Ball MJ, Murdoch GH. Neuropathological criteria for the diagnosis of Alzheimer's
disease: are we really ready yet? Neurobiol Aging. 1997 Jul-Aug ; 18(4 Suppl):S3-12
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The National Institute on Aging and Reagan Institute Working
Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's
Address For Correspondence:
Dr. John Q. Trojanowski , Working Group Chair
Department of Pathology and Laboratory Medicine
Univ. of Pennsylvania School of Medicine
HUP, Maloney Bldg., Room A009
Philadelphia, PA, USA 19104-4283
Telephone Number: (215)-662-6399
Fax Number: (215)-349-5909
The National Institute on Aging and Reagan Institute Working Group on Diagnostic
Criteria for the Neuropathological Assessment of Alzheimer's Disease. Consensus recommendations
for the postmortem diagnosis of Alzheimer's disease. NEUROBIOL. AGING. This
report summarizes the consensus recommendations of a panel of neuropathologists
from the United States and Europe to improve the postmortem diagnostic criteria
for Alzheimer's disease. The recommendations followed from a two day workshop sponsored
by the National Institute on Aging (NIA) and the Ronald and Nancy Reagan Institute
of the Alzheimer's Association to re-assess the original NIA criteria for the postmortem
diagnosis of Alzheimer's disease published in 1985 (1).
The consensus recommendations for improving the neuropathological criteria for the
postmortem diagnosis of Alzheimer's disease are reported here, and the "position
papers" by members of the Working Group that accompany this report [not yet available]
elaborate on the research findings and concepts upon which these recommendations
were based. Further, commentaries [not yet available] by other experts in the field
also are included here to provide additional perspectives on these recommendations.
Finally, it is anticipated that future meetings of the Working Group will re-assess
these recommendations and the implementation of postmortem diagnostic criteria for
Indexing Terms: Plaques, Tangles, Amyloid, A, Tau, Neurodegenerative Disease
A. Guiding Principles for the Postmortem Diagnosis of Alzheimer's Disease
1. Alzheimer's disease is a heterogeneous clinico-pathological entity. Thus, based
on the pathological changes detected in the postmortem brain alone (i.e., Alzheimer's
disease lesions), only probabilistic statements about the presence or absence of
dementia can be made in a given patient. Similarly, the presence or amount of Alzheimer's
disease lesions in the postmortem brain can only be inferred and not predicted with
certainty when a progressive dementia has been documented antemortem in an elderly
2. Since dementia in an elderly individual may arise from more than one disorder,
more than one pathological process (i.e., stroke, Parkinson's disease, progressive
supranuclear palsy, etc.), in addition to Alzheimer's disease lesions, may contribute
to the dementia in many patients.
3. Any Alzheimer's disease changes in the postmortem brain (i.e., diffuse amyloid
or neuritic plaques, neurofibrillary tangles) are considered to be abnormal and
should be recorded as such. In other words, these changes are considered to be pathological
even in instances where they appear to be incidental.
B. Neuropathological Assessment
The following categories are recommended to provide an estimate of the likelihood
that Alzheimer's disease pathological changes underlie dementia:
1. There is a high likelihood that dementia is due to Alzheimer's disease lesions
when the postmortem brain shows the presence of both neuritic plaques and neurofibrillary
tangles in neocortex (i.e., a frequent neuritic plaque score according to CERAD
[Consortium to Establish a Registry for Alzheimer's Disease; 2,3], and a Stage V/VI according to Braak and Braak; 4).
2. There is an intermediate likelihood that dementia is due to Alzheimer's disease
lesions when the postmortem brain shows moderate neocortical neuritic plaques and
neurofibrillary tangles in limbic regions (i.e., CERAD moderate, and Braak and Braak
3. There is a low likelihood that dementia is due to Alzheimer's disease lesions
when the postmortem brain shows neuritic plaques and neurofibrillary tangles in
a more limited distribution and/or severity (i.e., CERAD infrequent, and Braak and
Braak Stage I/II).
Criteria for the recognition of "incipient" dementia due to Alzheimer's disease
remain to be determined. Further, it is expected that Alzheimer's disease may occur
with combinations of neuritic plaques and neurofibrillary tangles in the postmortem
brain other than those specified above. Finally, the contribution of diffuse A(
deposits to cognitive impairments remains uncertain at this time, but the presence
of these lesions should be noted.
C. Specific Recommendations
1. For the routine diagnosis of Alzheimer's disease in the postmortem brain by general
pathologists and neuropathologists, it is recommended that semi-quantitative methodologies
(i.e., the CERAD approach) be used to assess neuritic plaques and neurofibrillary
tangles. In addition to CERAD Guidelines, it is emphasized that the examination
of the hippocampal formation and the neocortex for the presence of neurofibrillary
tangles is essential to enhance confidence in the postmortem diagnosis of Alzheimer's
2. In Alzheimer's disease research settings, it is recommended that topographic
staging methods (i.e., that of Braak and Braak) be used as an important approach
for establishing the extent of neurofibrillary lesions including neuritic plaques,
neurofibrillary tangles and neuropil threads.
