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Pathologic diagnosis of Alzheimer disease.


Alzheimer disease (AD) is a neurodegenerative disease and is the most common cause of dementia, affecting approximately 50 percent of the population over the age of 85 years. (1) Its diagnosis depends on a combination of clinical and pathologic features. Neuropathologic findings at the time of post-mortem examination remain the gold standard for definitive diagnosis. Herein, we review the gross and microscopic features characteristic of Alzheimer's disease and discuss commonly used criteria for establishing a neuropathologic diagnosis of this disorder. (2-6)

Pathologic Findings

The external appearance of the brain in AD, although sometimes characteristic, is not specific. Obvious atrophy affecting the frontal, temporal, and parietal lobes may be evident. Many cases that on microscopic examination prove to be AD have an undistinguished external appearance with either mild, generalized frontotemporal atrophy not greater than that seen in aged brains or have no detectable atrophy at all. On coronal sections, the hippocampal formations are typically visibly atrophic with expansion of the temporal horns of the lateral ventricles (Figure 1). Dilatation of the frontal and occipital poles of the lateral ventricles is usually apparent. In the deep gray nuclei of the cerebral hemispheres, atrophy, when it is detectable, is usually restricted to the caudate and putamen. The degree of atrophy is almost always symmetric.

The characteristic microscopic features of AD, senile plaques and neurofibrillary tangles (Figure 2), were initially described by Alois Alzheimer in 1907. (7) Since then, multiple different types of amyloid-containing plaques have been described. (8,9) Senile or neuritic plaques, which are composed of tortuous neuritic processes surrounding a central amyloid core, are best visualized using silver stains or immunohistochemistry for amyloid beta (A[beta]) protein. Reactive astrocytes and microglia may be present at the periphery of these plaques, but there is usually no evidence of neuronal damage. Though these plaques may easily be found in the hippocampus, their presence in increased numbers in neocortex is necessary for a diagnosis of AD. The amyloid core consists primarily of A[beta] which is derived from the larger amyloid precursor protein (APP). Plaques composed of amyloid protein but lacking neuritic processes are known as diffuse plaques. Burned-out or end-stage plaques consist of a dense amyloid core without accompanying dystrophic neurites and are thought to be remnants of neuritic plaques. (10)

Neurofibrillary tangles, which are composed of abnormally phosphorylated tau protein aggregates, appear as parallel, thickened fibrils that extend toward the apical dendrite of pyramidal neurons. These structures are difficult to identify using a hematoxylin-eosin stain and are best visualized with silver stains or immunohistochemistry for tau protein.

Granulovacuolar degeneration (of Simchowitz) and Hirano bodies (11) (Figure 3) are non-specific lesions often present in the hippocampi of patients with AD. Granulovacuolar degeneration consists of clusters of small vacuoles, each of which contains a dense, basophilic granule, within pyramidal neurons. Hirano bodies are intracellular aggregates of actin and actin-associated protein observed within or adjacent to the neurons of individuals afflicted with certain neurodegenerative disorders. They are rod-shaped or crystal-like and intensely eosinophilic.

Amyloid or congophilic angiopathy is also commonly seen in AD. It is a form of angiopathy in which A[beta] protein deposits in the walls of the blood vessels of leptomeninges and gray matter of the cerebral cortex. The abnormal aggregation of amyloid can be demonstrated by examining Congo red-stained sections under polarized light or with AS protein immunohistochemistry. Amyloid deposition predisposes these blood vessels to failure, increasing the risk of hemorrhage.



Neuropathologic Diagnosis and Classification

Since many of the above-described findings can occur in non-demented elderly patients, an accurate pathologic diagnosis of AD requires information regarding the age and clinical history of the patient as well as an evaluation of the number and distribution of senile plaques and neurofibrillary tangles. It is also important to consider other causes of dementia including other degenerative disorders (Table 1) such as frontotemporal lobar degeneration (including Pick disease, frontotemporal lobar degeneration with TDP43 and ubiquitin inclusions/motor neuron disease inclusion dementia, and frontotemporal dementia with parkinsonism linked to chromosome 17-tau) and dementia with Lewy bodies, as well as other non-neurodegenerative conditions including vascular dementia, normal pressure hydrocephalus, and CreutzfeldtJakob disease. (12,13) Cases with mixed neuropathologic features also occur.


