) Prevalence and pathology of vascular dementia in the oldest-old. J Alzheimers Dis 21:1283–1293

    PubMed  Google Scholar 

  81. Jellinger KA, Bancher C (1998) Senile dementia with tangles (tangle predominant form of senile dementia). Brain Pathol 8:367–376

    CAS  PubMed  Google Scholar 

  82. Jicha GA, Abner EL, Schmitt FA, et al. (2012) Preclinical AD Workgroup staging: pathological correlates and potential challenges. Neurobiol Aging. 33:622 e621–622 e616. doi:10.1016/j.neurobiolaging.2011.02.018

  83. Jicha GA, Parisi JE, Dickson DW et al (2006) Neuropathologic outcome of mild cognitive impairment following progression to clinical dementia. Arch Neurol 63:674–681

    PubMed  Google Scholar 

  84. 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  PubMed  Google Scholar 

  85. Kidd M (1963) Paired helical filaments in electron microscopy of Alzheimer’s disease. Nature 197:192–193

    CAS  PubMed  Google Scholar 

  86. Knopman DS, Caselli RJ (2012) Appraisal of cognition in preclinical Alzheimer’s disease: a conceptual review. Neurodegener Dis Manag 2:183–195. doi:10.2217/NMT.12.5

    PubMed Central  PubMed  Google Scholar 

  87. Knopman DS, Jack CR Jr, Wiste HJ et al (2013) Brain injury biomarkers are not dependent on beta-amyloid in normal elderly. Ann Neurol 73:472–480. doi:10.1002/ana.23816

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Knopman DS, Parisi JE, Salviati A et al (2003) Neuropathology of cognitively normal elderly. J Neuropathol Exp Neurol 62:1087–1095

    CAS  PubMed  Google Scholar 

  89. Kovacs GG, Milenkovic I, Wohrer A et al (2013) Non-Alzheimer neurodegenerative pathologies and their combinations are more frequent than commonly believed in the elderly brain: a community-based autopsy series. Acta Neuropathol 126:365–384. doi:10.1007/s00401-013-1157-y

    CAS  PubMed  Google Scholar 

  90. Kovacs GG, Molnar K, Laszlo L et al (2011) A peculiar constellation of tau pathology defines a subset of dementia in the elderly. Acta Neuropathol 122:205–222. doi:10.1007/s00401-011-0819-x

    CAS  PubMed  Google Scholar 

  91. Liu L, Drouet V, Wu JW et al (2012) Trans-synaptic spread of tau pathology in vivo. PLoS One 7:e31302. doi:10.1371/journal.pone.0031302

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Malkani RG, Dickson DW, Simuni T (2012) Hippocampal-sparing Alzheimer’s disease presenting as corticobasal syndrome. Parkinsonism Relat Disord 18:683–685. doi:10.1016/j.parkreldis.2011.11.022

    PubMed  Google Scholar 

  93. Markesbery WR, Schmitt FA, Kryscio RJ et al (2006) Neuropathologic substrate of mild cognitive impairment. Arch Neurol 63:38–46

    PubMed  Google Scholar 

  94. Matsui Y, Tanizaki Y, Arima H et al (2009) Incidence and survival of dementia in a general population of Japanese elderly: the Hisayama study. J Neurol Neurosurg Psychiatry 80:366–370. doi:10.1136/jnnp.2008.155481

    CAS  PubMed  Google Scholar 

  95. McKee AC, Cantu RC, Nowinski CJ et al (2009) Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol 68:709–735. doi:10.1097/NEN.0b013e3181a9d503

    PubMed Central  PubMed  Google Scholar 

  96. Mirra SS (1997) The CERAD neuropathology protocol and consensus recommendations for the postmortem diagnosis of Alzheimer’s disease: a commentary. Neurobiol Aging 18:S91–S94

    CAS  PubMed  Google Scholar 

  97. 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  PubMed  Google Scholar 

  98. Mitchell TW, Mufson EJ, Schneider JA et al (2002) Parahippocampal tau pathology in healthy aging, mild cognitive impairment, and early Alzheimer’s disease. Ann Neurol 51:182–189

    PubMed  Google Scholar 

  99. Mizutani T, Kasahara M, Yamada S, Mukai M, Amano N (1993) Study on the neuropathological diagnosis of senile dementia of the Alzheimer type. No To Shinkei 45:333–342