3. The CERAD protocols are recommended for tissue fixation, tissue processing, sectioning
and tissue staining. Modified Bielschowsky, Gallayas or Thioflavine S methods are
4. It is recommended that the following regions be sampled in the coronal plane
after careful macroscopic examination of the postmortem brain to evaluate Alzheimer's
disease and to rule out potentially confounding disorders:
- Neocortical areas: superior temporal gyrus, inferior parietal lobe, mid-frontal
cortex, occipital cortex (including primary visual cortex and association cortex).
- Hippocampal formation at the level of the lateral geniculate nucleus.
- Hippocampal formation including entorhinal cortex at the level of the uncus.
Substantia nigra and locus coeruleus.
Optional regions to sample include: thalamus, caudate, putamen, cerebellum, motor
cortex, cingulate cortex, mamillary bodies, and spinal cord. Any lesions seen on
macroscopic examination also should be examined. Finally, the remaining brain should
be saved until a microscopic diagnosis has been established.
5. In Alzheimer's disease research centers, it is recommended that specific immunostains
be used to correlate immunostained Alzheimer's disease lesions (neuritic plaques,
neurofibrillary tangles, A-beta deposits) with conventional stains that demonstrate
D. Assessment of Major Co-Existing Lesions in Addition to Alzheimer's Disease Lesions
in the Postmortem Brain
The most common confounding lesions are Lewy bodies and vascular lesions. The lesions
that are present in the postmortem brain should be recorded and all diagnoses ascribed
to the presence of these lesions should be specified. The relative extent to which
Alzheimer's disease lesions and other co-existing pathological lesions contribute
to clinical symptoms cannot always be determined with certainty. With regard to
the Alzheimer's disease lesions, the CERAD score and the Braak and Braak stage should
be noted. Immunohistochemical procedures using anti-ubiquitin antibodies were recommended
by the International Workshop on Lewy Bodies (5) as an adjunct
for the diagnosis of Lewy body disorders.
E. Recommendations for Strategies to Improve the Postmortem Diagnosis of Alzheimer's
To improve upon currently recommended procedures for the postmortem diagnosis of
Alzheimer's disease, the following goals were suggested:
1. Validate and refine the procedures recommended above.
2. Establish if heterogeneity in Alzheimer's disease changes reflect genetic and
gender based factors.
3. Investigate well-characterized cohorts of demented patients to determine the
effects of age on the clinical and pathological criteria for the diagnosis of Alzheimer's
4. Investigate the pathological, cellular and molecular basis for mild cognitive
impairment that does not progress to Alzheimer's disease in well-characterized cohorts
of individuals from age 50 to the end of the human lifespan and contrast this with
normal aging as well as Alzheimer's disease.
5. Develop biochemical and molecular methods (i.e., soluble assays for hyperphosphorylated
tau, A-beta, etc.) for the rapid postmortem diagnosis of Alzheimer's disease and
compare data obtained using these methods with data obtained from the currently
recommended pathological methods.
6. Seek to standardize diagnostic methods and reagents used for the postmortem diagnosis
of Alzheimer's disease including the establishment of common sources or core facilities
for the production and distribution of diagnostic reagents.
7. Seek to develop and standardize quantitative methods including stereology, for
application to the postmortem diagnosis of Alzheimer's disease.
8. Determine the nature and significance of white matter pathological changes in
1. Khachaturian ZS. Diagnosis of Alzheimer's disease. Arch Neurol.
1985 Nov 1;42(11):1097-105.
2. Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM,
Vogel FS, Hughes JP, van Belle G, Berg L. The Consortium to Establish a Registry
for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic
assessment of Alzheimer's disease. Neurology. 1991 Apr 1;41(4):479-86.
3. Mirra SS, Hart MN, Terry RD. Making the diagnosis of Alzheimer's
disease. A primer for practicing pathologists. Arch Pathol Lab Med. 1993 Feb 1;117(2):132-44.
4. Braak H, Braak E. Neuropathological stageing of Alzheimer-related
changes. Acta Neuropathol (Berl). 1991 Jan 1;82(4):239-59.
Abstract. [See also online seminar
by H. Braak for images, charts and data.]
5. McKeith IG, Galasko D, Kosaka K, Perry EK, Dickson DW, Hansen
LA, Salmon DP, Lowe J, Mirra SS, Byrne EJ, Lennox G, Quinn NP, Edwardson JA, Ince
PG, Bergeron C, Burns A, Miller BL, Lovestone S, Collerton D, Jansen EN, Ballard
C, de Vos RA, Wilcock GK, Jellinger KA, Perry RH. Consensus guidelines for the clinical
and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium
on DLB international workshop. Neurology. 1996 Nov 1;47(5):1113-24.