Brain sections recommended to establish a diagnosis in most cases of dementia include medulla, pons, midbrain, cerebellar vermis, cerebellar hemisphere including the dentate, hippocampus and adjacent parahippocampal gyrus, basal ganglia (caudate, putamen, and globus pallidus), thalamus, middle frontal gyrus, inferior parietal lobule, occipital lobe, superior and middle temporal gyri, cingulate gyrus, spinal cord if available, and any detectable macroscopic lesions. (4,5,14-17) If possible, selected sections should be stained with a silver stain (Bielschowsky, Bodian, or Gallyas) and/or with antibodies directed against A[beta] protein, phosphorylated tau, [alpha]-synuclein, ubiquitin, and TDP-43, depending in part on which entities are part of the differential diagnosis. (14)

In situations where resources and expertise in evaluating these types of cases are limited, using a single immunohistochemical stain for ubiquitin in combination with routine hematoxylin-eosin has been recommended. (18) This stain will highlight senile plaques and neurofibrillary tangles as well as many of the lesions seen in other neurodegenerative diseases. (19)

There are several consensus criteria for the neuropathologic diagnosis of AD, each of which has advantages and pitfalls. (20) The first formal, widely utilized neuropathologic criteria to establish a diagnosis of AD were proposed by Khachaturian in 1985. (21) In this schema, the number of plaques is quantified and correlated with patient age; older patients require more plaques than younger ones to be given a diagnosis of AD. Subsequently, the Consortium to Establish a Registry for AD (CERAD) modified these criteria, in part to simplify the diagnostic procedure and make the diagnosis of AD more reproducible. (5,6) Using this protocol, the number of senile/neuritic plaques is assessed semiquantitatively in neocortical regions where they are most dense as none, sparse (less than 2 per 100X light microscopic field), moderate (approximately 6), or frequent (more than 30). This information is then cross-referenced with the age of the patient and the presence or absence of dementia to make an interpretation of no, possible, probable, or definite AD (Table 2).

At about the same time, a different classification system was put forth by Braak and Braak. (2,3) This paradigm emphasizes the anatomic distribution and density of neurofibrillary tangles. Patients with lesions limited to transentorhinal cortex (Braak stages I and II) are usually not clinically demented, those with lesions involving limbic regions (including Ammon's horn, Braak stages III and IV) are approximately evenly divided between those with dementia and those without, and those with lesions in isocortical/neocortical regions (Braak stages V and VI) are almost invariably demented.

Advantages of the CERAD protocol include the fact that it is relatively simple to apply and can be used by most practicing pathologists. (5) The main criticism of this system is that it fails to adequately address the significance of neurofibrillary tangles, which in many studies correlate better with clinically identified dementia.8 In contrast, Braak staging correlates well with clinical dementia but does not adequately address the contribution of amyloid/plaque pathology to some cases of AD, particularly familial forms. (22)

To address these issues, in 1997, the National Institute on Aging (NIA) and the Ronald and Nancy Reagan Institute of the Alzheimer's Association suggested new guidelines for making the diagnosis of AD.4 These criteria essentially encompass both CERAD and Braak criteria (Table 3). Unlike the CERAD criteria, they do not require a clinical history of dementia to establish a pathologic diagnosis of AD, however, they do correlate well with a clinical diagnosis of dementia. (16,23,24)


The accurate diagnosis of AD requires clinical and pathologic information. Adequate neuropathologic assessment should include an evaluation of the quantity and distribution of senile plaques and neurofibrillary tangles using either silver stains or immunohistochemistry. Other causes of dementia should be considered in the differential diagnosis, and it should be recognized that cases with mixed pathologic features can occur.


Despite recent advances in the clinical diagnosis of Alzheimer disease (AD), pathologic evaluation at the time of postmortem examination remains the gold-standard for the diagnosis of this disorder. Our objectives in this article are to: 1) Review and illustrate the pathologic findings characteristic of AD; and 2) Discuss the neuropathologic classification of AD, emphasizing techniques available to general, community-based pathologists.


(1.) Desai AK, Grossberg GT. Diagnosis and treatment of Alzheimer's disease. Neurology 2005;64(Suppl 3):S34-S39.

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

(3.) Braak H, Braak E. Staging of Alzheimer's disease-related neurofibrillary changes. Neurobiol Aging 1995;16(3):271-284.

(4.) 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 Jul-Aug;18(4 Suppl):S1-2.

(5.) Mirra SS, Hart MN, Terry RD. Making the diagnosis of Alzheimer's disease. A primer for practicing pathologists. Arch Pathol Lab Med 1993 Feb;117(2):132-144.