    CAS  PubMed  Google Scholar 

  100. Mizutani T, Shimada H (1992) Neuropathological background of twenty-seven centenarian brains. J Neurol Sci 108:168–177

    CAS  PubMed  Google Scholar 

  101. Mizutani T, Shimada H (1991) Quantitative study of neurofibrillary tangles in subdivisions of the hippocampus. CA2 as a special area in normal aging and senile dementia of the Alzheimer type. Acta Pathol Jpn 41:597–603

    CAS  PubMed  Google Scholar 

  102. Montine TJ, Phelps CH, Beach TG et al (2012) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach. Acta Neuropathol 123:1–11. doi:10.1007/s00401-011-0910-3

    CAS  PubMed Central  PubMed  Google Scholar 

  103. Mungas D, Tractenberg R, Schneider JA, Crane PK, Bennett DA (2014) A 2-process model for neuropathology of Alzheimer’s disease. Neurobiol Aging 35:301–308. doi:10.1016/j.neurobiolaging.2013.08.007

    CAS  PubMed  Google Scholar 

  104. Murray ME, Cannon A, Graff-Radford NR et al (2014) Differential clinicopathologic and genetic features of late-onset amnestic dementias. Acta Neuropathol. doi:10.1007/s00401-014-1302-2

    Google Scholar 

  105. Murray ME, Graff-Radford NR, Ross OA et al (2011) Neuropathologically defined subtypes of Alzheimer’s disease with distinct clinical characteristics: a retrospective study. Lancet Neurol 10:785–796. doi:10.1016/S1474-4422(11)70156-9

    PubMed Central  PubMed  Google Scholar 

  106. Nakaya H, Miki T, Seino S et al (2003) Molecular and functional diversity of ATP-sensitive K+ channels: the pathophysiological roles and potential drug targets. Nihon Yakurigaku Zasshi 122:243–250

    CAS  PubMed  Google Scholar 

  107. Nelson PT, Abner EL, Schmitt FA et al (2009) Brains with medial temporal lobe neurofibrillary tangles but no neuritic amyloid plaques are a diagnostic dilemma but may have pathogenetic aspects distinct from Alzheimer disease. J Neuropathol Exp Neurol 68:774–784. doi:10.1097/NEN.0b013e3181aacbe9

    PubMed Central  PubMed  Google Scholar 

  108. Nelson PT, Alafuzoff I, Bigio EH et al (2012) Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol 71:362–381. doi:10.1097/NEN.0b013e31825018f7

    PubMed Central  PubMed  Google Scholar 

  109. Nelson PT, Jicha GA, Schmitt FA et al (2007) Clinicopathologic correlations in a large Alzheimer disease center autopsy cohort: neuritic plaques and neurofibrillary tangles “do count” when staging disease severity. J Neuropathol Exp Neurol 66:1136–1146

    PubMed Central  PubMed  Google Scholar 

  110. Noda K, Sasaki K, Fujimi K et al (2006) Quantitative analysis of neurofibrillary pathology in a general population to reappraise neuropathological criteria for senile dementia of the neurofibrillary tangle type (tangle-only dementia): the Hisayama Study. Neuropathology 26:508–518

    PubMed  Google Scholar 

  111. Perl DP, Hof PR, Purohit DP, Loerzel AJ, Kakulas BA (2003) Hippocampal and entorhinal cortex neurofibrillary tangle formation in Guamanian Chamorros free of overt neurologic dysfunction. J Neuropathol Exp Neurol 62:381–388

    PubMed  Google Scholar 

  112. Petersen RC, Aisen P, Boeve BF et al (2013) Criteria for mild cognitive impairment due to alzheimer’s disease in the community. Ann Neurol. doi:10.1002/ana.23931

    Google Scholar 

  113. Petersen RC, Parisi JE, Dickson DW et al (2006) Neuropathologic features of amnestic mild cognitive impairment. Arch Neurol 63:665–672. doi:10.1001/archneur.63.5.665

    PubMed  Google Scholar 

  114. Prestia A, Caroli A, van der Flier WM et al (2013) Prediction of dementia in MCI patients based on core diagnostic markers for Alzheimer disease. Neurology 80:1048–1056. doi:10.1212/WNL.0b013e3182872830

