There are several characteristic lesions of AD, of which neurofibrillary tangles (NFTs) and senile plaques are considered essential for the neuropathologic diagnosis of AD (Text Box 1
). NFTs are, at least initially, intraneuronal fibrils of primarily abnormal tau. NFTs can be visualized with a variety of histochemical stains or with immunohistochemistry directed against tau or phospho-tau epitopes. NFTs commonly are observed in limbic regions early in the disease but, depending on disease stage, also involve other brain regions, including association cortex, some subcortical nuclei, and even some brainstem regions [19
] where their formation may proceed that in limbic structures [20
]. The 1997 Criteria utilized a staging scheme for NFTs described by Braak and Braak [21
], which proposes six stages that can be reduced to four with improved inter-rater reliability [22
]: no NFTs, Braak stages I/II with NFTs predominantly in entorhinal cortex and closely related areas, stages III/IV with NFTs more abundant in hippocampus and amygdala while extending slightly into association cortex, and stages V/VI with NFTs widely distributed throughout the neocortex^
and ultimately involving primary motor and sensory areas. Neuropil threads and dystrophic neurites, lesions often associated with NFTs, likely represent dendrites and axons of NFT-containing soma that can be used to further elaborate disease [23
Text Box 1. AD Neuropathologic Change
Recommended brain regions for tiered evaluation are presented in . Preferred method for β-amyloid (Aβ) plaques is immunohistochemistry for Aβ, and for neurofibrillary tangles (NFTs) is immunohistochemistry for tau or phospho-tau [89
] (other acceptable methods are Thioflavin S or sensitive silver histochemical stains [21
]). Preferred method for neuritic plaques is Thioflavin S or modified Bielschowsky as recommended by the Consortium to Establish a Registry for Alzheimer’s disease (CERAD) protocol [31
]. It is essential to score as neuritic only those plaques that exhibit dystrophic neurites; diffuse plaques should not be included. Note that immunohistochemistry probes for neuritic processes within senile plaques, such as amyloid precursor protein, ubiquitin, neurofilament or phospho-tau, will identify specific, and partially overlapping, subtypes of dystrophic neurites that may differ in disease relevance [24
Minimum recommended brain regions to be sampled and evaluated
AD neuropathologic change should be ranked along three parameters (Amyloid, Braak, CERAD) to obtain an “ABC score”:
- Aβ plaque score (modified from Thal, et al. ):
A0 no Aβ or amyloid plaques
A1 Thal phases 1 or 2
A2 Thal phase 3
A3 Thal phases 4 or 5
- NFT stage (modified from Braak for silver-based histochemistry  or phospho-tau immunohistochemistry )
B0 no NFTs
B1 Braak stage I or II
B2 Braak stage III or IV
B3 Braak stage V or VI
- Neuritic plaque score (modified from CERAD )
C0 no neuritic plaques
C1 CERAD score sparse
C2 CERAD score moderate
C3 CERAD score frequent
An alternative method that assesses progressive accumulation of Aβ deposits in medial temporal lobe structures only [33
] is highly correlated with Thal phases [34
]; we recommend the Thal phases to more directly link with neuroimaging studies. Although cerebral amyloid angiopathy (CAA), as well as capillary CAA, are not considered in these rankings, they should be reported (e.g
., the Vonsattel, et al., staging system for CAA [90
]) and association with inheritance of the ε4 allele of APOE
For all cases, regardless of clinical history, reporting should follow the format of these examples:
“Alzheimer Disease Neuropathologic Changes: A1, B0, C0” or
“Alzheimer Disease Neuropathologic Changes: A3, B3, C3”
Using the system shown in , the ABC scores are transformed into one of four levels of AD neuropathologic change: Not, Low, Intermediate or High.
Level of AD Neuropathologic Change
Notes: It is important to recognize that pathologic evaluation can be applied to specimens from surgery as well as autopsy; however, regional evaluation will be limited in biopsy specimens. Nevertheless, involvement of the neocortex by NFTs indicates B3, while involvement of cerebral cortex by Aβ deposits indicates A1 or possibly a higher score. In these circumstances, the neuritic plaque score may be especially important.
should follow these guidelines. For individuals without cognitive impairment
at the time tissue was obtained, it is possible that AD neuropathologic change may predate onset of symptoms by years [3
For individuals with cognitive impairment at the time tissue was obtained, “Intermediate” or “High” level () of AD neuropathologic change should be considered adequate explanation of cognitive impairment or dementia. When “Low” level of AD neuropathologic change is observed in the setting of cognitive impairment, it is likely that other diseases are present. In all cases with cognitive impairment, regardless of the extent of AD neuropathologic change, it is essential to determine the presence or absence, as well as extent, of other disease(s) that might have contributed to the clinical deficits.
For cases with incomplete clinical history, large clinicopathologic studies indicate that higher levels of AD neuropathologic change typically are correlated with greater likelihood of cognitive impairment. The National Alzheimer’s Coordinating Center (NACC) experience is outlined in . These data may help guide interpretation of results from autopsies with insufficient clinical history.
Table 1 Cases were selected from the National Alzheimer’s Coordinating Center Data Set, 2005–2010, as described in the text and then stratified by all combinations of Braak neurofibrillary tangle (NFT) stage and CERAD neuritic plaque score. The (more ...)