(6.) 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;41(4):479-486.

(7.) Alzheimer A, Stelzmann RA, Schnitzlein HN, Murtagh FR. An English translation of Alzheimer's 1907 paper, "Uber eine eigenartige Erkankung der Hirnrinde". Clin Anat 1995;8(6):429-431.

(8.) Duyckaerts C, Delatour B, Potier M-C. Classification and basic pathology of Alzheimer disease. Acta Neuropathol 2009;118:5-36.

(9.) Castellani RJ, Rolston RK, Smith MA. Alzheimer disease. Dis Mon 2010 Sep;56:484-546.

(10.) Perl DP. Neuropathology of Alzheimer's disease. Mt Sinai J Med 2010;77:32-42.

(11.) Hirano A. Hirano bodies and related neuronal inclusions. Neuropathol Appl Neurobiol 1994 Feb;20(1):3-11.

(12.) Dickson DW. Neuropathology of non-Alzheimer degenerative disorders. Int J Clin Exp Pathol 2010;3(1):1-23.

Fahad F. Bafakih, MD

Resident in Anatomic and Clinical Pathology, WVU,


Yara M. Daous, MD

Post-sophomore Fellow in Pathology, WVU Morgantown

Kymberly A. Gyure, MD

Vice Chair and Director of Anatomic Pathology and

Neuropathology, WVU, Morgantown

Please contact the authors for a complete list of references.

CME Post-Test

13. Which of the following statements is true of the CERAD criteria?

a. Clinical information is not required.

b. The diagnosis of AD depends primarily on the number of neuritic plaques.

c. The diagnosis of AD depends primarily on the number of neurofibrillary tangles.

d. It is not necessary to know the age of the patient to make a diagnosis.

14. What are the most important pathologic findings in making the diagnosis of Alzheimer disease?

a. Hirano bodies and granulovacuolar degeneration

b. Amyloid angiopathy

c. Neuritic plaques and neurofibrillary tangles

d. Atrophy of the frontal and temporal lobes

15. Which of the following stains should be used to evaluate a case of dementia?

a. A silver stain or ubiquitin immunohistochemistry

b. Hematoxylin-eosin-stained sections alone

c. No stains are necessary; gross evaluation is sufficient

d. A luxol-fast blue stain
Table 1. Pathologic findings in neurodegenerative disorders

                       Important              Useful
                       pathologic             immunohistochemical
Disorder               findings               stains

Alzheimer disease      Senile plaques and     Ass protein, tau,
                       neurofibrillary        ubiquitin

Frontotemporal lobar
degeneration (FTLD):

  Pick disease         Pick bodies            Tau

  FTLD with TDP43      Motor neuron           TDP43, ubiquitin
  and ubiquitin        disease inclusions

  FTLD with
  parkinsonism         Neurofibrillary        Tau, ubiquitin
  linked to            tangles

  Corticobasal         Ballooned neurons,     Tau
  degeneration         tufted
                       astrocytes, coiled

  Progressive          Globose                Tau, ubiquitin
  supranuclear         neurofibrillary
  palsy                tangles

Dementia with          Cortical Lewy          [alpha]-
Lewy bodies            bodies                 synuclein,

Table 2. CERAD criteria for AD

                      Plaque Frequency

  Age     None   Sparse   Moderate   Frequent

<50        0       C         C          C
50-75      0       B         C          C
>75        0       A         B          C

No evidence of AD: 0

Possible AD: A plus dementia or B/C and no dementia

Probable AD: B plus dementia

Definite AD: C plus dementia

Example: A 60-year-old man with a clinical history of dementia
has moderate numbers (approximately 6-100X field) of senile
plaques at autopsy. Based on his age (50-75), his age-related
plaque score is "C", giving him a diagnosis of "definite AD" (C
plus dementia) using these criteria.

Table 3. NIA-Reagan criteria for AD

High likelihood of AD--frequent
plaques (CERAD) and Braak
stage V-VI

Moderate likelihood of AD moderate
plaques (CERAD) and
Braak stage III-IV

Low likelihood of AD--sparse
plaques (CERAD) and Braak
stage I-II
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Title Annotation:Scientific Article: Special Issue
Author:Bafakih, Fahad F.; Daous, Yara M.; Gyure, Kymberly A.
Publication:West Virginia Medical Journal
Article Type:Disease/Disorder overview
Date:May 1, 2011
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