    CAS  PubMed  Google Scholar 

  115. Ranginwala NA, Hynan LS, Weiner MF, White CL 3rd (2008) Clinical criteria for the diagnosis of Alzheimer disease: still good after all these years. Am J Geriatr Psychiatry 16:384–388. doi:10.1097/JGP.0b013e3181629971

    PubMed  Google Scholar 

  116. Rijal Upadhaya A, Kosterin I, Kumar S et al (2014) Biochemical stages of amyloid-beta peptide aggregation and accumulation in the human brain and their association with symptomatic and pathologically preclinical Alzheimer’s disease. Brain 137:887–903. doi:10.1093/brain/awt362

    PubMed  Google Scholar 

  117. Robinson JL, Geser F, Corrada MM et al (2011) Neocortical and hippocampal amyloid-beta and tau measures associate with dementia in the oldest-old. Brain 134:3708–3715. doi:10.1093/brain/awr308

    PubMed  Google Scholar 

  118. Rohrer JD, Schott JM (2011) Primary progressive aphasia—defining genetic and pathological subtypes. Curr Alzheimer Res 8:266–272 (BSP/CAR/0119 [pii])

    CAS  PubMed  Google Scholar 

  119. Ruben GC, Wang JZ, Iqbal K, Grundke-Iqbal I (2005) Paired helical filaments (PHFs) are a family of single filament structures with a common helical turn period: negatively stained PHF imaged by TEM and measured before and after sonication, deglycosylation, and dephosphorylation. Microsc Res Tech 67:175–195. doi:10.1002/jemt.20197

    CAS  PubMed  Google Scholar 

  120. Sabbagh MN, Sandhu SS, Farlow MR et al (2009) Correlation of clinical features with argyrophilic grains at autopsy. Alzheimer Dis Assoc Disord 23:229–233. doi:10.1097/WAD.0b013e318199d833

    PubMed Central  PubMed  Google Scholar 

  121. Saito Y, Ruberu NN, Sawabe M et al (2004) Staging of argyrophilic grains: an age-associated tauopathy. J Neuropathol Exp Neurol 63:911–918

    PubMed  Google Scholar 

  122. Santa-Maria I, Haggiagi A, Liu X et al (2012) The MAPT H1 haplotype is associated with tangle-predominant dementia. Acta Neuropathol 124:693–704. doi:10.1007/s00401-012-1017-1

    CAS  PubMed Central  PubMed  Google Scholar 

  123. Schmidt ML, Garruto R, Chen J, Lee VM, Trojanowski JQ (2000) Tau epitopes in spinal cord neurofibrillary lesions in Chamorros of Guam. Neuroreport 11:3427–3430

    CAS  PubMed  Google Scholar 

  124. Schmidt ML, Zhukareva V, Perl DP et al (2001) Spinal cord neurofibrillary pathology in Alzheimer disease and Guam Parkinsonism-dementia complex. J Neuropathol Exp Neurol 60:1075–1086

    CAS  PubMed  Google Scholar 

  125. Schneider JA, Aggarwal NT, Barnes L, Boyle P, Bennett DA (2009) The neuropathology of older persons with and without dementia from community versus clinic cohorts. J Alzheimers Dis 18:691–701. doi:10.3233/JAD-2009-1227

    PubMed Central  PubMed  Google Scholar 

  126. Schnitzler JG (1911) Zur Abgrenzung der sogenannten Alzheimerschen Erkrankung. Z ges Neurol Psychiat. 7:34–57

    Google Scholar 

  127. Schultz C, Ghebremedhin E, Del Tredici K, Rüb U, Braak H (2004) High prevalence of thorn-shaped astrocytes in the aged human medial temporal lobe. Neurobiol Aging 25:397–405. doi:10.1016/S0197-4580(03)00113-1

    PubMed  Google Scholar 

  128. Serrano-Pozo A, Qian J, Monsell SE et al (2014) Mild to moderate Alzheimer dementia with insufficient neuropathological changes. Ann Neurol 75:597–601. doi:10.1002/ana.24125

