Acta Neuropathologica

, Volume 123, Issue 1, pp 1–11 | Cite as

National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach

  • Thomas J. MontineEmail author
  • Creighton H. Phelps
  • Thomas G. Beach
  • Eileen H. Bigio
  • Nigel J. Cairns
  • Dennis W. Dickson
  • Charles Duyckaerts
  • Matthew P. Frosch
  • Eliezer Masliah
  • Suzanne S. Mirra
  • Peter T. Nelson
  • Julie A. Schneider
  • Dietmar Rudolf Thal
  • John Q. Trojanowski
  • Harry V. Vinters
  • Bradley T. Hyman
Consensus Paper


We present a practical guide for the implementation of recently revised National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease (AD). Major revisions from previous consensus criteria are: (1) recognition that AD neuropathologic changes may occur in the apparent absence of cognitive impairment, (2) an “ABC” score for AD neuropathologic change that incorporates histopathologic assessments of amyloid β deposits (A), staging of neurofibrillary tangles (B), and scoring of neuritic plaques (C), and (3) more detailed approaches for assessing commonly co-morbid conditions such as Lewy body disease, vascular brain injury, hippocampal sclerosis, and TAR DNA binding protein (TDP)-43 immunoreactive inclusions. Recommendations also are made for the minimum sampling of brain, preferred staining methods with acceptable alternatives, reporting of results, and clinico-pathologic correlations.


Dementia With Lewy Body Prion Disease Cerebral Amyloid Angiopathy Hippocampal Sclerosis Neuritic Plaque 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Support was provided by the National Institute on Aging (AG05134, AG05136, AG03991, AG05681, AG24904, AG28383, AG10161, AG17917, AG10124, AG13854, AG19610, NS62684, AG16570, AG15819, AG12435, AG05131, AG016976, AG16570, AG15866 and AG18840) as well as the Alzheimer’s Association, Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Consortium), Deutsche Forschungsgemeinschaft (DFG TH-624-4-1) and Alzheimer Forschung Initiative (AFI #10810), the Nancy and Buster Alvord Endowment, and the Charles and Joanne Knight Alzheimer Research Initiative. We thank Dr. Joshua Sonnen for providing some photomicrographs. The authors extend their deepest thanks to Dr. Heiko Braak, Dr. Kelly Del Tredici, Dr. Nina Silverberg, Dr. Walter Kukull, Dr. Kathleen Montine, Dr. Cerise Elliott, Dr. Bill Thies, Dr. Maria C. Carrillo, and Ms. Sarah Monsell for their valuable input.