Senile plaques, the other major component of AD neuropathologic change, are extracellular deposits of the β-amyloid (Aβ) peptides, but their nomenclature and morphologic features are complex. Aβ deposits can be at the center of a cluster of dystrophic neurites that frequently, but not always, have phospho-tau immunoreactivity; these are a subset of senile plaques called neuritic plaques. Aβ deposits are morphologically diverse and also include non-neuritic structures called diffuse plaques, cotton wool plaques, amyloid lakes and subpial bands. The situation is further complicated because different types of plaques tend to develop in different brain regions [24
], and even though all genetic causes of AD result in Aβ deposits, they do not invariably result in extensive neuritic plaques [25
]. Further, Aβ peptides are diverse proteins with heterogeneous lengths, amino- and carboxy-termini, post-translational modifications, and assembly states that span from small oligomers and protofibrils to fibrils with the physicochemical properties of amyloid [26
Among these different forms of Aβ plaques, neuritic plaques have been considered to be most closely associated with neuronal injury. Indeed, neuritic plaques are characterized by the occurrence of dystrophic neurites, greater local synapse loss and glial activation [27
]. The 1997 Criteria adopted a previously developed Consortium to Establish a Registry for AD (CERAD) neuritic plaque scoring system, which ranks the density of neuritic plaques identified histochemically in several regions of neocortex [31
]. Several alternative protocols for assessing plaque accumulation have been proposed, including a hybrid that uses CERAD scoring of Aβ deposits identified by immunohistochemistry [32
] and those of Thal, et al
., which propose categorization based on progressive Aβ deposition in medial temporal lobe structures [33
] or on phases of Aβ distribution across multiple areas of brain [34
]. While the outcomes of these different approaches are—at least in some cases—highly correlated, which single protocol or combination of protocols optimally represents this facet of AD neuropathologic change is not clear.
Other features of AD neuropathologic change are less straightforward to assess by conventional histopathologic methods or are considered less closely related to upstream causes of neural system damage than NFTs and plaques. These include synapse loss, neuron loss, atrophy, gliosis, degenerative changes in white matter, granulovacuolar degeneration, and other protein aggregates like TAR-DNA-binding protein (TDP-43)–immunoreactive inclusions, Lewy bodies (LBs), actin-immunoreactive Hirano bodies, and cerebral amyloid angiopathy (CAA). The timing of any of these pathologic changes relative to functional changes is difficult to assess with certainty in autopsy samples. In addition, soluble forms of both Aβ and tau have been implicated in AD pathogenesis, but would not be apparent by conventional morphologic techniques [26
]. It is important to recognize that the recommended use of NFTs, parenchymal Aβ deposits, and neuritic plaques as the defining histopathologic lesions of AD neuropathologic change according to the criteria proposed here does not preclude the possibility that other processes or lesions may be critical contributors to the pathophysiology of AD.
NFTs and neuritic plaques do, however, correlate with the presence of the clinical symptoms of AD. For example, NACC has collected data on individuals who have come to autopsy and who had been clinically evaluated in a standardized fashion in one of the approximately 30 AD Centers located throughout the United States. While there are limitations to these data, including the potential biases introduced by varied cohort selection criteria and the fact that they did not come from a population-based sample, this data nonetheless represents one of the largest clinicopathologic correlations yet assembled. By end of 2010, data from over 1200 autopsies had been collected utilizing the Uniform Data Set that has been in place since 2005. We analyzed these data to provide pathologists with a general guide to the clinical correlations of various levels of AD neuropathologic change.
The sample was narrowed by several criteria: subjects were excluded if the primary neuropathologic diagnosis was a dementia other than AD, if they had not had a formal clinical evaluation within 2 years of death (mean duration between clinical evaluation and death = 288 days), or if there was a medical condition felt to be a major contributor to cognitive or behavioral impairments. The remaining 562 individuals were then analyzed in terms of Braak NFT stage, CERAD neuritic plaque score, and the Clinical Dementia Rating Scale (CDR) [35
] sum of boxes (). The CDR sum of boxes score is the sum of scores of clinical impression of symptom severity in each of six domains of behavioral and cognitive function; each domain is scored from 0 (normal) to 3 (marked impairments). Of these individuals, 95 were reported as being cognitively normal (CDR sum of boxes 0), 52 had very mild symptoms of cognitive impairment (CDR sum of boxes 0.5 to 3.0), and 415 had dementia. Of the patients with dementia, 63 had mild dementia (CDR sum of boxes 3.5 to 6.0), 108 had moderate dementia (CDR sum of boxes 6.5 to 12), and 244 had severe dementia (CDR sum of boxes > 12). Although the number of individuals in some cells is relatively modest, the overall pattern supports the 1997 Criteria. For individuals with Braak NFT stage V or VI and frequent CERAD neuritic plaque score, 91% had moderate or severe dementia. Similarly, there was an intermediate probability of cognitive impairment in individuals with an intermediate level of AD neuropathologic change. For example, just over half the individuals with Braak NFT stage III or IV and intermediate CERAD neuritic plaque score had a diagnosis of at least mild dementia. Finally, although most individuals who were cognitively normal clustered in the cells with no or low levels of AD neuropathologic change, rare individuals appeared to be able to withstand at least some AD neuropathologic change and remain cognitively intact. Similarly, individuals who had very little AD neuropathologic change and no other detected lesions were generally normal clinically, but an occasional patient was reported with dementia despite no obvious neuropathologic explanation.