    PubMed Central  PubMed  Google Scholar 

  129. Serrano-Pozo A, Qian J, Monsell SE et al (2013) Examination of the clinicopathologic continuum of Alzheimer disease in the autopsy cohort of the National Alzheimer Coordinating Center. J Neuropathol Exp Neurol 72:1182–1192. doi:10.1097/NEN.0000000000000016

    CAS  PubMed  Google Scholar 

  130. Shiarli AM, Jennings R, Shi J et al (2006) Comparison of extent of tau pathology in patients with frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration with Pick bodies and early onset Alzheimer’s disease. Neuropathol Appl Neurobiol 32:374–387. doi:10.1111/j.1365-2990.2006.00736.x

    CAS  PubMed  Google Scholar 

  131. Simic G, Stanic G, Mladinov M et al (2009) Does Alzheimer’s disease begin in the brainstem? Neuropathol Appl Neurobiol 35:532–554. doi:10.1111/j.1365-2990.2009.01038.x

    CAS  PubMed Central  PubMed  Google Scholar 

  132. Sonnen JA, Santa Cruz K, Hemmy LS et al (2011) Ecology of the aging human brain. Arch Neurol 68:1049–1056. doi:10.1001/archneurol.2011.157

    PubMed Central  PubMed  Google Scholar 

  133. Syed A, Chatfield M, Matthews F et al (2005) Depression in the elderly: pathological study of raphe and locus ceruleus. Neuropathol Appl Neurobiol 31:405–413. doi:10.1111/j.1365-2990.2005.00662.x

    CAS  PubMed  Google Scholar 

  134. Takahashi J, Shibata T, Sasaki M, et al (2014) Detection of changes in the locus coeruleus in patients with mild cognitive impairment and Alzheimer’s disease: high-resolution fast spin-echo T1-weighted imaging. Geriatr Gerontol Int. doi:10.1111/ggi.12280

  135. Thal DR, Capetillo-Zarate E, Del Tredici K, Braak H (2006) The development of amyloid beta protein deposits in the aged brain. Sci Aging Knowl Environ 2006:re1. doi:10.1126/sageke.2006.6.re1

    Google Scholar 

  136. 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  PubMed  Google Scholar 

  137. Thal DR, von Arnim C, Griffin WS et al (2013) Pathology of clinical and preclinical Alzheimer’s disease. Eur Arch Psychiatry Clin Neurosci 263(Suppl 2):S137–S145. doi:10.1007/s00406-013-0449-5

    PubMed  Google Scholar 

  138. Togo T, Sahara N, Yen SH et al (2002) Argyrophilic grain disease is a sporadic 4-repeat tauopathy. J Neuropathol Exp Neurol 61:547–556

    CAS  PubMed  Google Scholar 

  139. Trachtenberg DI, Trojanowski JQ (2008) Dementia: a word to be forgotten. Arch Neurol 65:593–595. doi:10.1001/archneur.65.5.593

    PubMed  Google Scholar 

  140. Trojanowski JQ, Ishihara T, Higuchi M et al (2002) Amyotrophic lateral sclerosis/parkinsonism dementia complex: transgenic mice provide insights into mechanisms underlying a common tauopathy in an ethnic minority on Guam. Exp Neurol 176:1–11

    CAS  PubMed  Google Scholar 

  141. Tsuboi Y, Wszolek ZK, Graff-Radford NR, Cookson N, Dickson DW (2003) Tau pathology in the olfactory bulb correlates with Braak stage, Lewy body pathology and apolipoprotein epsilon4. Neuropathol Appl Neurobiol 29:503–510

    CAS  PubMed  Google Scholar 

  142. Ulrich J, Spillantini MG, Goedert M, Dukas L, Staehelin HB (1992) Abundant neurofibrillary tangles without senile plaques in a subset of patients with senile dementia. Neurodegeneration 1:257–284

  143. Vos SJ, Xiong C, Visser PJ et al (2013) Preclinical Alzheimer’s disease and its outcome: a longitudinal cohort study. Lancet Neurol 12:957–965. doi:10.1016/S1474-4422(13)70194-7

    PubMed Central  PubMed  Google Scholar 

  144. West MJ, Coleman PD, Flood DG, Troncoso JC (1994) Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer’s disease. Lancet 344:769–772