  1. 1.
    Adler CH, Connor DJ, Hentz JG et al (2010) Incidental Lewy body disease: clinical comparison to a control cohort. Mov Disord 25:642–646PubMedCrossRefGoogle Scholar
  2. 2.
    Alafuzoff I, Arzberger T, Al-Sarraj S et al (2008) Staging of neurofibrillary pathology in Alzheimer’s disease: a study of the BrainNet Europe Consortium. Brain Pathol 18:484–496PubMedGoogle Scholar
  3. 3.
    Alafuzoff I, Parkkinen L, Al-Sarraj S et al (2008) Assessment of alpha-synuclein pathology: a study of the BrainNet Europe Consortium. J Neuropathol Exp Neurol 67:125–143PubMedCrossRefGoogle Scholar
  4. 4.
    Alafuzoff I, Pikkarainen M, Al-Sarraj S et al (2006) Interlaboratory comparison of assessments of Alzheimer disease-related lesions: a study of the BrainNet Europe Consortium. J Neuropathol Exp Neurol 65:740–757PubMedCrossRefGoogle Scholar
  5. 5.
    Alafuzoff I, Thal DR, Arzberger T et al (2009) Assessment of beta-amyloid deposits in human brain: a study of the BrainNet Europe Consortium. Acta Neuropathol 117:309–320PubMedCrossRefGoogle Scholar
  6. 6.
    Albert MS, Dekosky ST, Dickson D et al (2011) The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:270–279PubMedCrossRefGoogle Scholar
  7. 7.
    Amador-Ortiz C, Dickson DW (2008) Neuropathology of hippocampal sclerosis. Handb Clin Neurol 89:569–572PubMedCrossRefGoogle Scholar
  8. 8.
    Amador-Ortiz C, Lin WL, Ahmed Z et al (2007) TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer’s disease. Ann Neurol 61:435–445PubMedCrossRefGoogle Scholar
  9. 9.
    Arai T, Mackenzie IR, Hasegawa M et al (2009) Phosphorylated TDP-43 in Alzheimer’s disease and dementia with Lewy bodies. Acta Neuropathol 117:125–136PubMedCrossRefGoogle Scholar
  10. 10.
    Aswathy PM, Jairani PS, Mathuranath PS (2010) Genetics of frontotemporal lobar degeneration. Ann Indian Acad Neurol 13:S55–S62PubMedCrossRefGoogle Scholar
  11. 11.
    Beach TG, Adler CH, Lue L et al (2009) Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol 117:613–634PubMedCrossRefGoogle Scholar
  12. 12.
    Beach TG, Adler CH, Sue LI et al (2008) Reduced striatal tyrosine hydroxylase in incidental Lewy body disease. Acta Neuropathol 115:445–451PubMedCrossRefGoogle Scholar
  13. 13.
    Beach TG, White CL, Hamilton RL et al (2008) Evaluation of alpha-synuclein immunohistochemical methods used by invited experts. Acta Neuropathol 116:277–288PubMedCrossRefGoogle Scholar
  14. 14.
    Braak H, Alafuzoff I, Arzberger T et al (2006) Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 112:389–404PubMedCrossRefGoogle Scholar
  15. 15.
    Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259PubMedCrossRefGoogle Scholar
  16. 16.
    Braak H, Del Tredici K, Rub U et al (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211PubMedCrossRefGoogle Scholar
  17. 17.
    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 114:5–22PubMedCrossRefGoogle Scholar
  18. 18.
    Dejesus-Hernandez M, Mackenzie IR, Boeve BF et al (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72:245–256PubMedCrossRefGoogle Scholar
  19. 19.
    DeKosky ST, Scheff SW (1990) Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 27:457–464PubMedCrossRefGoogle Scholar
  20. 20.
    Del Tredici K, Rub U, De Vos RA et al (2002) Where does Parkinson disease pathology begin in the brain? J Neuropathol Exp Neurol 61:413–426PubMedGoogle Scholar
  21. 21.
    Dickson DW (1997) The pathogenesis of senile plaques. J Neuropathol Exp Neurol 56:321–339PubMedCrossRefGoogle Scholar
  22. 22.
    Dickson DW, Fujishiro H, DelleDonne A et al (2008) Evidence that incidental Lewy body disease is pre-symptomatic Parkinson’s disease. Acta Neuropathol 115:437–444PubMedCrossRefGoogle Scholar
  23. 23.
    Dlouhy SR, Hsiao K, Farlow MR et al (1992) Linkage of the Indiana kindred of Gerstmann-Straussler-Scheinker disease to the prion protein gene. Nat Genet 1:64–67PubMedCrossRefGoogle Scholar
  24. 24.
    Gorelick PB, Scuteri A, Black SE et al (2011) Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 42:2672–2713PubMedCrossRefGoogle Scholar
  25. 25.
    Grinberg LT, Thal DR (2010) Vascular pathology in the aged human brain. Acta Neuropathol 119:277–290PubMedCrossRefGoogle Scholar
  26. 26.
    Hachinski V, Iadecola C, Petersen RC et al (2006) National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards. Stroke 37:2220–2241PubMedCrossRefGoogle Scholar
  27. 27.
    Hamilton RL (2000) Lewy bodies in Alzheimer’s disease: a neuropathological review of 145 cases using alpha-synuclein immunohistochemistry. Brain Pathol 10:378–384PubMedCrossRefGoogle Scholar
  28. 28.
    Hatanpaa KJ, Blass DM, Pletnikova O et al (2004) Most cases of dementia with hippocampal sclerosis may represent frontotemporal dementia. Neurology 63:538–542PubMedGoogle Scholar
  29. 29.
    Hyman BT, Phelps CH, Beach TG et al (2011) National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimer’s Dement (in press)Google Scholar
  30. 30.
    Hyman BT, Trojanowski JQ (1997) Consensus recommendations for the postmortem diagnosis of Alzheimer disease from the National Institute on Aging and the Reagan Institute Working Group on diagnostic criteria for the neuropathological assessment of Alzheimer disease. J Neuropathol Exp Neurol 56:1095–1097PubMedCrossRefGoogle Scholar
  31. 31.
    Jicha GA, Schmitt FA, Abner E et al (2010) Prodromal clinical manifestations of neuropathologically confirmed Lewy body disease. Neurobiol Aging 31:1805–1813PubMedCrossRefGoogle Scholar
  32. 32.
    Leverenz JB, Fishel MA, Peskind ER et al (2006) Lewy body pathology in familial Alzheimer disease: evidence for disease- and mutation-specific pathologic phenotype. Arch Neurol 63:370–376PubMedCrossRefGoogle Scholar
  33. 33.
    Lippa CF, Duda JE, Grossman M et al (2007) DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers. Neurology 68:812–819PubMedCrossRefGoogle Scholar
  34. 34.
    Mackenzie IR, Neumann M, Bigio EH et al (2010) Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol 119:1–4PubMedCrossRefGoogle Scholar
  35. 35.
    Mackenzie IR, Neumann M, Bigio EH et al (2009) Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations. Acta Neuropathol 117:15–18PubMedCrossRefGoogle Scholar
  36. 36.
    Masliah E, Mallory M, Deerinck T et al (1993) Re-evaluation of the structural organization of neuritic plaques in Alzheimer’s disease. J Neuropathol Exp Neurol 52:619–632PubMedCrossRefGoogle Scholar
  37. 37.
    Masliah E, Terry RD, Mallory M et al (1990) Diffuse plaques do not accentuate synapse loss in Alzheimer’s disease. Am J Pathol 137:1293–1297PubMedGoogle Scholar
  38. 38.
    McKeith IG, Dickson DW, Lowe J et al (2005) Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65:1863–1872PubMedCrossRefGoogle Scholar
  39. 39.
    McKhann GM, Knopman DS, Chertkow H et al (2011) The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:263–269PubMedCrossRefGoogle Scholar
  40. 40.
    Miki Y, Mori F, Hori E et al (2009) Hippocampal sclerosis with four-repeat tau-positive round inclusions in the dentate gyrus: a new type of four-repeat tauopathy. Acta Neuropathol 117:713–718PubMedCrossRefGoogle Scholar
  41. 41.
    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 41:479–486PubMedGoogle Scholar
  42. 42.
    Nagy Z, Yilmazer-Hanke DM, Braak H et al (1998) Assessment of the pathological stages of Alzheimer’s disease in thin paraffin sections: a comparative study. Dement Geriatr Cogn Disord 9:140–144PubMedCrossRefGoogle Scholar
  43. 43.
    Nakashima-Yasuda H, Uryu K, Robinson J et al (2007) Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta Neuropathol 114:221–229PubMedCrossRefGoogle Scholar
  44. 44.
    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 68:774–784PubMedCrossRefGoogle Scholar
  45. 45.
    Nelson PT, Abner EL, Schmitt FA et al (2010) Modeling the association between 43 different clinical and pathological variables and the severity of cognitive impairment in a large autopsy cohort of elderly persons. Brain Pathol 20:66–79PubMedCrossRefGoogle Scholar
  46. 46.
    Nelson PT, Kryscio RJ, Jicha GA et al (2009) Relative preservation of MMSE scores in autopsy-proven dementia with Lewy bodies. Neurology 73:1127–1133PubMedCrossRefGoogle Scholar
  47. 47.
    Nelson PT, Schmitt FA, Lin Y et al (2011) Hippocampal sclerosis in advanced age: clinical and pathological features. Brain 134:1506–1518PubMedCrossRefGoogle Scholar
  48. 48.
    Rauramaa T, Pikkarainen M, Englund E et al (2011) TAR-DNA binding protein-43 and alterations in the hippocampus. J Neural Transm 118:683–689PubMedCrossRefGoogle Scholar
  49. 49.
    Saito Y, Ruberu NN, Sawabe M et al (2004) Lewy body-related alpha-synucleinopathy in aging. J Neuropathol Exp Neurol 63:742–749PubMedGoogle Scholar
  50. 50.
    Selnes OA, Vinters HV (2006) Vascular cognitive impairment. Nat Clin Pract Neurol 2:538–547PubMedCrossRefGoogle Scholar
  51. 51.
    Sonnen JA, Larson EB, Brickell K et al (2009) Different patterns of cerebral injury in dementia with or without diabetes. Arch Neurol 66:315–322PubMedCrossRefGoogle Scholar
  52. 52.