    CAS  PubMed  Google Scholar 

  145. Wirth M, Villeneuve S, Haase CM et al (2013) Associations between Alzheimer disease biomarkers, neurodegeneration, and cognition in cognitively normal older people. JAMA Neurol 70:1512–1519. doi:10.1001/jamaneurol.2013.4013

    PubMed  Google Scholar 

  146. Wisniewski HM, Narang HK, Terry RD (1976) Neurofibrillary tangles of paired helical filaments. J Neurol Sci 27:173–181

    CAS  PubMed  Google Scholar 

  147. Yamada M (2003) Senile dementia of the neurofibrillary tangle type (tangle-only dementia): neuropathological criteria and clinical guidelines for diagnosis. Neuropathology 23:311–317

    PubMed  Google Scholar 

  148. Yamada M, Itoh Y, Sodeyama N et al (1998) Aging of the human limbic system: observations of centenarian brains and analyses of genetic risk factors for senile changes. Neuropathology 18:228–234

    Google Scholar 

  149. Yamada M, Itoh Y, Sodeyama N et al (2001) Senile dementia of the neurofibrillary tangle type: a comparison with Alzheimer’s disease. Dement Geriatr Cogn Disord 12:117–126. doi:10.1159/000051245

    CAS  PubMed  Google Scholar 

  150. Yamada M, Itoh Y, Suematsu N, Otomo E, Matsushita M (1996) Apolipoprotein E genotype in elderly nondemented subjects without senile changes in the brain. Ann Neurol 40:243–245. doi:10.1002/ana.410400217

    CAS  PubMed  Google Scholar 

  151. Yamada M, Itoh Y, Yohinori I et al (1996) Dementia of the Alzheimer type and related dementias in the aged: DAT subgroups and senile dementia of the neurofibrillary tangle type. Neuropathology 16:89–98

    Google Scholar 

  152. Yoshida M (2006) Cellular tau pathology and immunohistochemical study of tau isoforms in sporadic tauopathies. Neuropathology 26:457–470

    PubMed  Google Scholar 

  153. Yu L, Boyle PA, Leurgans S, Schneider JA, Bennett DA (2014) Disentangling the effects of age and APOE on neuropathology and late life cognitive decline. Neurobiol Aging 35:819–826. doi:10.1016/j.neurobiolaging.2013.10.074

    CAS  PubMed  Google Scholar 

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Acknowledgments

We are extremely grateful to the patients, clinicians, and fellow researchers that made this effort possible. We also acknowledge the following funding sources: the Society for Supporting Research in Experimental Neurology, Vienna, Austria, National Institutes of Health Grants P50AG08702, R01 AG037212, P01AG07232, P30 AG028383, P50 AG005138, P50 AG016574, U01 AG006786, R01 AG041851, R01 AG011378, P30 AG028383, P50 AG016574, P01 AG003949, P30 AG012300, P50 AG005146, P50 AG005136, P50 AG025688, P50 AG005138, P01 AG002219, P50 AG005133, P50 AG005681, P01 AG003991, R01 AG038651, P30 AG019610, P30 AG013854, P30 AG036453, P30 AG010124, AG005131, AG184440, AG008051, Medical Research Council (MRC, G0400074), National Institute for Health Research (NIHR, R:CH/ML/0712), the Dunhill Medical Trust (R173/1110), Alzheimer’s Research UK (ARUK), and the Alzheimer’s Society (AS-PG-2013-011), Louis V. Gerstner, Jr., Foundation, Alzheimer’s Association (NIRG-11-204450), FP7 EU Project Develage (No. 278486), Comprehensive brain research network, Grant-in-Aid for Scientific Research (C; 26430060), and Daiwa Health Science Foundation, BrightFocus Foundation, Alzheimer’s Association NIRGD-12-242642, Alzheimer Forschung Initiative (AFI # 13803) (DRT); German Ministry for Research and Education (BMBF) FTLD-Net, Robert H. and Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Program of the Mayo Foundation.

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Authors and Affiliations

  1. Department of Pathology and Cell Biology and the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center, New York, NY, 10032, USA

    John F. Crary, Ismael Santa-Maria, Michael L. Shelanski & Jean Paul Vonsattel

  2. Department of Pathology, Division of Neuropathology, University of Pennsylvania, Philadelphia, PA, 19104, USA

    John Q. Trojanowski & Jonathan B. Toledo

  3. Departments of Pathology (Neuropathology) and Neurological Sciences, Rush University Medical Center, Chicago, IL, 60612, USA

    Julie A. Schneider

  4. Department of Physiology and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40536, USA

    Jose F. Abisambra

  5. Department of Public Health and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40536, USA

    Erin L. Abner

  6. Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85, Uppsala, Sweden

    Irina Alafuzoff

  7. Departments of Psychiatry and Neurology, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Steven E. Arnold

  8. Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, NE45PL, UK

    Johannes Attems

  9. Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, 85351, USA

    Thomas G. Beach

  10. Department of Pathology (Neuropathology), Northwestern Cognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA

    Eileen H. Bigio

  11. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA

    Nigel J. Cairns

  12. Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Dennis W. Dickson & Melissa E. Murray

  13. Department of Pathology and Laboratory Medicine (Neuropathology), Emory University School of Medicine, Atlanta, GA, 30322, USA

    Marla Gearing

  14. Departments of Neurology and Pathology, UC, San Francisco, CA, 94110, USA

    Lea T. Grinberg

  15. Department of Pathology, University of Sao Paulo, Sao Paulo, Brazil

    Lea T. Grinberg

  16. Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Patrick R. Hof

  17. Department of Neurology, Harvard Medical School and Massachusetts General Hospital, Charlestown, MA, 02129, USA

    Bradley T. Hyman

  18. Institute of Clinical Neurobiology, 1070, Vienna, Austria

    Kurt Jellinger

  19. Department of Neurology and the Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA

    Gregory A. Jicha

  20. Institute of Neurology, Medical University Vienna, 1090, Vienna, Austria

    Gabor G. Kovacs

  21. Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA

    David S. Knopman

  22. Department of Pathology (Neuropathology), University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA

    Julia Kofler

  23. Department of Epidemiology, University of Washington, Seattle, WA, 98104, USA

    Walter A. Kukull

  24. Department of Pathology, University of British Columbia, 855 West 12th Avenue, Vancouver, BC, V5Z 1M9, Canada

    Ian R. Mackenzie

  25. Departments of Neurosciences and Pathology, University of California, San Diego, La Jolla, CA, 92093, USA

    Eliezer Masliah

  26. Department of Pathology (Neuropathology), Boston University, Boston, MA, 02118, USA

    Ann McKee

  27. Department of Pathology, University of Washington, Seattle, WA, 98104, USA

    Thomas J. Montine

  28. Department of Pathology, University of Kentucky, Lexington, KY, 40536, USA

    Janna H. Neltner

  29. Departments of Neurology and Pathology, University of California, San Francisco, CA, 94143, USA

    William W. Seeley

  30. Department of Neurology, University of Iowa Hospitals and Clinics, Iowa city, IA, 52242, USA

    Alberto Serrano-Pozo

  31. Department of Pathology (Neuropathology), VA Medical Center and Boston University School of Medicine, Boston, MA, 02118, USA

    Thor Stein

  32. Department of Neuropathology, Tokyo Metropolitan Geriatric Hospital, Tokyo, 173-0015, Japan

    Masaki Takao

  33. Laboratory of Neuropathology, University of Ulm, 89081, Ulm, Germany

    Dietmar R. Thal

  34. Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA

    Juan C. Troncoso

  35. Department of Pathology (Neuropathology), University of Texas Southwestern Medical School, Dallas, TX, 75390, USA

    Charles L. White 3rd

  36. Departments of Neurology, Pathology and Psychiatry, New York University School of Medicine, New York, NY, 10016, USA

    Thomas Wisniewski

  37. Department of Pathology L113, Oregon Health Sciences University, Portland, OR, 97239, USA

    Randall L. Woltjer

  38. Departments of Neurology & Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan

    Masahito Yamada

  39. Department of Pathology (Neuropathology) and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40536, USA

    Peter T. Nelson

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Corresponding authors

Correspondence to John F. Crary or Peter T. Nelson.

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Crary, J.F., Trojanowski, J.Q., Schneider, J.A. et al. Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol 128, 755–766 (2014). https://doi.org/10.1007/s00401-014-1349-0

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Keywords

  • TPSD
  • TOD
  • Braak
  • Neuropathology
  • Consensus