    Sonnen JA, Larson EB, Crane PK et al (2007) Pathological correlates of dementia in a longitudinal, population-based sample of aging. Ann Neurol 62:406–413PubMedCrossRefGoogle Scholar
  53. 53.
    Soontornniyomkij V, Lynch MD, Mermash S et al (2010) Cerebral microinfarcts associated with severe cerebral beta-amyloid angiopathy. Brain Pathol 20:459–467PubMedCrossRefGoogle Scholar
  54. 54.
    Sperling RA, Aisen PS, Beckett LA et al (2011) Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:280–292PubMedCrossRefGoogle Scholar
  55. 55.
    Terry RD, Masliah E, Salmon DP et al (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580PubMedCrossRefGoogle Scholar
  56. 56.
    Thal DR, Griffin WS, de Vos RA, Ghebremedhin E (2008) Cerebral amyloid angiopathy and its relationship to Alzheimer’s disease. Acta Neuropathol 115:599–609PubMedCrossRefGoogle Scholar
  57. 57.
    Thal DR, Rub U, Orantes M, Braak H (2002) Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 58:1791–1800PubMedGoogle Scholar
  58. 58.
    Uchihara T, Nakamura A, Yamazaki M et al (2001) Different conformation of neuronal tau deposits distinguished by double immunofluorescence with AT8 and thiazin red combined with Gallyas method. Acta Neuropathol 102:462–466PubMedGoogle Scholar
  59. 59.
    Uchikado H, Lin WL, DeLucia MW, Dickson DW (2006) Alzheimer disease with amygdala Lewy bodies: a distinct form of alpha-synucleinopathy. J Neuropathol Exp Neurol 65:685–697PubMedCrossRefGoogle Scholar
  60. 60.
    Vinters HV, Ellis WG, Zarow C et al (2000) Neuropathologic substrates of ischemic vascular dementia. J Neuropathol Exp Neurol 59:931–945PubMedGoogle Scholar
  61. 61.
    Vonsattel JP, Myers RH, Hedley-Whyte ET et al (1991) Cerebral amyloid angiopathy without and with cerebral hemorrhages: a comparative histological study. Ann Neurol 30:637–649PubMedCrossRefGoogle Scholar
  62. 62.
    White L (2009) Brain lesions at autopsy in older Japanese-American men as related to cognitive impairment and dementia in the final years of life: a summary report from the Honolulu-Asia aging study. J Alzheimers Dis 18:713–725PubMedGoogle Scholar
  63. 63.
    Wilson AC, Dugger BN, Dickson DW, Wang DS (2011) TDP-43 in aging and Alzheimer’s disease—a review. Int J Clin Exp Pathol 4:147–155PubMedGoogle Scholar
  64. 64.
    Zarow C, Sitzer TE, Chui HC (2008) Understanding hippocampal sclerosis in the elderly: epidemiology, characterization, and diagnostic issues. Curr Neurol Neurosci Rep 8:363–370PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Thomas J. Montine
    • 1
    Email author
  • Creighton H. Phelps
    • 2
  • Thomas G. Beach
    • 3
  • Eileen H. Bigio
    • 4
  • Nigel J. Cairns
    • 5
  • Dennis W. Dickson
    • 6
  • Charles Duyckaerts
    • 7
  • Matthew P. Frosch
    • 8
  • Eliezer Masliah
    • 9
  • Suzanne S. Mirra
    • 10
  • Peter T. Nelson
    • 11
  • Julie A. Schneider
    • 12
  • Dietmar Rudolf Thal
    • 13
  • John Q. Trojanowski
    • 14
  • Harry V. Vinters
    • 15
  • Bradley T. Hyman
    • 16
  1. 1.Department of PathologyUniversity of Washington School of MedicineSeattleUSA
  2. 2.National Institute on AgingBethesdaUSA
  3. 3.Civin Laboratory for NeuropathologyBanner Sun Health Research InstituteSun CityUSA
  4. 4.Department of Pathology and Northwestern Alzheimer Disease CenterNorthwestern University Feinberg School of MedicineChicagoUSA
  5. 5.Departments of Neurology and Pathology & ImmunologyWashington University School of MedicineSt. LouisUSA
  6. 6.Department of NeuroscienceMayo ClinicJacksonvilleUSA
  7. 7.Service de Neuropathologie Raymond EscourolleHôpital de la SalpêtriéreParisFrance
  8. 8.C.S. Kubik Laboratory for Neuropathology, Massachusetts General HospitalHarvard Medical SchoolBostonUSA
  9. 9.Departments of Neurosciences and Pathology, School of MedicineUniversity of California, San DiegoLa JollaUSA
  10. 10.Department of PathologySUNY Downstate Medical CenterBrooklynUSA
  11. 11.Sanders-Brown Center on AgingUniversity of KentuckyLexingtonUSA
  12. 12.Departments of Pathology and Neurological Sciences, Rush Alzheimer’s Disease CenterRush University Medical CenterChicagoUSA
  13. 13.Laboratory of Neuropathology, Institute of PathologyUniversity of UlmUlmGermany
  14. 14.Department of Pathology and Laboratory MedicineInstitute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of MedicinePhiladelphiaUSA
  15. 15.Departments of Pathology & Laboratory Medicine (Neuropathology) and NeurologyUniversity of California Los AngelesLos AngelesUSA
  16. 16.Neurology Department, Massachusetts General HospitalHarvard UniversityBostonUSA

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